encyclopedia of pharmaceutical technology, third edition

DrugDelivery

Buccal–Mono

Drug Delivery: Buccal Route

James C. McElnayQueen’s University Belfast, Belfast, U.K.

Carmel M. HughesSchool of Pharmacy, Medical Biology Centre, The Queen’s University of Belfast,Belfast, U.K.

INTRODUCTION

A drug can be administered via many different routesto produce a systemic pharmacologic effect. The mostcommon method of drug administration is via theperoral route, in which the drug is swallowed andenters the systemic circulation primarily through themembranes of the small intestine. Although this typeof drug administration is commonly termed oral, per-oral is a better term because oral administration moreaccurately describes drug absorption from the mouthitself. The mouth is lined with a mucous membraneand among the least known of its functions is its capa-bility of serving as a site for the absorption of drugs.[1]

In general, drugs penetrate the mucous membrane bysimple diffusion and are carried in the blood, whichrichly supplies the salivary glands and their ducts, intothe systemic circulation via the jugular vein. Activetransport, pinocytosis, and passage through aqueouspores usually play only insignificant roles in movingdrugs across the oral mucosa.[2]

The administration of drugs by the buccal route hasseveral main advantages over peroral administration,including the following:

1. The drug is not subjected to the destructiveacidic environment of the stomach.

2. Therapeutic serum concentrations of the drugcan be achieved more rapidly.

3. The drug enters the general circulation withoutfirst passing through the liver.

This last phenomenon is important for drugsthat are highly metabolized during their first passagethrough the liver. This metabolism (governed by thehepatic extraction ratio) can lead to a dramaticreduction in the amount of drug available systemicallyfrom a given peroral dose but is avoided by buccalabsorption.

Two sites within the buccal cavity have been usedfor drug administration. Using the sublingual route,as for glyceryl trinitrate (GTN), the medicament isplaced under the tongue, usually in the form of a

rapidly dissolving tablet. The second anatomic sitefor drug administration is between the cheek and gin-giva. Although this second application site is itselfknown as buccal absorption, the absorption from allareas within the buccal or oral cavity are consideredin this article.

Of the range of pharmaceutic preparations availablefor administration into the oral cavity, the mostpopular form is that of a rapidly dissolving tabletthat releases its drug contents for absorption acrossthe oral mucosa. Alternatively, a tablet or capsulecan be chewed to release its contents. This lattermethod is less successful because mastication tends toproduce a large volume of saliva that increases theprobability of premature swallowing. The same prob-lem occurs in the administration of drug in the formof a chewing gum.

The aim of the present article is to review the pub-lished literature on the absorption of drugs throughthe oral mucosa. Special attention is given to theprevention of presystemic metabolism via drug admin-istration by the buccal and sublingual routes.Consideration is also given to the types of pharmaceu-tical preparations that are commercially available fordrug administration into the mouth. Before prog-ressing to drug absorption, however, the structure andblood supply of the oral mucosa are discussed becauseof the important role they play in the transfer of drugsfrom the mouth into the systemic circulation.

STRUCTURE AND SECRETIONS

OF THE ORAL MUCOSA

Epithelial Lining

The major function of the oral epithelium is to providea protective surface layer between the oral environ-ment and the deeper tissues. The oral epithelium hasa squamous epithelium of tightly packed cells thatform distinct layers by a process of maturation fromthe deeper layers to the surface.[3] The pattern of matu-ration differs in different regions of the oral mucosa

Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100001050Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved. 1071

DrugDelive

ryBucca

l–Mono

due to the variation in the specific function of thetissues. The surface layer of the hard palate and tongueforms keratin to yield a tough, non-flexible epithelialsurface resistant to abrasion, but the epithelium ofthe cheek, floor of the mouth, and soft palate is non-keratinized and facilitates distensibility. The majorfeatures of the keratinized and non-keratinized oralepithelium have been extensively investigated by Squierand Rooney.[4] Together with the presence or absenceof keratin, the second main feature likely to influenceregional differences in drug absorption is the epithelialthickness. This varies in different regions of the mouth:the hard palate, buccal mucosa, lip mucosa, and floorof the mouth have been found to have thicknesses of100–120mm, 500–600mm, 500–600mm, and 100–200mm,respectively.[5,6]

Secretion of Saliva

In addition to the protective function afforded by theoral mucosa, it also has the ability to maintain a moistsurface, which enhances permeability of the membraneto drugs.[3] Although the mucous membrane lining inthe mouth contains many minute glands called buccalglands, which pour their secretions into the mouth, thechief secretion is supplied by three pairs of glands,namely, the parotid (under and in front of the ear),the submaxillary (below the jaw), and the sublingual(under the tongue) glands. Blood is richly supplied tothe salivary glands and their ducts by branches of theexternal carotid artery and afterwards, travellingthrough the many branch arteries and capillaries,returns to the systemic circulation via the jugularveins.[1] The presence of saliva in the mouth is impor-tant to drug absorption for two main reasons:

1. Drug permeation across moist (mucous) mem-branes occurs much more readily than acrossnonmucous membranes.

2. Drugs are commonly administered to the mouthin the clinical setting in a solid form. The drugmust, therefore, first dissolve in saliva before itcan be absorbed across the oral mucosa; thatis, the drug cannot be absorbed directly froma tablet.

VASCULAR SYSTEM OF THE ORAL MUCOSA

The vascular system and blood supply to the oralmucosa have been clearly described by Stablein andMeyer.[7] Netter’s excellent drawings of the blood sup-ply to the mouth and pharynx, venous drainage of themouth and pharynx, and lymphatic drainage of themouth and pharynx have been published by Ciba.[8]

This latter publication also includes definitive docu-mentation of the blood supply and drainage from themouth.

The blood supply to the mouth is delivered princi-pally via the external carotid artery. The maxillaryartery is the major branch, and the two minor branchesare the lingual and facial arteries. The lingual artery andits branch, the sublingual artery, supply the tongue, thefloor of the mouth, and the gingiva, and the facialartery supplies blood to the lips and soft palate. Themaxillary artery supplies the main cheek, hard palate,and the maxillary and mandibular gingiva.[7,9] Theinternal jugular vein eventually receives almost all ofthe blood derived from the mouth and pharynx.[8]

Drugs diffusing across the membranes have easy accessto the systemic circulation via the internal jugular vein.

FACTORS INFLUENCING DRUG ABSORPTION

FROM THE ORAL CAVITY

Because the oral mucosa is a highly vascular tissue,the two main factors that influence drug absorptionfrom the mouth are the permeability of the oralmucosa to the drug and the physicochemical character-istics of the drug that is presented at the site of absorption.

Permeability of the Oral Mucosa to Drugs

The lipid membranes of the oral mucosa are resistantto the passage of large macromolecules; however, smallun-ionized molecules tend to cross the membrane withrelative ease. This passage is in either direction, andindeed passage of drugs from the circulation into themouth can be used in therapeutic drug monitoring bymeasuring drug concentrations in saliva. The per-meability of the oral mucosa has been comprehensivelyreviewed by Siegel.[10]

Mechanisms involved in drug absorption

across the oral mucosa

The mechanisms by which drugs cross biologic lipidmembranes are passive diffusion, facilitated diffusion,active transport, and pinocytosis. Small, water-solublemolecules may pass through small, water-filled pores.The main mechanism involved in drug transfer acrossthe oral mucosa, common with all regions of thegastrointestinal tract, is passive diffusion, althoughfacilitated diffusion has also been shown to take place,primarily with nutrients. Passive diffusion involves themovement of a solute from a region of high concen-tration in the mouth to a region of low concentrationwithin the buccal tissues. Further diffusion then takes

1072 Drug Delivery: Buccal Route

DrugDelivery

Buccal–Mono

place into the venous capillary system, with the drugeventually reaching the systemic circulation via thejugular vein. The physicochemical characteristics of adrug are very important for this diffusion process.Although passive diffusion is undoubtedly the majortransport mechanism for drugs, the absorption ofnutrients from the mouth has been shown to involvecarrier systems (facilitated diffusion), which lead toa more rapid absorption than the concentration gradi-ent would promote. Such a carrier system, unlike pas-sive diffusion, exhibits stereospecificity, and indeed theabsorption of D-glucose and L-arabinose across thebuccal mucosa has been shown to be stereospecific.[11]

The same authors also showed that the absorption ofD-glucose, galactose, and 3-0-methyl-D-glucose was atleast partially dependent on the presence of sodiumions in the luminal fluids. Furthermore, the transportof D-glucose was inhibited by galactose and 3-0-methyl- D-glucose, suggesting at least one common car-rier system. Similarly, Kurosaki et al.[12] demonstratedthat the absorption of cefadroxil (a cephalosporin anti-biotic) from the human oral cavity occurs through acarrier-mediated mechanism; this absorption wasinhibited by the presence of cephalexin, which sharesa common carrier-mediated process with cefadroxil inthe small intestine of rat.

Membrane storage during buccal absorption

of drugs

The absorption of a drug from the mouth is not syn-onymous with drug entry into the systemic circulation.Instead, the drug appears to be stored in the buccalmembranes, sometimes known as the membranereservoir effect.[13] Due to this phenomenon, buccalpartitioning has been suggested as a more accurateterm to describe the diffusion of drugs across the oralmucosa.[14] Although several authors have devisedschematic representations of the kinetics of oral drugabsorption (Fig. 1)[1,14] the mucosal constituentsresponsible for drug binding have not been identified.

Regional differences in mucosal permeability

The epithelial lining of the mouth differs in both com-position (keratinized and non-keratinized) and thick-ness in different regions of the mouth. Therefore,drug absorption may vary from different oral sites.This site-dependent absorption has been shown to takeplace by Pimlott and Addy,[15] who measured theabsorption of isosorbide dinitrate into the systemic cir-culation after applying tablets to the buccal, palatal, orsublingual mucosa in six healthy volunteer subjects.Serum levels of drug were detected from the buccaland sublingual sites after 1min. The drug concen-tration progressively increased, peaking at 5min, andthen decreased during the 30min sampling period. Atmost of the time periods, serum concentrations werehigher from sublingual sites than from buccal sites(Fig. 2). The drug was not detected in the serum ofany subject after application to the palatal mucosa.These authors concluded that the keratinized layer ofthe oral mucosa may be an important barrier to drugabsorption because the palatal epithelium is kerati-nized, but the buccal and sublingual mucosa arenot.[16] Absorption across the sublingual epithelium islikely to be greater than across the buccal epitheliumbecause the former is thinner and is immersed in alarger volume of saliva.

Rapid absorption from the sublingual mucosa wasalso demonstrated through work by Al-Furaihet al.,[17] who reported that sublingual administration

Solid drugpowder or tablet

* Pathway to account for back-partitioning into buccal fluids of drug

absorbed by membrane.

Drug removed from oral cavityby swallowing

Drug in bloodcirculation

Drug in lymphatic circulation

Dissolved drugin buccal fluids

Dissolved drug inbuccal membrane

∗

Fig. 1 Schematic representation of the absorption kineticsof buccally presented drugs. (From Ref.[10].)

0

0.4

0.8

1.2

1.6

2

2.4

2.8

3.2

Pla

sma

ISD

N n

g/m

l

Tabletremoved Time (mins)

Buccal

Sublingual

0 5 10 15 20 2 305

Fig. 2 Mean plasma isosorbide dinitrate concentrationsafter application of isosorbide dinitrate (5mg) to the buccaland sublingual mucosa in six healthy male volunteer subjects.(Redrawn from Ref.[15].)

Drug Delivery: Buccal Route 1073

DrugDelive

ryBucca

l–Mono

of captopril led to a more rapid attainment of plasmacaptopril concentrations and had a more rapid phar-macological effect (i.e., lower systolic blood pressure)compared to peroral administration of the drug.

Physicochemical Characteristics of the Drug

Various experimental techniques have demonstratedthat cell membranes have a large lipid component,[18]

and most drugs cross such membranes by simple pass-ive diffusion. In order to cross these lipid membranes, adrug should be in the lipid-soluble or un-ionized formand also be in solution. The various physicochemicalcharacteristics of the drug are, therefore, of paramountimportance as far as drug penetration across the oralmucosa is concerned.

Molecular weight

In general, molecules penetrate the oral mucosa morerapidly than ions, and smaller molecules penetratemore rapidly than larger molecules. However, thisrule is not absolute because dextrans with a molecularweight of up to 70,000 cross keratinized rabbit oralmucosa,[19] but horseradish peroxidase (molecularweight 40,000) does not.[20] High-molecular-weightmucopolysaccarides such as heparin are not wellabsorbed,[21] although inclusion of penentrationenhancers in some insulin formulations have improvedbioavailability.[22]

Degree of ionization

The average pH of saliva is 6.4. Because the un-ionizedform of a drug is the lipid-soluble-diffusible form, thepKa of the drug plays an important role in its absorp-tion across the lipid membranes of the oral mucosa.The degree of ionization of a drug at a specified pHcan be calculated using the Henderson–Hasselbalchequation as follows:

For an acid:

pH ¼ pKa þ log10½un-ionized species�

½ionized species�

For a base:

pH ¼ pKa þ log

The importance of pH on drug absorption from themouth has been extensively studied using the buccalabsorption model, in which loss of drug from buffereddrug solutions placed in the mouth is monitored.[23]

The influence of pH on the absorption of the weakbase chloroquine and of the weak acid phenobarbitoneis shown in Fig. 3.[24]

However, pH does not always influence the rate orextent of absorption. For example, McElnay et al.[25]

found that captopril pharmacodynamic parameters(blood pressure, heart rate, and plasma renin activity)did not differ significantly between buffered andunbuffered sublingual administration, suggesting thatmanipulation of pH had little effect. It was, therefore,proposed that a mechanism other than passive diffusionwas involved in the buccal absorption of this drug.

Although many studies illustrate the importanceof ionization on drug absorption, the pH of saliva isrelatively constant, and in the absence of a buffer,the pKa of the drug plays the deciding role as to thestate of drug ionization. Also, due to the relativelylarge surface area available for absorption and to themaintenance of an equilibrium between ionized andun-ionized drug, only a small percentage of drug hasto be present in the un-ionized form before significantabsorption can take place.

Lipid solubility

Although the undissociated (un-ionized) form of adrug has the higher lipid solubility, the un-ionizedmoieties themselves have differing lipid solubilities. Acommon way of assessing the lipid solubility of a drugis to measure its oil–water partition coefficient. As withpH, buccal absorption has been shown to be positivelycorrelated with a drug’s oil–water partition coefficient.

0

0

1 2 3 4 5 6 7 8 9 10

10

20

30

40

50

60

70

80

90

100

Per

centa

ge

of

dose

abso

rbed

pH

Chloroquine

Phenobarbitone

Fig. 3 The influence of pH on the absorption of the weakacid phenobarbitone and the weak base chloroquine fromthe buccal cavity in three healthy volunteer subjects.(Redrawn from Ref.[24].)


DrugDelivery

Buccal–Mono

Beckett and Moffat,[26] for example, found a correlationof partition coefficients in n-heptane/aqueous systemswith buccal absorption data for a series of amines andacids when the degree of ionization was held constant.

In conclusion, to penetrate the oral mucosa to a sig-nificant degree, a drug should have a relatively lowmolecular weight and exhibit biphasic solubility pat-terns, that is, be soluble in both the aqueous salivaryfluid and the lipid membrane barrier to penetration.A significant amount of the drug should be un-ionizedat salivary pH, and the drug should also not bindstrongly to the oral mucosa.

BUCCAL ADMINISTRATION AS A METHOD OF

PREVENTING PRESYSTEMIC METABOLISM

The systemic availability of a drug is a measure of thefraction of the administered amount of drug that isabsorbed into the general circulation in an unchangedform from its site of administration. Disregardingpharmaceutical reasons (e.g., poor tablet disinte-gration) and inappropriate physicochemical propertiesof the drug, the two main reasons for poor bio-availability after peroral administration are drugdestruction by stomach acid and drug modificationby metabolic enzyme systems prior to its entry intothe systemic circulation. The principal organs involvedin presystemic elimination are the gut wall, the liver,and the lung.[27] Drug metabolism of this type is knownas first-pass metabolism. A number of drugs havehigh affinities for the enzyme systems in these organsand are, therefore, highly extracted during theirflow through the organs. These drugs, which are saidto have a high extraction ratio (Fig. 4), include pro-pranolol, terbutaline, levodopa, imipramine, aspirin,morphine, pentazocine, nitroglycerin, lignocaine,hydralazine, verapamil, and methyldopa. The mainmetabolizing organ in the body is the liver. Becauseblood draining from the gut via the portal vein mustpass through the liver prior to entry into the generalcirculation, the total drug absorbed from the gutmust pass through the liver before it can reach its site

of action. Once the drug has entered the systemic circu-lation, it is distributed to other areas of the body(depending on its volume distribution); although theextraction ratio remains constant, the proportion ofthe total drug in the body that is metabolized on sub-sequent passes through the liver is reduced due to alowered drug concentration in the plasma after distri-bution has taken place. The liver receives only 20%of the cardiac output (as compared with 100% fromthe portal vein), which also protects the drug thathas already been absorbed from the metabolic systemsof this organ. Presystemic elimination can, therefore,be avoided by choosing a site of administration fromwhich the drug enters the systemic circulation directly,without first passing through the liver, lung, or gutwall. Because blood draining from the oral cavityenters the general circulation via the internal jugularvein, oral administration by the buccal or sublingualroutes provides a useful strategy for improving bio-availability of drugs that are susceptible to extensivefirst-pass metabolism. A high first-pass effect doesnot, however, mean that drugs with a high extractionratio cannot be given perorally. If a sufficient dose ofthe drug is given, an adequate amount of drug (to pro-duce the required therapeutic effect) often remainsintact during its first passage through the liver. Also,a high peroral dose of drug or, indeed, serum levelsof the drug from previous doses may saturate thehigh-affinity metabolizing systems in the liver and,thereby, decrease the first-pass effect and increase bio-availability. With some drugs, moreover, the metabolitesthemselves may have good pharmacologic activity.

DRUGS AND PHARMACEUTICAL

FORMULATIONS FOR ADMINISTRATION

BY THE BUCCAL AND

SUBLINGUAL ROUTES

Although the data produced using the buccal partition-ing model of drug absorption[23] have shown thatnumerous drugs are absorbed efficiently from the oralcavity, few drugs have been assessed clinically afteradministration by this route, and not all drugs thathave given encouraging clinical data have specific for-mulations available for intraoral administration.Drugs within the cardiovascular and strong analgesicpharmacologic classes have received the most attention.

Cardiovascular Drugs

Glyceryl trinitrate (GTN)

This vasodilator has been used for over 100 years inthe treatment of angina pectoris, and today, many

CA

CA – CV

CA

CVORGAN

extraction ratio =

Fig. 4 Diagrammatic representation of the extraction ratioof a drug. The extraction ratio is a measure of the tendencyof a drug to be removed from the blood during its passagethrough an organ such as the liver. In the diagram, CA isthe arterial drug concentration and CV is the venous drugconcentration.


DrugDelive

ryBucca

l–Mono

clinicians consider it the most effective drug despiteexhaustive efforts to find alternatives. It is also usedin the treatment of congestive heart failure. This drugis rapidly absorbed from the mouth, with much ofthe drug bypassing the liver. The liver has a highmetabolic capacity for organic nitrates by virtue ofthe enzyme glutathione reductase.[28] Sublingualadministration of GTN is the most appropriateaction to alleviate the pain of an acute angina attackbecause of its rapid action, its long-established efficacy,and its low cost.[29] The traditional pharmaceuticalformulation of the drug is a rapidly dissolving tabletfor administration under the tongue. This approach,however, has two main disadvantages:

1. The time taken for the tablet to disintegrate anddissolve may vary from person to person. Adelayed and varied onset of action may result.

2. The tablets of GTN lose significant potencyafter only 8 weeks of the initial opening of themanufacturer’s bottle and should be discardedafter that period because exposure to moistureand to the atmosphere accelerates nitrate break-down. Heat also accelerates drug deterioration.

In an attempt to overcome the previously noted pro-blems with the sublingual tablet formulations, GTN isnow widely available in metered-dose aerosol prepara-tions. The sprays usually contain 0.4mg GTN per unitdose. The manufacturers suggest that 1 or 2 metereddoses be sprayed on the oral mucosa (preferably underthe tongue) and then the mouth should be closed.

A slightly different approach has been taken byPharmax, the manufacturer of Suscard Buccal tablets.Instead of the traditional 300-, 500-, and 600-mg sublin-gual tablets, the Pharmax tablets contain 1, 2, 3, or5mg of GTN and are placed between the upper lipand the gum on either side of the front teeth. Duringthe dissolution phase, the tablet softens and adheresto the gum, after which dissolution continues in a uni-form and gradual manner. Because this is a prolonged-release dosage form, the patient should not increase thetablet’s dissolution rate by moving it around themouth. The tablet should be replaced if accidentallyswallowed, and the placement of successive tabletsshould be alternated on either side of the mouth. Aswell as an effective prophylactic in angina, this formu-lation has been shown to be effective in congestiveheart failure.[30]

Isosorbide dinitrate

This nitrate is also active sublingually and is a morechemically stable drug for those who require nitratesonly infrequently. It is a longer-acting drug than GTN.The activity of isosorbide dinitrate may depend on the

production of active metabolites, the most importantof which is isosorbide 5-mononitriate. Isosorbidemononitrate is also available for angina prophylaxis,though the advantages over isosorbide dinitrate havenot yet been firmly established.[31] The general consen-sus is that the activity of the dinitrate is also longerthan that of GTN Kattus et al.,[32] for example, foundthat sublingual isosorbide dinitrate offered protectionagainst angina for 2.5–3 h compared to 1 h relief withGTN The finding of equal bioavailability of chewable(buccal absorption) and slow-release capsules (intesti-nal absorption) ‘‘infers that buccal or sublingualabsorption does not circumvent the first pass effect,that presystemic metabolism occurs in the buccalmucosa, that buccal absorption is not as effective asbelieved or that isosorbide dinitrate is swallowed andnot absorbed by the buccal mucosa. The identicalpattern of metabolites after buccal and intestinaladministration favours the theory that buccal absorp-tion is slow and that isosorbide dinitrate is swallowedwith the saliva in which it is dissolved.’’[33] Currentknowledge concerning the buccal absorption routesupports this theory. The main advantage of sublingualand buccal dosing may be the rapid disintegration anddissolution of the tablet in saliva. Present knowledgesuggests using the drug buccally for the treatment ofacute attacks of angina and using a sustained-releaseformulation for prophylactic purposes. Iga andOgawa[34] demonstrated that a sustained release buccalformulation of both GTN and isosorbide dinitrateincreased the bioavailability of both drugs when admi-nistered to dogs, compared to oral administration.A number of isosorbide dinitrate preparations areavailable for administration by the buccal or sublin-gual routes, the usual strengths being 5 or 10mg.Although chewable preparations are available, themore traditional quick-disintegrating tablets predomi-nate. Because mastication tends to increase salivaproduction, in order to prevent premature swallowingof the drug, the traditional tablet type may also bepreferable. Sublingual rather than buccal administra-tion may also be preferable because higher plasmaconcentrations have been found in healthy volunteerswhen the former route was used (Fig. 2).[15]

Nifedipine

In the past, the difficulties presented in the adminis-tration of drugs in the treatment of hypertensiveemergencies were largely overcome with the use ofnifedipine administered sublingually.[35] The onset ofaction was rapid, and the drug was also used sublin-gually for the treatment of acute attacks of angina pec-toris. Presently, two types of formulation of nifedipineare available, both intended primarily for peroraladministration. The sustained-release formulation is


DrugDelivery

Buccal–Mono

solely used perorally; however, the rapid-releasecapsule, which contains nifedipine in solution form,was formerly administered to the buccal cavity. How-ever, the manufacturers now state in their literaturethat ‘‘nifedipine should not be used for the treatmentof acute attacks of angina’’ as it has been associatedwith large variations in blood pressure and reflextachycardia.[36]

Captopril

Two studies[37,38] have indicated the usefulness ofsublingual captopril in the treatment of severe hyper-tension. The hypertensive patients thus treated showeda marked decrease in systolic and diastolic blood pres-sure, with the onset of action being 2–5 min and thepeak effect at 10min.[37] Perorally administered capto-pril takes 1–2 h to achieve a maximal therapeuticeffect[39] and, therefore, is unsuitable for the treatmentof hypertensive crisis. Al-Furaih et al.[17] reported thatsublingual administration of captopril (followed byplasma monitoring of drug levels) led to a more rapidattainment of plasma captopril concentrations and hada more rapid pharmacological effect (i.e., lower systolicblood pressure) compared to peroral administration ofthe drug as shown in Fig. 5.

Iscan et al.[40] compared a number of parameters ofa specially formulated buccal bioadhesive captopriltablet with that of a conventional tablet. The buccalformulation provided controlled release of captoprilwith a smooth plasma level profile and a long durationof action; however, its bioavailability was 40% via thebuccal route as compared to 65% following an oraldose. This was attributed to the intestinal mucosabeing more permeable than the buccal mucosa, and itwas concluded that further work was required toimprove its bioavailability.

Analgesics

Buprenorphine

In common with other phenolic opiate analgesics,buprenorphine shows low peroral potency, suggestinga high first-pass metabolism effect; indeed, work in ratshas shown this to be the case.[27] Intravenous studieshave estimated that the extraction ratio of buprenor-phine is 85% and that peroral systemic availability isconsequently expected to be 15% or less.[41] Althoughabsorption from the mouth is slow and, therefore,not as useful as parenteral administration in the treat-ment of acute pain, it offers a major bioavailabilityadvantage over the peroral route for this drug.[42] Ifrequired, the patient can be given a parenteral doseof buprenorphine to achieve rapid pain relief and

thereafter be maintained on sublingual drug. The drugis available as a sublingual tablet containing 200 or400 mg of buprenorphine hydrocholoride for thetreatment of moderate to severe pain.

Morphine

Although not routinely given by the buccal or sublin-gual routes, several research studies have shown thatabsorption of morphine from the mouth gives rise toeffective analgesia and that these routes may providesuitable alternatives to parenteral administration.[43]

Clinical studies have suggested that the bioavailabilityof morphine is 40–50% greater after buccal thanintramuscular administration; as plasma morphine

0

0

50

100

150

200

250

300

A

95

90

100

105

110

115

120

30 60 90 120 150 180

Time (min)

Cap

top

ril

con

c. (

ng

/ml)

Syst

oli

c B

P

0

0

50

100

150

200

250

300

B

95

90

100

105

110

115

120

30 60 90 120 150 180

Time (min)

Cap

top

ril

con

c. (

ng

/ml)

Syst

oli

c B

P

Captopril conc.

Systolic BP

Captopril conc.

Systolic BP

Fig. 5 Correlation over time of systolic blood pressure (c)with plasma unchanged captopril concentration ( ) aftersublingual (A) and peroral (B) administration of 25 mg ofcaptopril. (From Ref.[17].)


DrugDelive

ryBucca

l–Mono

concentrations decline more slowly after buccal admin-istration, buccal morphine may be associated withenhanced analgesia.[44] Anlar et al.[45] administeredbuccoadhesive morphine sulphate tablets to six healthyvolunteers, resulting in up to 30% of active drug beingabsorbed; this is in contrast to absolute bioavailabilityof a morphine sulphate solution of 23%.[46] Christrupet al.[47] found that buccal delivery of morphinesulphate could be enhanced further by using esterprodrugs with higher lipophilicity than the parentdrug itself.

Ketobemidone

Ketobemidone is a narcotic analgesic that has beenused clinically in Scandinavia and other Europeancountries. The mean bioavailability in humans hasbeen reported to be approximately 35% following oraladministration, but this can be substantially improvedwhen administered by the sublingual or buccalroute.[48] To date, in vitro work has focussed on theuse of the ketobemidone prodrugs (largely esters),and published results suggest that, as with morphinesulfate, buccal mucosa permeation is greatlyimproved.[49,50]

Flurbiprofen

Studies have suggested that this nonsteroidal anti-inflammatory drug may be useful in the treatment ofperidontal disease. Manipulation of pH was shownto influence the amount of drug absorbed; an increasein pH resulted in a reduction of drug absorbed, thusresulting in a poor local effect.[51] Gonzalez-Youneset al.[52] reported that the drug was tightly bound tothe membrane of the tissues in the mouth.

Peptide Drugs

The oral mucosa has been cited as a route of admin-istration for peptide drugs as a way of avoidingparenteral delivery, although permeability is low,which reduces its value as a viable option.[22] However,modifications to drug formulation may offer greatersuccess. The addition of penetration enhancers todosage forms appears to improve bioavailability tothe greatest extent, by improving the permeability ofthe epithelium and/or affecting the nature of thedrug.[53] To date, much of the experimental work hasbeen conducted in animals.

Insulin

To achieve hypoglycemia with insulin, the traditionalroute of administration has been via subcutaneous

injection. Peroral preparations are not feasible due tothe degradation of insulin by gastric acid and enzymes.However, studies carried out in animals utilising buccalformulations have been more successful. Ritschelet al.[54] administered insulin to beagle dogs using solu-tions of different pHs. Bioavailability (22.3%) wasmaximized at pH 7.5, and the addition of penetrationenhancers (bile salts) did not increase this further.Experimental work in rabbits found that in the absenceof penetration enhancers, insulin solutions over arange of pHs did not show any significant hypoglycae-mic response, indicating that insulin was not absorbedto a significant degree through the buccal mucosa.[55]

Buserelin

This luteinizing hormone-releasing hormone has beenused in the treatment of endometriosis and hormone-dependent tumors. Modes of administration haveincluded injections, nasal sprays and subcutaneousimplantations. One study, conducted in pigs, demon-strated the value of glycodeoxycholate (a penetrationenhancer) in improving the bioavailability of buserelinby up to five-fold after buccal delivery.[56]

a-Interferon

a-Interferon has broad antiviral and antiproliferativeactivity and has been used in HIV and certain forms ofhepatitis. As with other peptide drugs, ways have beensought to improve the buccal delivery of a-interferonto avoid gastro-intestinal degradation and first-passmetabolism. Using a range of penetration enhancers,Stewart, Bayley, and Howes[57] noted improved bioavail-ability, particularly with sodium taurocholate, in rats.As with all of the studies reviewed under the categoryof peptide drugs, extrapolation to the human situationshould be done with caution.

Miscellaneous Drugs

Nicotine

The absorption of nicotine from chewing tobacco hasbeen widely used for many years. Buccal absorptionof nicotine is also the route of absorption for pipeand cigar smokers if the smoke is not inhaled. Nicotinereplacement therapy has been used in smoking ces-sation strategies. Nicotine in the form of chewing gumcarries no cancer risk and is a useful part of a smokingcessation strategy.[58] A recent innovation has been thedevelopment of a sublingual tablet (available in 2 mg);a clinical trial has shown that this formulation is a safeform of administration,[59] and patients may use onetablet every 1–2 h.


DrugDelivery

Buccal–Mono

Zinc

Zinc gluconate in the form of a lozenge has beenmarketed for the treatment of the common cold; therehas been no definitive conclusion as to whether it iseffective in treating cold symptoms, although dif-ferences in study methodology may partially explainthe conflicting results that have been reported.[60,61]

Midazolam

Midazolam administered bucally in solution has beenshown to be rapidly absorbed and produces changesin EEG readings.[62] The authors suggested that thismay offer an alternative to rectal administration ofdiazepam in the emergency treatment of seizures.

CONCLUSIONS

The buccal cavity provides a highly vascular mucousmembrane site for the administration of drugs. Theepithelial lining of the oral cavity differs both in type(keratinized and nonkeratinized) and in thickness indifferent areas, and the differences give rise to regionalvariations in permeability to drugs. Although somemacromolecules have been shown to cross the absorp-tion barrier (lipid membrane), the absorption of smal-ler drug molecules occurs more reproducibly andrapidly. The main absorption mechanism is passive dif-fusion of the un-ionized (lipid-soluble) form of thedrug. Facilitated diffusion has also been shown to takeplace with nutrients. Drugs are often stored or boundto the buccal mucosa prior to entry into the blood-stream. The blood drainage from the mouth entersthe general circulation directly without first passingthrough the liver. This feature enhances the bioavail-ability of certain drugs as compared with peroraladministration because first-pass metabolism isavoided. To ensure adequate absorption from themouth, a drug administered as a solid dosage formmust exhibit biphasic solubility, that is, be soluble insaliva and in the lipid membranes of the buccal cavity.The major drugs currently available for buccal admin-istration fall within the vasodilator and strong anal-gesic pharmacologic classes. Although the main typeof formulation available for buccal absorption is rap-idly disintegrating tablets, new approaches includemucoadhesive tablets and spray formulations. Muchof the current knowledge on the mechanism and char-acteristics of drug absorption from the buccal cavityhas been gained from volunteer studies in which buff-ered drug solutions are placed in the mouth (buccalabsorption model) rather than from clinical pharmaco-logic studies in patients. This former method providesuseful information on the bioavailability of new and

existing drugs. The main advantages of the buccalroute of administration over the traditional peroralroute are that drug degradation in the stomach isavoided, first-pass metabolism is avoided, and thera-peutic blood levels of drug can be achieved rapidly.Clearly these advantages are presently clinically rel-evant for only a limited number of drugs. However,with the recent developments of formulation types,such as mucoadhesive preparations and the use of pep-tides as drugs, this number may increase in the future.The main disadvantage of the buccal route is that thedrug may have an unwanted local effect in the mouth,such as bad taste, or may be absorbed slowly and,therefore, be swallowed prior to sufficient absorptiontaking place. The buccal route, like the rectal andintranasal routes, has been largely neglected by clini-cians and manufacturing companies in the past andclearly merits further intensive research.

REFERENCES

1. Harris, D.; Robinson, J.R. Drug delivery via the mucousmembranes of the oral cavity. J. Pharm. Sci. 1992, 81,1–10.

2. Beckett, A.H.; Hossie, R.D. Buccal absorption of drugs. InHandbuch der Experimentellen Pharmakologie; Gillette,T.R., Ackermann, H.S., Eds.; Springer-Verlag: Berlin,1971; 28, 1–60.

3. Feldman, R.S.; Szabo, G. Comparative microanatomy ofskin and oral mucosa. In Textbook of Oral Biology, 1stEd.; Shaw, J.H., Sweeney, E.A., Cappuccino, C.C., Meller,S.M., Eds.; W.B. Saunders: Philadelphia, 1978; 166–167.

4. Squier, C.A.; Rooney, L. The permeability of keratinizedand non-keratinized oral epithelium to lanthanum in vivo.J. Ultrastruct. Res. 1976, 54, 286–295.

5. Schroeder, H.E. Classification of stratified epithelia. In Dif-ferentiation of Human Oral Stratified Epithelia; Karger:Basel, 1981; 33.

6. Chen, S.Y.; Squier, C.A. The ultrastructure of the oral epi-thelium. In The Structure and Function of Oral Mucosa;Meyer, J., Squier, C.A., Gerson, S.J., Eds.; Pergamon Press:Oxford, 1984; 7–30.

7. Stablein, M.J.; Meyer, J. The vascular system and bloodsupply. In The Structure and Function of Oral Mucosa;Meyer, J., Squier, C.A., Gerson, S.J., Eds.; Pergamon Press:Oxford, 1984; 237–256.

8. Netter, F.H. Upper digestive tract. In The DigestiveSystem, Part 1: The Ciba Collection of Medical Illustra-tions; Oppenheimer, E., Ed.; Ciba: New York, 1959; 3,24–28.

9. Boyer, C.C.; Neptune, C.M. Patterns of blood supply toteeth and adjacent tissue. J. Dent. Res. 1962, 41, 158–171.

10. Siegal, I.A. Permeability of the oral mucosa. In The Struc-ture and Function of Oral Mucosa; Meyer, J., Squier,C.A., Gerson, S.J., Eds.; Pergamon Press: Oxford, 1984;95–108.

11. Manning, A.S.; Evered, D.F. The absorption of sugars fromthe human buccal cavity. Clin. Sci. Mol. Med. 1976, 51,127–132.

12. Kurosaki, Y.; Nishimura, H.; Terao, K.; Nakayama, T.;Kimura, T. Existence of a specialised absorption mech-anism for cefadroxil, an aminocaphalosporin antibiotic, inthe human oral cavity. Int. J. Pharm. 1992, 82, 165–169.

13. Ho, H.F.H. Biophysical kinetic modeling of buccal absorp-tion. Adv. Drug Del. Rev. 1993, 12, 61–97.


DrugDelive

ryBucca

l–Mono

14. Henry, J.A.; Ohashi, K.; Wadsworth, J.; Turner, P. Drugrecovery following buccal absorption of propranolol. Br.J. Clin. Pharmacol. 1980, 10, 61–65.

15. Pimlott, S.J.; Addy, M. A study into the mucosal absorp-tion of isosorbide dinitrate at different intra-oral sites. OralSurg. Oral Med. Oral Pathol. 1985, 59, 145–148.

16. Squier, C.A.; Johnson, N.W.; Hopps, R.M. The human oralmucosa: innervation of the oral mucosa. In Human OralMucosa; Blackwell Scientific Publications: Oxford, 1975; 63.

17. Al-Furaih, T.A.; McElnay, J.C.; Elborn, J.S.; Rusk, R.;Scott, M.G.; McMahon, J.; Nicholls, D.P. Sublingual cap-topril—a pharmacokinetic and pharmacodynamic evalu-ation. Eur. J. Clin. Pharmacol. 1991, 40, 393–398.

18. Gurr, M.I.; Harwood, J.L. Lipids in cellular structure:membrane structure. In Lipid Biochemistry; Chapmanand Hall: London, 1991; 265–281.

19. Squier, C.A.; Johnston, N.W. Permeability of oral mucosa.Br. Med. Bull. 1975, 31, 169–175.

20. Squier, C.A. The permeability of keratinized and nonkera-tinized oral epithelium to horseradish peroxidase. J. Ultra-struct. Res. 1973, 43, 160–177.

21. Fuller, H.L. Effect of sublingual heparin on lipemia clearingand on recurrence of myocardial infarction. Angiology1960, 11, 200–206.

22. Merkle, H.P.; Wolany, G. Buccal delivery for peptide drugs.J. Controlled Release 1992, 21, 155–164.

23. Beckett, A.H.; Triggs, E.F. Buccal absorption of basicdrugs and its application as an in vivo model of passivedrug transfer through lipid membranes. J. Pharm. Pharma-col. 1967, 19, 31S–41S.

24. McElnay, J.C.; Sidahmed, A.M.; D’Arcy, P.F. Experi-mental modeling of drug absorption and drug absorptioninteractions. Int. J. Pharm. 1986, 31, 107–117.

25. McElnay, J.C.; Al-Furaih, T.A.; Hughes, C.M.; Scott,M.G.; Elborn, J.S.; Nicholls, D.P. The effect of pH on thebuccal and sublingual absorption of captopril. Eur. J. Clin.Pharmacol. 1995, 48, 373–379.

26. Beckett, A.H.; Moffat, A.C. Correlation of partition coeffi-cients in n-heptane-aqueous systems with buccal absorptiondata for a series of amines and acids. J. Pharm. Pharmacol.1969, 21, 144S–150S.

27. Brewster, D.; Humphrey, M.J.; McLeavy, M.A. The sys-temic bioavailability of buprenorphine by various routesof administration. J. Pharm. Pharmacol. 1981, 33, 500–506.

28. Needleman, P.; Hunter, F.E. The transformation of glyceryltrinitrate and other nitrates by glutathione-organic nitratereductase. Mol. Pharmacol. 1965, 1, 77–86.

29. Goldstein, R.E.; Rosing, D.R.; Redwood, D.R.; Beiser,F.D.; Epstein, S.E. Clinical and circulatory effects of isosor-bide dinitrate comparison with nitroglycerin. Circulation1971, 43, 629–639.

30. Sanghera, S.S.; Goldberg, A.A.J.; Parson, D.F. Buccalnitroglycerin in elderly patients with congestive heart fail-ure. Practitioner 1985, 229, 1054–1055.

31. British national formulary No. 40, british medical associ-ation and the pharmaceutical society of great britain. ThePharmaceutical Press: London, 2000.

32. Kattus, A.A.; Alvaro, A.B.; Zohman, L.R.; Coulson, A.Comparison of placebo, nitroglycerin, and isosorbide dini-trate for effectiveness of relief of angina and duration ofaction. Chest 1979, 75, 17–21.

33. Galeazzi, R.L.; Platzer, R.; Reuteman, G. Plasma isosor-bide dinitrate concentrations and effect after chewableand high-dose sustained-release formulations. Int. J. Clin.Pharmacol. Ther. 1983, 21, 393–397.

34. Iga, K.; Ogawa, Y. Sustained-Release buccal dosage formsfor nitroglycerin and isosorbide dinitrate: increasedbioavailability and extended time of absorption whenadministered to dogs. J. Controlled Release 1997, 49,105–113.

35. Mathur, M.M.; Chaturvedi, M.K.; Rai, R.R.; DasKhatri, T. Role of nifedipine sublingually in acceleratedhypertension. J. Assoc. Phys. India 1986, 34, 137–138.

36. A., B.P.I. Compendium of Data Sheets and Summaries ofProduct Characteristics 1999–2000; Datapharm Publica-tions: London, 1999.

37. Tschollar, W.; Belz, G.G. Sublingual captopril in hyperten-sive crisis. Lancet 1985, 2, 34–35.

38. Hauger-Klevene, J.H. Comparison of sublingual captopriland nifedipine. Lancet 1986, 1, 219.

39. Ohman, K.P.; Kagedal, B.; Larsson, R.; Karlberg, B.E.Pharmacokinetics of captopril and its effects on bloodpressure during acute and chronic administration and inrelation to food intake. J. Cardiovasc. Pharmacol. 1985,7 (Suppl. 1), 20–24.

40. Iscan, Y.Y.; Capan, Y.; Senel, S.; Sahin, M.F.; Kes, S.;Duchene, D.; Hincal, A.A. Formulation and in vitro/ invivo evaluation of buccal bioadhesive captopril tablets.STP Pharma. Sci. 1998, 8, 357–363.

41. Bullingham, R.E.S.; McQuay, H.J.; Moore, R.A.; Bennett,M.R.D. Buprenorphine kinetics. Clin. Pharmacol. Ther.1980, 28, 667–672.

42. Cassidy, J.P.; Landzert, N.M.; Quadros, E. Controlled buc-cal delivery of buprenorphine. J. Controlled Release 1993,25, 21–29.

43. Whitman, H.H. Sublingual morphine: a novel route ofnarcotic administration. Am. J. Nursing 1984, 84, 939

44. Bell, M.D.D.; Murray, G.R.; Mishra, P.; Calvey, T.N.;Weldon, B.D.; Williams, N.E. Buccal morphine—a newroute for analgesia. Lancet 1985, 1, 71–73.

45. Anlar, S.; Capan, Y.; Guven, O.; Gogus, A.; Dalkara, T.;Hincal, A.A. Formulation and in vitro–in vivo evaluationof buccoadhesive morphine sulphate tablets. Pharm. Res.1994, 11, 231–236.

46. Hoskin, P.J.; Hanks, G.W.; Aheme, G.W.; Chapman, D.;Littleton, P.; Filshie, J. The bioavailability and pharmaco-kinetics of morphine after intravenous, oral and buccaladministration in healthy volunteers. Br. J. Clin. Pharma-col. 1989, 27, 499–505.

47. Christrup, L.L.; Christensen, C.B.; Friis, G.J.; Jorgensen, A.Improvement of buccal delivery of morphine using the pro-drug approach. Int. J. Pharm. 1997, 154, 157–165.

48. Hansen, L.B.; Christrup, L.L.; Bundgaard, H. Ketobemi-done prodrugs for buccal delivery. Acta Pharma. Nord.1991, 3, 77–82.

49. Hansen, L.B.; Christrup, L.L.; Bundgaard, H. Enhanceddelivery of ketobemidone through porcine buccal mucosain vitro via more lipophilic ester prodrugs. Int. J. Pharm.1992, 88, 237–242.

50. Hansen, L.B.; Jorgensen, A.; Rasmussen, S.N.; Christrup,L.L.; Bundgaard, H. Buccal absorption of ketobemidoneand various ester prodrugs in the rat. Int. J. Pharm. 1992,88, 243–250.

51. Barsuhn, C.L.; Olanoff, L.S.; Gleason, D.D.; Adkins, E.L.;Ho, N.F.H. Human buccal absorption of flurbiprofen. Clin.Pharmacol. Ther. 1988, 44, 225–231.

52. Gonzalez-Younes, I.; Wagner, J.G.; Gaines, D.A.; Ferry,J.J.; Hageman, J.M. Absorption of flurbiprofen throughhuman buccal mucosa. J. Pharm. Sci. 1991, 80, 820–823.

53. Hoogstraate, A.J.; Bodde, H.E. Methods for assessing thebuccal mucosa as a route of drug delivery. Adv. DrugDel. Rev. 1993, 12, 99–125.

54. Ritschel, W.A.; Ritschel, G.B.; Forusz, H.; Kraeling, M.Buccal absorption of insulin in the dog. Res. Comm. Chem.Path. Pharmacol. 1989, 63, 53–67.

55. Oh, C.K.; Ritschel, W.A. Biopharmaceutic aspects of buc-cal absorption of insulin. Meth. Find. Exp. Clin. Pharma-col. 1990, 12, 205–212.

56. Hoogstraate, A.J.; Verhoef, J.C.; Pijpers, A.; van Leengoed,L.A.M.G.; Verheijden, J.H.M.; Junginger, H.E.; Bodde,H.E. In vivo buccal delivery of the peptide drug buserelinwith glycodeoxycholate as an absorption enhancer in pigs.Pharm. Res. 1996, 13, 1233–1237.

57. Steward, A.; Bayley, D.L.; Howes, C. The effect of enhan-cers on the buccal absorption of hybrid (BDBB) a-inter-feron. Int. J. Pharm. 1994, 104, 145–149.


DrugDelivery

Buccal–Mono

58. Henningfield, J.E. Nicotine medications for smokingcessation. N. Engl. J. Med. 1995, 333, 1196–1203.

59. Wallstrom, M.; Sand, L.; Nilsson, F.; Hirsch, J.M. Thelong-term effect of nicotine on the oral mucosa. Addiction1999, 94, 417–423.

60. Mossad, S.B.; Macknin, M.L.; Medendorp, S.V.; Mason, P.Zinc gluconate lozenges for treating the common cold—arandomized double-blind, placebo-controlled study. Ann.Intern. Med. 1996, 125, 81–89.

61. Macknin, ML.; Piedmonte, M.; Calendine, C.; Janosky, J.;Wald, E. Zinc gluconate lozenges for treating the commoncold in children—a randomized controlled trial. JAMA1998, 279, 1962–1967.

62. Scott, R.C.; Besag, F.M.C.; Boyd, S.G.; Berry, D.; Neville,B.G.R. Buccal absorption of midazolam: pharmacokineticsand EEG pharmacodynamics. Epilepsia 1998, 39, 290–294.

BIBLIOGRAPHY

Chidambaran, N.; Srivatsava, A.K. Buccal drug deliverysystems. Drug Dev. Indust. Pharm. 1995, 21, 1009–1036.

Gandhi, R.B.; Robinson, J.R. Oral cavity as a site for bioadhe-sive drug delivery. Adv. Drug Del. Rev. 1994, 13, 43–74.

Harris, D.; Robinson, J.R. Drug delivery via the mucous mem-branes of the oral cavity. J. Pharm. Sci. 1992, 81, 1–10.

Meyer, J.; Squier, C.A.; Gerson, S.J. The Structure and Functionof the Oral Mucosa; Pergamon Press: Oxford, 1984.

Rathbone, M.J.; Tucker, I.G. Mechanisms, barriers and path-ways of oral mucosal drug permeation. Adv. Drug Del.Rev. 1993, 12, 41–60.

Rathbone, M.J.; Drummond, B.K.; Tucker, I.G. The oral cavityas a site for systemic drug delivery. Adv. Drug Del. Rev.1994, 13, 1–22.


DrugDelive

ryBucca

l–Mono

Drug Delivery: Controlled Release

Yie W. ChienResearch and Development, Kaohsiung Medical University,Kaohsiung, Taiwan

Senshang LinCollege of Pharmacy and Allied Health Professions, St. John’s University,Jamaica, New York, U.S.A.

INTRODUCTION

Over the past decades, the treatment of illness has beenaccomplished by administering drugs to the humanbody via various pharmaceutical dosage forms, liketablets. These traditional pharmaceutical products arestill commonly seen today in the prescription andover-the-counter drug marketplace. To achieve andmaintain the drug concentration in the body withinthe therapeutic range required for a medication, it isoften necessary to take this type of drug delivery sys-tem several times a day. This yields an undesirable‘‘seesaw’’ drug level in the body (Fig. 1).

A number of advancements have been maderecently in the development of new techniques for drugdelivery. These techniques are capable of regulating therate of drug delivery, sustaining the duration of thera-peutic action, and/or targeting the delivery of drug toa specific tissue.[1–6] These advancements have alreadyled to the development of several novel drug deliverysystems that could provide one or more of the follow-ing benefits:

1. Controlled administration of a therapeutic doseat a desirable rate of delivery.

2. Maintenance of drug concentration within anoptimal therapeutic range for prolongedduration of treatment.

3. Maximization of efficacy-dose relationship.4. Reduction of adverse side effects.5. Minimization of the needs for frequent dose

intake.6. Enhancement of patient compliance.

Based on the technical sophistication of thecontrolled-release drug delivery systems (CrDDSs) thathave been marketed so far, or that are under activedevelopment, the CrDDSs can be classified (Fig. 2)as follows:

1. Rate-preprogrammed drug delivery systems.2. Activation-modulated drug delivery systems.

3. Feedback-regulated drug delivery systems.4. Site-targeting drug delivery systems.

In this article, the scientific concepts and technicalprinciples behind the development of this newgeneration of drug-delivery systems are outlined anddiscussed.

RATE-PREPROGRAMMED DRUG

DELIVERY SYSTEMS

In this group of CrDDSs, the release of drug moleculesfrom the delivery systems has been preprogrammed ata specific rate profile. This is accomplished by systemdesign, which controls the molecular diffusion of drugmolecules in and/or across the barrier medium withinor surrounding the delivery system. Fick’s laws of dif-fusion are often followed. These CrDDSs can furtherbe classified as follows:

1. Polymer membrane permeation-controlled drugdelivery systems.

2. Polymer matrix diffusion-controlled drug deliv-ery systems.

3. Polymer (membrane/matrix) hybrid-type drugdelivery systems.

4. Microreservoir partition-controlled drug deliv-ery systems.

Polymer Membrane Permeation-Controlled

Drug Delivery Systems

In this type of CrDDS, a drug formulation is eithertotally or partially encapsulated in a drug reservoircompartment whose drug-releasing surface is coveredby a rate-controlling polymeric membrane. The drugreservoir can be drug solid particles, a dispersion ofdrug solid particles, or a concentrated drug solution ina liquid- or solid-type dispersing medium. The poly-mericmembrane can be fabricated from a homogeneous

Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100001051Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved.1082

DrugDelivery

Buccal–Mono

or a heterogeneous non-porous polymeric material ora microporous or semipermeable membrane. Theencapsulation of drug formulation inside the reservoircompartment can be accomplished by molding, cap-sulation, microencapsulation, or other techniques.Different shapes and sizes of drug delivery systemscan be fabricated (Fig. 3).

The release of drug from this type of CrDDSsshould be at a constant rate (Q/t), which is definedby the following general equation:

Q

t¼

Km=rKa=mDdDm

Km=rDmhd þ Ka=mDdhmCR ð1Þ

where Km/r and Ka/m are, respectively, the partition-coefficients for the interfacial partitioning of drugmolecules from the reservoir to the membrane andfrom the membrane to the aqueous diffusion layer;

Dm, and Dd are, respectively, the diffusion coefficientsin the rate-controlling membrane with a thickness ofhm, and in the aqueous diffusion layer with a thicknessof hd. For microporous membrane, the porosity, andtortuosity of the pores in the membrane should beincluded in the estimation of Dm and hm. CR is the drugconcentration in the reservoir compartment.

The release of drug molecules from this type ofCrDDS is controlled at a preprogrammed rate by mod-ulating the partition coefficient and the diffusivity ofdrug molecule and the rate-controlling membraneand the thickness of the membrane. Several CrDDSs

A1

1 2 3 4

Frequencies of dosing

Dru

g c

on

cen

trat

ion

A2

A3

A4

B

Adverse side effects

Toxic level

Therapeutic range

No therapeutic

effects

Minimum effective

concentration

Fig. 1 Drug concentration profiles in the systemic circu-lation as a result of taking a series of multiple doses of a con-ventional drug-delivery system (A1, A2, . . . ) in comparisonwith the ideal drug concentration profile (B). (Adapted fromRef.[6].)

Drug

reservoir

Rate-controlling

surface

Drug

A

Drug

reservoir

Rate-controlling

surface

Drug

Energy sensor

B

Drug

reservoir

Rate-controlling

surface

Biochemical responsive/

Energy sensor

Drug

C

Drug

reservoir

Rate-controlling

surface

Drug

Biochemical responsive/

Energy sensor

Site-

targeting

moiety

D

Fig. 2 The four major classes of controlled-release drug delivery systems: (A) Rate-preprogrammed DDS; (B) Activation-modu-lated DDS; (C) Feedback-regulated DDS and (D) Site-trageting DDS.

Sphere

D

Cp

CbCm

Cs

Pm

Pd

Dm Da

hd

hm

Sink

Elution medium

Polymer

coating

Cylinder

Drug

reservoir

Drug

reservoir

Porous membrane

Pore

Diffusion layer

Drug release

Nonporous

membrane

Drug

impermeable

barrier

Sheet

Cp

A

B

C

Fig. 3 Release of drug from various shapes of polymermembrane permeation-controlled drug-delivery systems: (A)sphere-type, (B) cylinder-type, and (C) sheet-type. In (D),the drug concentration gradients across the rate-controllingpolymeric membrane and hydrodynamic diffusion layer existin series. Both the polymer membrane, which is either porousor non-porous, and the diffusion layer have a controlledthickness (hm and hd, respectively).

Drug Delivery: Controlled Release 1083

DrugDelive

ryBucca

l–Mono

of this type have been successfully marketed for thera-peutical uses and some representatives are outlinedlater for illustration.

Progestasert� IUD

In this controlled-release intrauterine device, the drugreservoir exists as a dispersion of progesterone crystalsin silicone (medical grade) fluid encapsulated in thevertical limb of a T-shaped device walled by a non-porous membrane of ethylene–vinyl acetate copolymer(Fig. 4). It is engineered to release continuously a dailydose of 65 mg progesterone inside the uterine cavity toachieve contraception for one year.[6] The same tech-nology has been utilized in the development of theMirena� system, a plastic T-shaped frame with a ster-oid reservoir containing 52mg levonorgestrel, which isdesigned to release a daily dose of levonorgestrel at�20 mg/day for achieving effective contraception forfive years.[7–9]

Ocusert� system

In this controlled-release ocular insert, the drug reser-voir is a thin disc of pilocarpine–alginate complexsandwiched between two transparent discs of micro-porous membrane fabricated from ethylene–vinylacetate copolymer (Fig. 5). The microporous mem-branes permit the tear fluid to penetrate into the drug

reservoir compartment to dissolve pilocarpine from thecomplex. Pilocarpine molecules are then released at aconstant rate of 20 or 40 mg/h for a 4- to 7-day man-agement of glaucoma.[1,6,10,11]

Transderm-Nitro� system

In this controlled-release transdermal therapeuticsystem, the drug reservoir, which is a dispersion ofnitroglycerin–lactose triturate in a silicone (medicalgrade) fluid, is encapsulated in an ellipsoid-shaped thinpatch. The drug reservoir is sandwiched between a drug-impermeable metallic plastic laminate, as the backingmembrane, and a constant surface of drug-permeable,rate-controlling membrane of ethylene–vinyl acetatecopolymer (Fig. 6). This device is fabricated by aninjection-molding process. A thin layer of siliconeadhesive is further coated on the drug-permeablemembrane in order that an intimate contact of thedrug-releasing surface with the skin surface is achievedand maintained. It is engineered to have nitroglycerindelivered transdermally at a rate of 0.5 (mg/cm2)/dayfor a daily relief of angina.[2,3]

The same technology has been utilized in the develop-ment of the following: 1) the Estraderm� system, whichadministers a controlled dose of estradiol transdermallyover 3–4 days for the relief of postmenopausal syndromeand osteoporosis;[12–14] 2) the Duragesic� system, whichprovides a transdermal-controlled administration offentanyl, a potent narcotic analgesic, for 72-h reliefof chronic pain;[14] and 3) the Androderm� system,which provides a transdermal-controlled delivery of

00 100

Days

µg/d

ay

200

In Vitro

300 400

20

40

60

80

100

00 100

Days200

In Vivo

300 400

95% Confidence Level

20406080

100

Polyethylene

Ethylene

vinylacetate

copolymer

38 mg of progesterone microcrystals

(and barium sulfate)

suspended in silicone oil

A

B

Fig. 4 Diagrammatic illustration of a unit of ProgestasertIUD, showing various structural components (A) and thein vitro and in vivo delivery rate profiles of progesteronefor up to 400 days (B).

13.4mm

Ethylene/vinyl acetate membrane

Pilocarpine-core reservoir

Titanium dioxide-white ring

305µ74µ

5.7

mm

00 1 2 3

Time (days)

Pil

oca

rpin

e re

leas

e ra

te

(mcg

/hr)

4 5 6 7 8 9

20

40

60

Fig. 5 Diagrammatic illustration of a unit of Ocusert� sys-tem, showing various structural components, and the ocularrelease rate profile of pilocarpine from the Ocusert pilo-20system. (From Ref.[11].)

1084 Drug Delivery: Controlled Release

DrugDelivery

Buccal–Mono

testosterone, through non-scrotal skin, for the 24hreplacement therapy of testosterone-deficient patients.[14]

Norplant� subdermal implant

The controlled-release subdermal implant is fabricatedfrom a non-porous silicone (medical-grade) tubing, bysealing both ends with silicone (medical-grade)adhesive to encapsulate either levonorgestrel crystalsalone (generation I) or a solid dispersion of levonorges-trel in silicone elastomer matrix (generation II). It isdesigned to attain a continuous release of levonorges-trel, at a daily dosage rate of 30 mg, to each subject (fol-lowing the subcutaneous implantation of either 6 unitsof I or 2 units of II); (Fig. 7) for up to 7 years.[15–18]

Polymer Matrix Diffusion-Controlled


In this type of CrDDS, the drug reservoir is producedfrom the homogeneous dispersion of drug particles ineither a lipophilic or a hydrophilic polymer matrix. Thedrug dispersion in the polymer matrix is accomplished

by either 1) blending a dose of finely ground drugparticles with a viscous liquid (or a semisolid) poly-mer, followed by a crosslinking of polymer chainsor 2) mixing drug solids with a melted polymer atan elevated temperature. The resultant drug-polymerdispersion is then molded or extruded to form drug-delivery devices of various shapes and sizes designedfor a specific application (Fig. 8). It can also befabricated by dissolving the drug and the polymer in acommon solvent, followed by solvent evaporation, at anelevated temperature and/or under a vacuum, in a mold.

The release profile of drug from this matrix dif-fusion-controlled CrDDS is not constant, because therate of drug release is time dependent as defined by:

Q

t1=2 ¼ ð2ACRDPÞ1=2

ð2Þ

where A is the initial loading dose of drug dispersed inthe polymer matrix; CR is the drug solubility in thepolymer, which is also the drug reservoir concentrationin the polymer matrix; and Dp is the diffusivity of thedrug molecules in the polymer matrix.

The release of drug molecules from this type ofCrDDSs may be controlled at a preprogrammed rateby controlling the loading level and the polymersolubility of the drug and its diffusivity in the polymermatrix. Several CrDDSs of this type have been suc-cessfully marketed for therapeutical uses, and somerepresentatives are outlined later for illustration.

Nitro-Dur� system

This controlled-release transdermal therapeutic systemis fabricated by first heating an aqueous solution ofwater-soluble polymer, glycerol, and polyvinyl alcoholand then lowering the temperature of the mixture toform a polymer gel. Nitroglycerin/lactose triturate isdispersed in the gel, and the mixture is then solidifiedat room temperature to form a medicated polymer discby a molding and slicing technique. After assemblyonto a drug-impermeable metallic plastic laminate, apatch-type transdermal therapeutic system is producedwith an adhesive rim surrounding the medicated disc(Fig. 9). It is designed for application onto an intactskin to provide a continuous transdermal infusion ofnitroglycerin, at a daily dose of 0.5mg/cm2, for theprevention of angina pectoris.[2,19]

The drug reservoir can also be formulated bydirectly dispersing the drug in an adhesive polymer,such as poly(isobutylene) or poly(acrylate) adhesive,and then spreading the medicated adhesive by solventcasting or hot melt, onto a flat sheet of drug-impermeablebacking support to form a single- or multiple-layer drugreservoir. This type of transdermal CrDDS (TDD)

00 5

Time (h)10 15 20 25

Drug reservoir

Adhesive layer

Rate-controlling

polymeric membrane

Drug-impermeable

metallic plastic laminate

Pla

sma

nit

rog

lyce

rin

co

nc.

(ng

/ml

± S

D)

0.05

0.10

0.15

0.20

0.25

Night Period

Fig. 6 Cross-sectional view of a unit of Transderm-Nitro�

system, showing various structural components, and plasmaconcentration profiles of nitroglycerin in 14 human volunteers,each receiving one unit of Transderm-Nitro system (20 cm2,with a delivery rate of 10mg/day) for 24h. (From Refs.[11,55].)


DrugDelive

ryBucca

l–Mono

is best illustrated by the development and marketingof an isosorbide dinitrate-releasing TDD system,named Frandol� tape, by Toaeiyo/Yamanouchi inJapan, and of a nitroglycerin-releasing TDD system,named Nitro-Dur� II system by Key in the UnitedStates, for once-a-day medication for angina pectoris.This second generation of TDD system (NitroDur II)has also received FDA approval for marketing. Nitro-Dur II compares favorably with Nitro-Dur (Fig. 10)and has gradually replaced the first-generationNitro-Dur from the marketplace. The same technicalbasis has been also utilized in the development ofthe following: 1) Habitrol� and Nicotrol� systems,which provide a controlled dose of nicotine transder-mally over 24h for smoking cessation;[14] 2) Minitran�

system, which administers a controlled dose of nitrogly-cerin transdermally over 24h for the relief of anginalattacks;[14] 3) Testoderm� system, which administers acontrolled delivery of testosterone for transdermal per-meation through a scrotal skin[14] for the replacementtherapy of testosterone-deficient patients for 24h; and4) Climara� system, which provides a controlled

delivery of 17b-estradiol for transdermal permeationfor once-weekly treatment of vasomotor systems[14]

associated with menopause.

Compudose� implant

This controlled-release subdermal implant is fabricatedby dispersing micronized estradiol crystals in a viscousmixture of silicone elastomer and catalyst and thencoating the estradiol-polymer dispersion around a rigid(drug-free) silicone rod by an extrusion technique toform a cylinder-shaped implant (Fig. 11). This implantis designed for subcutaneous implantation in thesteer’s ear flap for a duration of 200 or 400 days, dur-ing which a controlled quantity of estradiol is releaseddaily for growth promotion.[20]

To improve the Q versus t1/2 drug release profiles[Eq. (2)], this polymer matrix diffusion-controlledCrDDS can be modified to have the drug-loadinglevel varied, in an incremental manner, to form a gradi-ent of drug reservoir along the diffusional path in thepolymer matrix. A constant drug release profile is thus

34 mm

2.4 mm

Milligrams Milligrams

total load of levonorgestrel

daily dose 30 µg

Years of use

216

90

70

50

30

10

216

90

70

50

30

10

1 2 3 4 5 6

~~ ~~

Concentration of

Levonorgestrel in plasma

ORAL

1.00

0.75

0.50

0.25

24 hr 1 2 3 4 5

Mean value and

95% confidence

intervals

Time of use (years)

Peak (mean)

Trough (mean)

NONPLANT SUBCERNAL INPLANTS

Fig. 7 Diagrammatic illustration of the subcutaneous implantation of Norplant� implants. The subcutaneous release profile oflevonorgestrel in female volunteers for up to 6 years and the resultant plasma profile as compared to those obtained by oraladministration. (Adapted from Refs.[15–18].)


DrugDelivery

Buccal–Mono

achieved, and the rate of drug release from this drugreservoir gradient-controlled drug delivery system isdefined by:

dQ

dt¼

Ka=rDa

haðtÞCpðhaÞ ð3Þ

in which the time-dependent thickness [ha(t)] of thediffusional path for drug molecules to diffuse through,which is increasing with time, is compensated by theproportional increase in the drug-loading level [Cp(ha)],and a constant drug release profile is thus obtained. Thistype of CrDDS is best illustrated by the nitroglycerin-releasing Deponit� system (Fig. 12), first marketedby Pharma-Schwartz/Lohmann in Europe.[21] Wyeth-Ayerst has received FDA approval for marketing thissystem in the United States.

Furthermore, it was recently demonstrated that therelease of a drug, such as propranolol, from the multila-minate adhesive-based TDD system can be maintainedat zero-order kinetics by controlling the particle sizedistribution of drug crystals in the various laminatesof adhesive matrix.[22]

Polymer (Membrane/Matrix) Hybrid-Type


This type of CrDDS is developed with the objective ofcombining the constant drug release kinetics of poly-mer membrane permeation-controlled drug deliverysystems with the mechanical superiority of polymermatrix diffusion-controlled drug delivery systems.The release profile of drug from a sandwich-type drugdelivery system (Fig. 13) is constant, and the instan-taneous rate of drug release is defined by:

dQ

dt¼

ACpDp

DpKmð1=Pm þ 1=Pd

� �2þ 4ACpDpt

1=2ð4Þ

where A is the initial amount of drug solid impregnatedin a unit volume of polyer matrix with solubility Cp

and diffusivity Dp; Km is the partition coefficient forthe interfacial partitioning of drug molecules frompolymer matrix toward polymer coating membrane;Pm is the permeability coefficient of the polymer coat-ing membrane with thickness hm; and Pd is the per-meability coefficient of the hydrodynamic diffusionlayer with thickness hd.

The hybrid system is exemplified by the develop-ment of clonidine-releasing and scopolamine-releasingtransdermal therapeutic systems (Catapres-TTS�

and Transderm-Scop�) (Fig. 14), in which a rate-controlling non-medicated polymeric membrane isadded to coat the surface of the drug-dispersing poly-mer matrix, and the release of drug molecules thusbecomes controlled by membrane permeation insteadof matrix diffusion. The same technology has beenutilized in the development of levonorgestrel-releasingsubdermal implants (Norplant� II).

Microreservoir Partition-Controlled


In this type of CrDDS, the drug reservoir is a suspen-sion of drug solid particles in an aqueous solution of awater-miscible polymer, like polyethylene glycols. Thisforms a homogeneous dispersion of many discrete,unleachable, microscopic drug reservoirs in a biocom-patible polymer, like silicone elastomers (Fig. 15). Themicrodispersion is achieved by applying a high-energydispersion technique.[13,23] Different shapes and sizes ofdrug-delivery devices can be fabricated from this

CRDp

hd

hp + dhp

Drug reservoir

Receding boundary

depletion zone

Matrix

Diffusion layer

A Elution medium

Perfect sink

C

Drug release

Drug release

Drug depletion

zone

A

Drug reservoir

(Dispersion)

Gel layer

B

Fig. 8 Release of drug from the polymer matrix diffusion-controlled drug delivery systems with drug reservoir existsas a homogeneous dispersion in (A) lipophilic, non-swellablepolymer matrix, with a growing thickness of drug depletionzone, or (B) a hydrophilic, swellable polymer matrix, with agrowing thickness of drug-depleted gel layer. In (C), the drugconcentration gradients across the time-dependent drugdepletion zone, with a growing thickness (hp þ dhp), andthe hydrodynamic diffusion layer, with a controlled thickness(hd), are shown in series.


DrugDelive

ryBucca

l–Mono

microreservoir-type CrDDS by molding or extrusiontechniques. Depending upon the physicochemicalproperties of drugs and the desired rate of drug release,the device can be further coated with a layer of bio-compatible polymer to modify the mechanism andthe rate of drug release.

The rate of drug release (dQ/dt) from this type ofCrDDS is defined by:

dQ

dt¼

DpDdmKp

Dphd þDdhpmKp

� nSp �DlSlð1� nÞ

ht

1

Klþ

1

Km

� ��

ð5Þ

where m ¼ a/b and n is the ratio of drug concen-tration at the inner edge of the interfacial barrier overthe drug solubility in the polymer matrix,[1,6] in which ais the ratio of drug concentration in the bulk of elutionsolution over drug solubility in the same medium and bis the ratio of drug concentration at the outer edge of

the polymer coating membrane over drug solubilityin the same polymer. Kl, Km, and Kp are, respectively,the partition coefficients for the interfacial partitioningof drug from the liquid compartments to the polymermatrix, from the polymer matrix to the polymer coat-ing membrane, and from the polymer coating mem-brane to the elution solution, whereas Dl, Dp, and Dd

are, respectively, the diffusivities of the drug in theliquid layer surrounding the drug particles, the poly-mer coating membrane enveloping the polymer matrix,and the hydrodynamic diffusion layer surrounding thepolymer coating membrane with respective thicknessesof hl, hp, and hd (Fig. 15); and Sl and Sp are the solubi-lities of the drug in the liquid compartments and in thepolymer matrix, respectively.

The release of drug from the microreservoir-typeCrDDS can follow either a dissolution- or a matrixdiffusion-control process, depending upon the relativemagnitude of Sl and Sp.

[24] Representatives of this typeof CrDDS is outlined below.

Night Period

Absorbent pad

Impermeable backing

(polyethylene coverstrip)

Occlusive baseplate

(aluminum foil)

Adhesive rim

(microporous acrylic polymer tape) Drug reservoir

(drug/hydrophilic polymer matrix)

Pla

sma

nit

rog

lyce

rin

co

nc.

(n

g/m

l ±

SE

M)

0.8

0.6

0.4

0.2

00 5 10 15 20 25

Time (h)

off

Fig. 9 Cross-sectional view of a unit of Nitro-Dur� system, showing various structural components, and the plasma nitrogly-cerin concentration profiles in six human volunteers, each receiving 1 unit of Nitro-Dur� system (20 cm2, with a delivery rate of10mg/day) for 24 h. (From Refs.[55–56].)


DrugDelivery

Buccal–Mono

Nitrodisc� system

In this transdermal CrDDS (Fig. 16), the drug reser-voir is a suspension of nitroglycerin/lactose trituratein an aqueous solution of 40% polyethylene glycol400. It is dispersed homogeneously by a high-energymixing technique, with isopropyl palmitate, a skinpermeation enhancer, in a mixture of viscous siliconeelastomer and catalyst.[25] The resultant drug-polymerdispersion is then formed in situ into a solid medicateddisc on a drug-impermeable metallic plastic laminate,with an adhesive rim, by an injection-molding tech-nique and application of an instantaneous heating. Itis engineered to provide a transdermal administrationof nitroglycerin at a daily rate of 0.5mg/cm2 foronce-a-day medication of angina pectoris.[2,26] AQversus t1/2 (matrix diffusion-controlled) release profileis obtained.

Syncro-Mate-C implant

This subdermal controlled-release implant is fabricatedby dispersing the drug reservoir, which is a suspensionof norgestomet in an aqueous solution of PEG 400, ina viscous mixture of silicone elastomers by a high-energy dispersion technique.[24] After adding catalyst,

the suspension is delivered into a silicone medical-gradetubing, which serves as the mold as well as the coatingmembrane, and then polymerized in situ. The polymer-ized drug-polymer composition is then cut into acylinder-shaped implant with its ends staying open(Fig. 17). This tiny cylindrical implant is designed tobe inserted into the subcutaneous tissue of the live-stock’s ear flap; norgestomet is released continuouslyinto the subcutaneous tissue for up to 20 days for thecontrol and synchronization of estrus and ovulationand up to 160 days for growth promotion. A constantQ versus t (dissolution-controlled) release profile hasbeen achieved, as compared to the Q versus t1/2 releaseprofile (matrix diffusion-controlled drug release) forthe Syncro-Mate-B implant and the Nitrodisc systemdiscussed above.

Transdermal contraceptive device

The transdermal contraceptive device is based on apatentable micro-drug-reservoir technique[26] to achieve

Drug-loaded

adhesive

Release liner

Impermeable film

1000

500

250

100

50

25

100 5 10 15 20 25

Time(h)

Nit

rogly

ceri

n (

pg/m

l)

Fig. 10 Cross-sectional view of Nitro-Dur II, showingvarious structural components, and the comparative 24 hplasma nitroglycerin concentration profiles in 24 healthymale volunteers, each receiving randomly 1 unit of Nitro-Dur II (open circle) or Nitro-Dur (closed circle), 20 cm2 each,with a delivery rate of 10mg/day, over the chest for 24 h(the arrow indicates unit removal). (From Ref.[56].) 0

0.2

0.4

0.6

0.8

1.0

0.0

1 2 3 4

(Days)½

Q

(mg

/cm

2)

75%

40%

20%

Silicone rod

Estradiol-releasing

polymer matrix

Fig. 11 Diagrammatic illustration of a unit of Compudose�

subdermal implant and in vitro release profiles of estradiolfrom the implants immersed in aqueous solution containingvarious volume fractions of polyethylene glycol 400.


DrugDelive

ryBucca

l–Mono

a dual-controlled release of levonorgestrel, a potentsynthetic progestin, and estradiol, a natural estrogen,at constant and enhanced rates, continuously, for aperiod of 7 days.[5] By applying 1 unit (10 or 20 cm2)of transdermal contraceptive device per week, beginningon day 5 of an individual’s menstrual cycle, for 3consecutive weeks (3 weeks on and 1 week off), steady-state serum levels of levonorgestrel have been obtained,and the secretion of gonadotropins and progesteronehave been effectively suppressed.

ACTIVATION-MODULATED DRUG

DELIVERY SYSTEMS

In this group of CrDDSs, the release of drug moleculesfrom the delivery systems is activated by some physical,

chemical, or biochemical processes and/or facilitated byan energy supplied externally (Fig. 2). The rate of drugrelease is then controlled by regulating the processapplied or energy input. Based on the nature of theprocess applied or the type of energy used, theseactivation-modulated CrDDSs can be classified intothe following categories:

1. Physical means

a. Osmotic pressure-activated drug deliverysystems

b. Hydrodynamic pressure-activated drugdelivery systems

c. Vapor pressure-activated drug deliverysystems

d. Mechanical force-activated drug deliverysystems

e. Magnetics-activated drug delivery systemsf. Sonophoresis-activated drug delivery systemsg. Iontophoresis-activated drug delivery systemsh. Hydration-activated drug delivery systems

2. Chemical means

a. pH-activated drug delivery systemsb. pH-activated drug delivery systemsc. Ion-activated drug delivery systemsd. Hydrolysis-activated drug delivery systems

3. Biochemical means

a. Enzyme-activated drug delivery systemsb. Biochemical-activated drug delivery systems

Several CrDDSs have been successfully developedand applied clinically to the controlled delivery ofpharmaceuticals and biopharmaceuticals. These areoutlined and discussed below.

Osmotic Pressure-Activated Drug

Delivery Systems

In this type of CrDDSs, the drug reservoir, which canbe either a solution or a solid formulation, is con-tained within a semipermeable housing with a con-trolled water permeability. The drug in solution isreleased through a special laser-drilled delivery orificeat a constant rate under a controlled gradient ofosmotic pressure.

For a solution-type osmotic pressure-activatedCrDDS, the intrinsic rate of drug delivery (Q/t) isdefined by:

Q

t¼

PwAm

hmðps � peÞ ð6Þ

Pla

sma

nit

rog

lyce

rin

co

nc.

(p

g/m

l)

400

200

100

80

60

40

0 4 8 12 16 20 24

Duration of Device/Skin contact (h)

Dose=5.0 ± 0.7 mg/day (n=6)

4.5 ± 0.8 mg/day (n=17)

Cmax = 255 ± 151 pg/ml (tmax = 3.6 ± 3.5 h)

Css = 125 ± 50 pg/ml (8-24 h)

AUC = 3.3 ± 1.6 ng·h/ml

Drug-impermeable

metallic plastic laminate

Drug reservoir

gradient layers

(R1 > R2 > R3)

R1

Adhesive layer

R2

R3

Fig. 12 Cross-sectional view of a unit of Deponit� system,showing various structural components, and the plasmanitroglycerin concentration profiles in six human volunteers,each receiving 1 unit of Deponit system (16 cm2, with a deliv-ery rate of 5mg/day) for 24 h. (Plasma profiles are plottedfrom data from Ref.[21].)


DrugDelivery

Buccal–Mono

For a solid-type osmotic pressure-activated CrDDS,the intrinsic rate of drug delivery should also be aconstant and is defined by:

Q

t¼

PwAm

hmðps � peÞSd ð7Þ

where Pw, Am, and hm are, respectively, the water per-meability, the effective surface area, and the thicknessof the semipermeable housing; (ps � pe) is the differen-tial osmotic pressure between the drug-delivery systemwith an osmotic pressure of ps and the environment

Sphere

Cylinder

Perfect sink

(Cb = 0)

Dp Dm

pm

Dd

pd

A

CR

hp(t) hm hd

Drug

reservoir

Polymer matrix Drug

depletion

zone

Polymer

coating

membrane

Diffusion

layer

Solution

bulk

Fig. 13 The controlled release of drug molecules from a (membrane-matrix) hybrid-type drug delivery system in which soliddrug is homogeneously dispersed in a polymer matrix, which is then encapsulated inside a polymeric membrane, where D, P,and h are the diffusivity, permeability, and thickness, respectively, and the subscripts p, m, and d denote the drug depletion zonein the polymer matrix, polymer coating membrane, and diffusion layer, respectively.

DRUG MOLECULES

MIC

RO

PO

RO

US

ME

MB

RA

NE

DRUG-IMPERMEABLE

BACKING LAMINATE

DR

UG

-DIS

PE

RS

ING

AD

HE

SIV

E

LA

YE

RS

Fig. 14 Cross-section view of various structural componentsin the Transderm-Scop� and Catapres-TTS� systems.


DrugDelive

ryBucca

l–Mono

with an osmotic pressure of pe; and Sd is the aqueoussolubility of the drug component in the solid reservoir.

The release of drug molecules from this type ofCrDDS is activated by osmotic pressure and controlledat a rate determined by the water permeability and the

effective surface area of the semipermeable housing aswell as the osmotic pressure gradient. Several CrDDSsof this type have been successfully marketed for thera-peutical uses and some representatives are outlinedlater.

Dp

Polymer matrix

Interfacial

barrier

Liquid

layer

Drug

particle

Dl

Sl Cl

Cp

Cm'

Cd

Cb = O

Solution

sinkCp

Dm

Polymer

coating

membrane

Diffusion

layer

δmδl δd

Ds

Cm

Polymer matrix

(cross-linked, solid)

Drug reservoir

(microscopic liquid

compartments)

Coating membrane

Polymer/Solution interface

'Cp'

Fig. 15 Microscopic view of a microreservoir-type drug-delivery system, which shows the microscopic structure of various com-ponents, and the physical model developed for the mechanistic analysis of the controlled release of drug. (Adapted from Refs.[1,57].)


DrugDelivery

Buccal–Mono

Alzet osmotic pump

In this implantable or insertable CrDDS, the drug res-ervoir, which is normally a solution formulation, iscontained within a collapsible, impermeable polyesterbag whose external surface is coated with a layer ofosmotically active salt, for example, sodium chloride.This reservoir compartment is then totally sealed insidea rigid housing walled with a semipermeable mem-brane (Fig. 19). At an implantation site, the watercontent in the tissue fluid will penetrate through thesemipermeable membrane at a controlled rate anddissolve the osmotically active salt. This creates anosmotic pressure in the narrow spacing between theflexible reservoir wall and the rigid semipermeablehousing. Under the osmotic pressure created [Eq. (6)],the reservoir compartment is thus reduced in volumeand the drug solution is forced to release through theflow moderator at a controlled rate.[27,28] By varyingthe drug concentration in the solution, different dosesof drug can be delivered at a constant rate for a periodof 1–4 weeks.

In addition to its application in the subcutaneouscontrolled administration of drugs for pharmacologi-cal studies, this technology has recently been extendedto the controlled administration of drugs in the rectumby zero-order kinetics. The hepatic first-pass metab-olism of drugs is thus bypassed.[29]

Acutrim� tablet

In this oral CrDDS, the drug reservoir, which is a solidtablet of water-soluble and osmotically-active phenyl-propanolamine (PPA) HCl, is enclosed within a semi-permeable membrane of cellulose triacetate.[2,30] Thesurface of the semipermeable membrane is furthercoated with a thin layer of immediately releasablePPA dose (Fig. 20). In the alimentary tract, the gastro-intestinal fluid will dissolve away the immediate releaselayer of PPA to provide an initial dose of PPA andthen penetrate through the semipermeable membraneto dissolve the sustained-release dose of PPA. Underthe osmotic pressure created [Eq. (7)], the PPA solutionis released continuously at a controlled rate, throughan orifice pre-drilled by a laser beam.[2,30,31] It isdesigned to provide a controlled delivery of PPA overa duration of 16 h for appetite suppression in a weight-control program.[31] The same delivery system hasalso been utilized for the oral controlled delivery ofindomethacin. An extension of this technology is thedevelopment of a push-pull type osmotic pressure-activated CrDDS for the oral controlled delivery ofnifedipine and metroprolol.[27] It has been furtherextended to the delayed-onset and controlled oraldelivery of verapamil[14] to produce a maximumplasma concentration in the morning hours.

Occlusive baseplate

(aluminum foil disc)

Adhesive foam pad

(flexible polyurethane)

Adhesive rim

(acrylic polymer coating)

Microscopic drug reservoirs

(drug/co-solvents)

Polymer matrix

(silicone elastomer)

0.0

0.1

0 4 8 12

Time (h)

Pla

sma

nit

rog

lyce

rin

con

c. (

ng

/ml±

SE

M)

16 20 24 28 32

0.2

0.3

0.4

0.5

0.6

Night Period

(C plasma)ss

Fig. 16 Cross-sectional view of a unit of Nitrodisc� system,showing various structural components, and the plasmanitroglycerin concentration profiles in 12 human volunteers,each receiving 1 unit of Nitrodisc system (16 cm2, with adelivery rate of 10mg/day) for 32 h. (From Ref.[23].)

Medicated MDD core

Drug

reservoirPolymer coating

membrane

Open ends

Days of implantation

Fra

ctio

n o

f d

rug

rel

ease

d (

%)

00 5 10 15 20 25 30

20

40

60

80

100

Fig. 17 Syncro-Mate-C implant, a subdermal implant fabri-cated from the microreservoir dissolution-controlled drug-delivery system, and subcutaneous controlled release of nor-gestomet, a potent synthetic progestin, at constant rate for 20days. The open ends on the implant do not affect the zero-order in vivo drug release profile. (Adapted from Ref.[57].)


DrugDelive

ryBucca

l–Mono

Hydrodynamic Pressure-Activated


In addition to the osmotic pressure systems discussedabove, hydrodynamic pressure has also been exploredas the potential source of energy to modulate the deliv-ery of therapeutic agents.[2]

A hydrodynamic pressure-activated drug-deliverysystem can be fabricated by placing a liquid drug for-mulation inside a collapsible, impermeable containerto form a drug reservoir compartment. This is thencontained inside a rigid, shape-retaining housing. Alaminate of an absorbent layer and a swellable,

hydrophilic polymer layer is sandwiched between thedrug reservoir compartment and the housing. In thegastrointestinal tract, the laminate will imbibe the gas-trointestinal fluid through the annular openings at thelower end of the housing and become swollen. Thisgenerates a hydrodynamic pressure in the system.The hydrodynamic pressure, thus created, forces thedrug reservoir compartment to reduce in volume andcauses the liquid drug formulation to release throughthe delivery orifice.[32] The drug release rate isdefined by:

Q

t¼

PfAm

hmðys � yeÞ ð8Þ

where Pf, Am, and hm are the fluid permeability, theeffective surface area, and the thickness of the wallwith annular openings, respectively; and ys � ye, isthe difference in hydrodynamic pressure between thedrug delivery system (ys) and the environment (ye).

The release of drug molecules from this type ofCrDDS is activated by hydrodynamic pressure andcontrolled at a rate determined by the fluid per-meability and effective surface area of the wall withannular openings as well as by the hydrodynamicpressure gradient.

Vapor Pressure-Activated


In this type of CrDDS, the drug reservoir, which is asolution formulation, is contained inside the infusioncompartment. It is physically separated from thepumping compartment by a freely movable partition(Fig. 21). The pumping compartment contains a vapor-izable fluid, such as fluorocarbon, which vaporizes atbody temperature and creates a vapor pressure. Underthe vapor pressure created, the partition moves upwardand forces the drug solution in the infusion compart-ment to be delivered, through a series of flow regulatorand delivery cannula, into the blood circulation at aconstant flow rate.[1,6,33] The process is defined by:

Q

t¼

d4dP

40:74mlð9Þ

where d and l are, respectively, the inner diameter andthelength of the delivery cannula; Dp is the pressuredifference between the vapor pressure in the pumpingcompartment and the pressure at the implantation site;and m is the viscosity of the drug formulation.

The delivery of drug from this type of CrDDS isactivated by vapor pressure and controlled at a ratedetermined by the differential vapor pressure, the for-mulation viscosity, and the size of the delivery cannula.

00 10 20 30 40

5

10

15

Ser

um

pro

ges

tero

ne

(ng

/ml)

20

25

30Subject Code MM

(Group A: 1 TCD patch)

Pretreatment

Treatment

Tmax

Tmax

0 10

Day of menstrual cycle

20 30 40

Subject Code MG

(Group B: 2 TCD patch)

Pretreatment

Treatment

B

0

m

0 168 336 504 672

48

96

Co

nce

ntr

atio

n (

pg

/ml

± S

.E.)

144

192

240

288

10 Sq. cm - Patch (n=6)

20 Sq. cm - Patch (n=6)

mm mm

Duration of study (h)

m p p

A

Fig. 18 (Upper panel) The 4–week serum levonorgestrelprofiles in 12 human volunteers, each receiving 1 or 2 unitsof a transdermal contraceptive system (10 cm2, with dailydosage of 28.3mg/day) once a week, consecutively for 3weeks, and the same size of placebo on week 4. (Lower panel)Comparative serum concentration profiles of progesteroneduring the pretreatment and treatment cycles in two subjects,each as the representative for group A (receiving 10 cm2) andgroup B (receiving 20 cm2), respectively. The suppression ofprogesterone peak during the treatment cycle is an indicationof effective fertility control.


DrugDelivery

Buccal–Mono

A typical example is the development of Infusaid�,an implantable infusion pump by Metal Bellows, forthe constant infusion of heparin in anticoagulationtreatment,[34] of insulin in the normoglycermic controlof diabetics,[33] and of morphine for patients sufferingfrom the intensive pain of a terminal cancer.[35]

Mechanical Force-Activated


In this type of CrDDS, the drug reservoir is a solutionformulation in a container equipped with a mechani-cally activated pumping system. A metered dose ofdrug formulation can be reproducibly delivered intoa body cavity, such as the nose, through the spray headupon manual activation of the drug-delivery pumpingsystem. The volume of solution delivered is fixed andis independent of the force and duration of activation.

A typical example of this type of drug-delivery sys-tem is the development of a metered-dose nebulizer forthe intranasal administration of a precision dose ofluteinizing hormone-releasing hormone (LHRH) and

its synthetic analogs, such as buserelin. Through nasalabsorption, the hepatic first-pass elimination of thesepeptide drugs is thus avoided.[24]

Magnetic-Activated Drug Delivery Systems

Macromolecular drugs, such as peptides, have beenknown to release only at a relatively low rate from apolymer-controlled drug-delivery system. This low rateof release can be improved by incorporating an electro-magnetism-triggering vibration mechanism into thepolymeric delivery device. With a hemispheric-shapeddesign, a zero-order drug-release profile is achieved.[36]

By combining these two approaches, a subdermallyimplantable, magnetic-activated hemispheric drug-delivery device is developed. It is fabricated by firstpositioning a tiny doughnut-shaped magnet at the cen-ter of a drug-dispersing biocompatible polymer matrixand then coating the external surface of the medicatedpolymer matrix, with the exception of one cavity at thecenter of the flat surface, with a pure polymer, forinstance, ethylene–vinyl acetate copolymer or silicone

0

Urine volume

Pump

implanted

Pump

removed

25

50

75

100

125

150

Dai

ly u

rin

e v

olu

me

(% o

f P

retr

eatm

ent

con

tro

l +

S.D

.)

175

200

00

Urine osmolality

Pump

implantedPump

removed

3 6

Time (day)

9 12 15

0 3 6 9 12 15

500

1000

1500

2000

Uri

ne

osm

ola

lilt

y

(mO

sm/

kg

H2O

+ S

.D.)

2500

3000

Drug solution leaving

via delivery portal

Removable cap

Flange

Flow moderator

Neck Plug

Flexible impermeable

reservoir wall

Semipermeable

membrane

Water entering

semipermeable

membrane

Reservoir

Osmotic agent

A B

Fig. 19 (A) Cross-sectional view of the Alzet� osmotic pump, an osmotic pressure-activated drug-delivery system. (B) The effectof 7 days of subcutaneous delivery of antidiuretic hormone (vasopressin) on the daily volume of urinary excretion and urineosmolality in the Brattleboro rats with diabetes insipidus.


DrugDelive

ryBucca

l–Mono

elastomers. This uncoated cavity is designed for allow-ing a peptide drug to release.

The hemispheric magnetic delivery device producedcan release macromolecular drugs, like bovine serumalbumin, at a low basal rate, by diffusion process, andunder a non-triggering condition, or it can release thesame drug at amuch higher rate, when themagnet is acti-vated, to vibrate by an external electromagnetic field.

Sonophoresis-Activated Drug

Delivery Systems

This type of activation-controlled drug delivery systemutilizes ultrasonic energy to activate (or trigger) thedelivery of drugs from a polymeric drug deliverydevice. The system can be fabricated from either anon-degradable polymer, such as ethylene–vinyl acet-ate copolymer, or a bioerodible polymer, such as poly[bis(p-carboxyphenoxy)alkane anhydride].[37] Thepotential application of sonophoresis (or phonophor-esis) to regulate the delivery of drugs was recentlyreviewed.[38]

Iontophoresis-Activated Drug

Delivery Systems

This type of CrDDS use electrical current to activateand to modulate the diffusion of a charged drug

molecule across a biological membrane, such as theskin, in a manner similar to passive diffusion under aconcentration gradient but at a much facilitated rate.The iontophoresis-facilitated skin permeation rate ofa charged molecule i consists of three componentsand is expressed by:

Jispi ¼ Jp þ Je þ Jc

¼ KsDsdC

hs

� �

ZiDiFi

RTCi

dE

hs

� �

þ ðkCsIdÞ ð10Þ

where J p, J e, and J c represent, respectively, the flux forthe skin permeation by passive diffusion, for the elec-trical current-driven permeation, and for the convec-tive flow-driven skin permeation; Ks is the partitioncoefficient for interfacial partitioning from the donorsolution to the stratum comeum; Ds and Di are,respectively, the diffusivity across the skin and thediffusivity of ionic species i in the skin; Ci and Cs are,respectively, the donor concentration of ionic species iand the concentration in the skin tissue; dE/hs is theelectrical potential gradient across the skin; dC/hs isthe concentration gradientacross the skin; Zi is theelectrical valence of ionic species i; Id is thecurrentdensity applied; F, k, and R are, respectively, the fara-day, proportionality, and gas constant; and T is theabsolute temperature.

A typical example of this type of activation-controlled CrDDS is the development of an iontophore-tic drug delivery system, named Phoresor by MotionControl, to facilitate the percutaneous penetration ofantiinflammatory drugs, such as dexamethasone sodiumphosphate,[39–41] to surface tissues.

Further development of the iontophoresis-activateddrug delivery technique has yielded a new design ofiontophoretic drug delivery system—the transdermalperiodic iontotherapeutic system (TPIS). This new sys-tem, which is capable of delivering a physiologically-acceptable pulsed direct current, in a periodic manner,with a special combination of waveform, intensity, fre-quency, and on/off ratio, for a specific duration, hassignificantly improved the efficiency of transdermaldelivery of peptide and protein drugs.[4] A typicalexample is the iontophoretic transdermal delivery ofinsulin, a protein drug, in the control of hyperglycemiain diabetic animals.

Hydration-Activated Drug Delivery Systems

In this type of CrDDS, the drug reservoir is homoge-neously dispersed in a swellable polymer matrix fabri-cated from a hydrophilic polymer. The release of drugis activated and modulated by hydration-induced

Drug reservoir/

osmotically active

solutes

Controlled-release

dose

Delivery orifice

Semi-permeable coating

Immediate releasing layer

(initial dose)

04 8 12

Time (h)16 20 24

20

40

60

Cu

mu

lati

ve

% l

oad

ing

do

se r

elea

sed

80

100 12.16 atm

30.16 atm

54.16 atm

114.0 atm

Fig. 20 Cross-sectional view of a unit of Acutrim� tablet, asolid-type osmotic pressure-activated drug delivery system,and the effect of increased osmotic pressure in the dissolutionmedium on the release profiles of phenylpropanolamine HClfrom the Acutrim tablet at intestinal condition. (Adaptedfrom Refs.[31,58].)


DrugDelivery

Buccal–Mono

swelling of the polymer matrix. Representatives of thistype of CrDDS are outlined below.

Syncro-Male-B implant

This subcutaneous CrDDS is fabricated by dissolvingnorgestomet, a potent progestin for estrus synchro-nization, in an alcoholic solution of linear ethyleneglycomethacrylate polymer (Hydron S). The drug-polymer mixture is then cross-linked by addingethylene dimethacrylate, in the presence of an oxidizingcatalyst, to form a cylinder-shaped subdermallyimplantable implant.[1,6] This tiny subdermal implantcan be activated by tissue fluid to swell and can be

engineered to deliver norgestomet, at a rate of504 mg/cm2/day1/2, in the subcutaneous tissue for upto 16 days for the control and synchronization ofestrus in livestock.[13]

Valrelease� tablet

This oral CrDDS is prepared by granulating Valium, anantidepression drug, with hydrocolloids (20–75 wt%)and pharmaceutical excipients. The granules are thencompressed to form an oral tablet. After oral intake,the hydrocolloids absorb the gastric fluid and areactivated to form a colloid gel matrix surrounding thetablet surface (Fig. 22). The release of Valium molecules

Infusate

chamber

Empty

weight = 181g

2.4 cm

Bacterial

filter

assembly

Inlet

septumNeedle stop

Flow

regulator

Silicone

polymer

coating

Bellows

8.6 cm

Fluorocarbon

fluid

chamber

Fluorocarbon

fluid

filling tube

00 8 16 24 32 40 48 56

200

400

600

800

1000

Do

se u

nit

s/k

g p

er d

ay

0

200

400

600

800

1000A

Pump

implanted

n = 7

n = 25

Weeks of infusion

B

Fig. 21 Cross-sectional view of a unit of Infusaid� system, a vapor pressure-activated drug-delivery system, and daily heparindose (mean � S.E.) delivered to 25 dogs for 6 months and to 7 dogs for 12 months. (Adapted from Ref.[34].)


DrugDelive

ryBucca

l–Mono

is then controlled by diffusion through the gel barrier,while the tablet remains buoyant in the stomach, dueto a density difference between the gastric fluid(d > 1) and the gelling tablet (d < 1).[2,3]

pH-Activated Drug Delivery Systems

For a drug labile to gastric fluid or irritating to gastricmucosa, this type of CrDDS has been developed to tar-get the delivery of the drug only in the intestinal tract,not in the stomach.[2] It is fabricated by coating a coretablet ofthe gastric fluid-sensitive drug with a combi-nation of intestinal fluid-insoluble polymer, like ethylcellulose, and intestinal fluid-soluble polymer, likehydroxylmethyl cellulose phthalate (Fig. 23).

In the stomach, the coating membrane resists thedegrading action of gastric fluid (pH <3), and the drugmolecules are thus protected from the acidic degradation.After gastric emptying, the CrDDS travels to the small

intestine, and the intestinal fluid-soluble componentin the coating membrane is dissolved away by theintestinal fluid (pH >7.5). This produces a micropor-ous membrane of intestinal fluid-insoluble polymerto control the release of drug from the core tablet.The drug is thus delivered in a controlled manner inthe intestine by a combination of drug dissolutionin the core and diffusion through the pore channels.By adjusting the ratio of the intestinal fluid-solublepolymer to the intestinal fluid-insoluble polymer inthe membrane, the rate of drug delivery can be regu-lated. Representative application of this type of CrDDSis in the oral controlled delivery of potassium chloride,which is highly irritating to gastric epithelium.

Ion-Activated Drug Delivery Systems

For controlling the delivery of an ionic or an ionizabledrug, this type of CrDDS has been developed.[2]

Because the gastrointestinal fluid has regularly main-tained a relatively constant level of ions, the deliveryof drug by this type of CrDDS can be modulated, the-oretically, at a constant rate.

Such a CrDDS is prepared by first complexing anionizable drug with an ion-exchange resin, such as

Hydrocolloids

(20–75% w/w)

Gastric fluid (d>1)

d<1

Colloid gel barrier

1000 1

Time (h)

Rad

ioac

tiv

ity

in

sto

mac

h

Valium

(Placebo)

Valrelease(Placebo)

2 3 4 5 6

200

400

600

800

1000

2000

A

B

Fig. 22 (A) Schematic illustration of Valrelease� tablet, aswelling-activated drug-delivery system, and the hydration-induced formation of colloid gel barrier. (B) Comparison inthe gastric residence profile between Valrelease with theconventional Valium capsule. (From Ref.[58].)

Coating of

Microporous membrane

of intestinal fluid-

insoluble polymer

Gastric emptying

(pH < 3)

Stomach

Intestinal fluid

(pH > 7.5)

Drug

Gastric fluid-

labile drug

Gastric fluid-

labile drug

Intestinal fluid-insoluble polymer

Intestinal fluid-soluble polymer

Fig. 23 Schematic illustration of a pH-activated drug-delivery system and the pH-dependent formation of micro-porous membrane in the intestinal tract.


DrugDelivery

Buccal–Mono

complexing a cationic drug with a resin containingSO3

� group or an anionic drug with a resin containingN(CH3)3

þ group. The granules of the drug–resin com-plex are further treated with an impregnating agent,like polyethylene glycol 4000, for reducing the rate ofswelling upon contact with an aqueous medium. Theyare then coated by an air-suspension coating techniquewith a water-insoluble but water-permeable polymericmembrane, such as ethylcellulose. This membraneserves as a rate-controlling barrier to modulate therelease of drug from the CrDDS. In the GI tract,hydronium and chloride ions diffuse into the CrDDSand interact with the drug–resin complex to triggerthe dissociation and release of ionic drug (Fig. 24).

This type of CrDDS is exemplified by the devel-opment of Pennkinetic� system (by Pennwalt Phar-maceuticals), which permits the formulation of oralliquid-type dosage forms with sustained release of acombination of hydrocodone and chlorpheniramine(Tussionex�).[14,42–44]

Hydrolysis-Activated Drug

Delivery Systems

This type of CrDDS depends on the hydrolysis processto activate the release of drug molecules. In this sys-tem, the drug reservoir is either encapsulated in micro-capsules or homogeneously dispersed in microspheresor nanoparticles. It can also be fabricated as animplantable device. All these systems are preparedfrom a bioerodible or biodegradable polymer, such aspolylactide, poly(lactide–glycolide) copolymer, poly(orthoester), or poly(anhydride). The release of a drugfrom the polymer matrix is activated by the hydrolysis-induced degradation of polymer chains, and the rate ofdrug delivery is controlled by polymer degradationrate.[45] A typical example is the development ofLupron Depot�, an injectable microspheres for thesubcutaneous controlled delivery of luprolide, a potentbiosynthetic analog of gonadotropin-releasing hormone(GnRH) for the treatment of gonadotropin-dependentcancers, such as prostate carcinoma inmen and endome-triosis in the females, for up to 4 months. Anotherexample is the development of Zoladex� system, animplantable cylinder for the subcutaneous controlleddelivery of goserelin, also a potent biosynthetic analogof GnRH for the treatment of patients with prostatecancer (Fig. 25) for up to 3 months.[14]

Enzyme-Activated Drug Delivery Systems

In this type of CrDDS, the drug reservoir is either phys-ically entrapped in microspheres or chemically boundto polymer chains fabricated from biopolymers, suchas albumins or polypeptides. The release of drugs is

made possible by the enzymatic hydrolysis of biopoly-mers by a specific enzyme in the target tissue.[46–48] Atypical example is the development of albumin micro-spheres, which release 5-fluorouracil, in a controlledmanner, by protease-activated biodegradation.

FEEDBACK-REGULATED DRUG

DELIVERY SYSTEMS

In this group of CrDDSs, the release of drug moleculesis activated by a triggering agent, such as a biochemicalsubstance, in the body via some feedback mechanisms(Fig. 2). The rate of drug release is regulated by the con-centration of a triggering agent detected by a sensorbuilt into the CrDDS.

Bioerosion-Regulated Drug

Delivery Systems

The feedback-regulated drug delivery concept has beenapplied to the development of a bioerosion-regulatedCrDDS by Heller and Trescony.[49] This CrDDS con-sists of a drug-dispersed bioerodible matrix fabricatedfrom poly(vinyl methyl ether) half-ester, which wascoated with a layer of immobilized urease (Fig. 26).In a solution with near neutral pH, the polymer onlyerodes very slowly. In the presence of urea, urease at

BloodGut wall

Polymer

Drug

IonCoating

membrane

Drug-resin complex particles

Polyethylene glycol treatment

Ethyl cellulose coating

Drug+Resin – SO3–

Resin [N(CH3)3+ ]Drug–

H+ + Resin – SO3– Drug+ Resin–SO3

– H+ + Drug+

CI – +Resin [N(CH3)3+ ] Drug – Resin [N(CH3)3

+ ] CI – +Drug–

Fig. 24 Cross-sectional view of an ion-activated drug-delivery system, showing various structural components,and diagrammatic illustration of ion-activated drug release.(Adapted from Ref.[58].)


DrugDelive

ryBucca

l–Mono

the surface of the drug delivery system metabolizesurea to form ammonia. This causes the pH to increaseand activates a rapid degradation of polymer matrix aswell as the release of drug molecules.

Bioresponsive Drug Delivery Systems

The feedback-regulated drug delivery concept has alsobeen applied to the development of a bioresponsiveCrDDS by Horbett et al.[50]. In this CrDDS, the drugreservoir is contained in a device enclosed by a biore-sponsive polymeric membrane whose permeability todrug molecules is controlled by the concentration ofa biochemical agent in the tissue where the CrDDS islocated.

A typical example of this bioresponsive CrDDS isthe development of a glucose-triggered insulin deliverysystem, in which the insulin reservoir is encapsulatedwithin a hydrogel membrane containing pendantNR2 groups (Fig. 27). In an alkaline solution, theNR2 groups exist at neutral state and the membraneis unswollen and thus impermeable to insulin. Asglucose penetrates into the membrane, it is oxidizedenzymatically by the glucose oxidase entrapped in themembrane to form gluconic acid. This process triggersthe protonation of NR2 groups to form NR2H

þ, andthe hydrogel membrane becomes swollen and is thuspermeable to insulin molecules (Fig. 27). The amountof insulin delivered is bioresponsive to the concen-tration of glucose penetrating into the CrDDS.

Self-Regulating Drug Delivery Systems

This type of feedback-regulated CrDDS depends on areversible and competitive binding mechanism to acti-vate and to regulate the release of drug. In this CrDDS,the drug reservoir is a drug complex encapsulatedwithin a semipermeable polymeric membrane. Therelease of drug from the CrDDS is activated by themembrane permeation of a biochemical agent fromthe tissue where the CrDDS is located.

Kim et al. first applied the mechanism of reversiblebinding of sugar molecules with lectin into the designof self-regulating CrDDS.[51] For this CrDDS, a biolo-gically-active insulin derivative, in which insulin iscoupled with a sugar (e.g., maltose), was first preparedand then conjugated with lectin to form an insulin–sugar–lectin complex. The complex is then encapsu-lated within a semipermeable membrane to produceCrDDS. As blood glucose diffuses into the CrDDS, itbinds, competitively, with the binding sites in the lectin

Drug-dispersed

polymer matrix

Hydrolytic erosion

goserelin

Glp His Trp Ser Tyr Leu Arg Pro

t-Bu

NHAzgly(D)Ser

MicroporesPhase I: surface erosion

Phase II: bulk erosion

0

0

Weeks

Ser

um

LH

(lU

/L)

4 8 12

20

40

0

0

Weeks

Ser

um

Tes

tost

erone

(nm

ol/

L)

4 8 12

15

30

Fig. 25 Amino acid sequence of goserelin, a biosyntheticanalog of gonadotropin-releasing hormone, and the effectof subcutaneous controlled release of goserelin from the bio-degradable poly(lactide-glycolide) implant on the serumlevels of luteinizing hormone and testosterone.

u

Hydrocortisone

u

Poly (vinyl methyl ether) half-ester

(monolithic matrix)

Urease

(Immobilized)

u

u

u

u

u

u u

urea

polymer

Hydrocortisone

erosionalkaline

pH

2NH4 + HCO3 + OH–urease

H2O

u u u

u u u u

00 20

Time (h)

Hydro

cort

isone

rele

ased

(%

)

40

urea (0.1M)

60 80 100 120 140 160

20

40

60

80

100

+ −

Fig. 26 Cross-sectional view of a bioerosion-regulatedhydrocortisone delivery system, a feedback-regulated drugdelivery system, showing the drug-dispersed monolithicbioerodible polymer matrix with surface-immobilizedureases. The mechanism of release and time course for theurea-activated release of hydrocortisone are also shown.(From Ref.[49].)


DrugDelivery

Buccal–Mono

molecules and activates the release of the insulin–sugarderivatives from the binding sites. The released insulin-sugar derivatives diffuse out of the CrDDS, and theamount of insulin-sugar derivatives released dependson the concentration of glucose. Thus, a self-regulatingdrug delivery is achieved. However, a potential prob-lem has remained to be resolved: that is, the releaseof insulin is non-linear in response to the changes inglucose level.[52]

Further development of the self-regulating insulindelivery system has utilized the complex of glycosy-lated insulin–concanavalin A, which is encapsulatedinside a polymer membrane.[53] As glucose penetratesinto the system, it activates the release of glycosylatedinsulin from the complex for a controlled release fromthe system (Fig. 28). The amount of insulin released isthus self-regulated by the concentration of glucose thathas penetrated into the insulin delivery system.

SITE-TARGETING DRUG DELIVERY SYSTEMS

Delivery of a drug to a target tissue that needs medi-cation is known to be a complex process that consists

of multiple steps of diffusion and partitioning. TheCrDDSs outlined above generally address only the firststep of this complex process. Essentially, theseCrDDSs have been designed to control the rate of drugrelease from the delivery systems, but the path for thetransport of drug molecules from the delivery systemto the target tissue remains largely uncontrolled.

Ideally, the path of drug transport should also beunder control. Then, the ultimate goal of optimal treat-ment with maximal safety can be achieved. This can bereasonably accomplished by the development of aCrDDS with a site-targeting specificity (Fig. 2). Anideal site-targeting CrDDS has been proposed byRingsdorf.[54] A model, which is shown in Fig. 29, isconstructed from a non-immunogenic and biodegrad-able polymer and acts as the backbone to contain threetypes of attachments: 1) a site-specific targeting moiety,which is capable of leading the drug delivery system tothe vicinity of a target tissue (or cell); 2) a solubilizer,which enables the drug delivery system to be trans-ported to and preferentially taken up by a target tissue;and 3) a drug moiety, which is convalently bonded tothe backbone, through a spacer, and contains a linkagethat is cleavable only by a specific enzyme(s) at thetarget tissue.

N

N

.. ......

..........

...

................

.

. . ... ...... ...... .

...... ....

....... .......

...

..

NR2

NR2NR2

Amine-containing

hydrogel membrane

Insulin

reservoir

Glucose oxidase

Glucose

Glucose

Hydrogel membrane swells

H

H

H

H

H

Swollen membrane

Insulin

Enzyme

H

Acidic pH

+

Gluconic acidOxidase

–NR2 –N R2H

NR2

N R2

NR2

+

N R2+

N R2+

R2

+

N R2+

+

Fig. 27 Cross-sectional view of a bioresponsive insulindelivery system, a feedback-regulated drug delivery system,showing the glucose oxidase-entrapped hydrogel membraneconstructed from amine-containing hydrophilic polymer.The mechanism of insulin release, in response to the influxof glucose, is also illustrated. (From Ref.[50].)

+

(Biochemical Approach)

Concanavalin A Glycosylated (G) insulin

Glucose in

Pancreatectomized dogs

100

9am 3pm 9pm 3am 9am 3am 9pm

Time of day

Blo

od g

luco

se l

evel

(m

g/d

l)

200

300

F F F F F F = Feeding

Normoglycemic

level

G-Insulin out

Polymer

membrane

Self-Regulating Insulin Delivery Systems

Fig. 28 Various components of a self-regulating insulindelivery system, a feedback-regulated drug delivery system,and its control of blood glucose level in the pancreatecto-mized dogs. (From Ref.[53].)


DrugDelive

ryBucca

l–Mono

Unfortunately, this ideal site-targeting CrDDS isonly in the conceptual stage. Its construction remainslargely unresolved and is still a challenging task inthe biomedical and pharmaceutical sciences.

CONCLUSIONS

The controlled-release drug delivery systems outlinedhere have been steadily introduced into the biomedicalcommunity since the middle of the 1970s. There is agrowing belief that many more of the conventionaldrug delivery systems we have been using for decadeswill be gradually replaced in the coming years by theseCrDDSs.

REFERENCES

1. Chien, Y.W. Novel Drug Delivery Systems: Fundamental,Developmental Concepts and Biomedical Assessments;Marcel Dekker, Inc.: New York, 1982.

2. Chien, Y.W. Industrial Pharmaceutical R&D SymposiumonTransdermalControlledReleaseMedication. Piscataway,New Jersey, Jan 14&15, 1982; Rutgers University, College ofPharmacy, Proceedings Published in Drug Develop. & Ind.Pharm. 1983; 9, 497–744.

3. Chien, Y.W. Industrial Pharmaceutical R&D Symposiumon Oral Controlled Drug Administrations. Piscataway,New Jersey, Jan 19&20, 1983; Rutgers University, College

of Pharmacy, Proceedings Published in Drug Develop. &Ind. Pharm. 1983; 9, 1077–1396.

4. Chien, Y.W. International Pharmaceutical R&DSymposium on Advances in Transdermal Controlled DrugAdministration for Systemic Medication. Piscataway, NewJersey, June 20&21, 1985; Rutgers University, College ofPharmacy, Proceedings Published in Transdermal ControlledSystemicMedications; Chien, Y.W., Ed.;Marcel Dekker, Inc.:New York, 1987.

5. Chien, Y.W. Rate-control drug delivery systems: controlledrelease vs. sustained release. Med. Prog. Technol. 1989,15 (1–2), 21–46.

6. Chien, Y.W. Novel Drug Delivery Systems: Second Edition,Revised and Expanded; Marcel Dekker, Inc.: New York,1992.

7. Luukkainen, T.; Allonen, H.; Haukkamaa, M.;Lahteenmaki, P.; Nilsson, C.G.; Toivonen, J. Five years’experience with levonorgestrel-releasing IUDs. Contracep-tion 1986, 33 (2), 139–148.

8. Andersson, K.; Odlind, V.; Rybo, G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during fiveyears of use: a randomized comparative trial. Contracep-tion 1994, 49 (1), 56–72.

9. Sivin, I.; Stern, J. Health during prolonged use of levonor-gestrel 20 micrograms/d and the copper TCu 380Agintrauterine contraceptive devices: a multicenter study.International committee for contraception research(ICCR). Fertil. Steril. 1994, 61 (1), 70–77.

10. Robinson, J.R. Sustained and Controlled Release DrugDelivery Systems; Marcel Dekker, Inc.: New York, 1978.

11. Baker, R.W.; Lonsdale, H.K. Controlled delivery—anemerging use for membranes. Chemtech. 1975, 5, 668.

12. Chien, Y.W. Methods to achieve sustained drug delivery.The physical approach: implants. In Sustained and Con-trolled Release Drug Delivery Systems; Robinson, J.R.,Ed.; Marcel Dekker, Inc.: New York, 1978.

13. Chien, Y.W. Microsealed Pharmaceutical Delivery Device.US Patent 3,992,518, Nov 16, 1976.

14. Physicians’ Desk Reference, 53rd Ed.; Medical EconomicsCompany. Montvale, 1999.

15. Segal, S.J. The development of NORPLANT implants.Stud. Fam. Plann. 1983, 14 (6–7), 159–163.

16. Diaz, S.; Pavez, M.; Miranda, P.; Robertson, D.N.; Sivin, I.;Croxatto, H.B. A five-year clinical trial of levonorgestrelsilastic implants (Norplant2). Contraception 1982, 25 (5),447–456.

17. Weiner, E.; Victor, A.; Johansson, E.D. Plasma levels of D-norgestrel after oral administration. Contraception 1976,14 (5), 563–570.

18. Croxatto, H.B.; Diaz, S.; Miranda, P.; Elamsson, K.;Johansson, E.D. Plasma levels of levonorgestrel in womenduring longterm use of Norplant. Contraception 1981,23 (2), 197–209.

19. Keith, A.D. Polymer matrix considerations for transdermaldevices. Drug Develop. & Ind. Pharm. 1983, 9, 605–625.

20. Hsieh, D.S.T. Subcutaneous controlled delivery of estradiolby compudose implants: in vitro and in vivo evaluations.Drug Develop. & Ind. Pharm. 1987, 13, 2651–2666.

21. Wolff, M.; Cordes, G.; Luckow, V. In vitro and in vivorelease of nitroglycerin from a new transdermal therapeuticsystem. Pharm. Res. 1985, 1, 23–29.

22. Corbo, M.; Liu, J.C.; Chien, Y.W. Transdermal controlleddelivery of propranolol from a multilaminate adhesivedevice. Pharm. Res. 1989, 6 (9), 753–758.

23. Microsealed Pharmaceutical Delivery device. US Patent4,053,580, Oct 11, 1977.

24. Chien, Y.W. Microsealed drug delivery systems: Fabricationand performance. In Methods in Enzymology; Widder, K.J.,Green, R., Eds.; Academic Press: New York, 1985; 461–470.

25. Sanvordeker, D.R.; Cooney, J.G.; Wester, R.C. Transder-mal Nitroglycerin Pad. US Patent 4,336,243, June 22, 1982.

26. Karim, A. Transdermal absorption: a unique opportunityfor constant delivery of nitroglycerin. Drug Develop. &Ind. Pharm. 1983, 9, 671.

Site-specifictargetingmoiety

Spacer

Enzyme

(at target tissue)

Cell membrane

Cell of

target tissue

Drug

Solubilizer

Polymer backbone

(nonimmunogenic

and blodegradable)

Facilitate systemic

distribution

and tissue uptake

Cleavablegroup

Drug

Drug

Fig. 29 An ideal site-targeting controlled-release drugdelivery. (From Ref.[54].)


DrugDelivery

Buccal–Mono

27. Theeuwes, F.; Yum, S.I. Principles of the design and oper-ation of generic osmotic pumps for the delivery of semisolidor liquid drug formulations. Ann. Biomed. Eng. 1976, 4 (4),343–353.

28. Theeuwes, F. Elementary osmotic pump. J. Pharm. Sci.1975, 64 (12), 1987–1991.

29. De Leede, L.G.J. Rate-Controlled and Site-Specified RectalDrug Delivery; Ph.D. Thesis; State University of Leiden:Leiden, The Netherlands, 1983.

30. Theeuwes, F. Oros-osmotic system development. DrugDevelop. & Ind. Pharm. 1983, 9, 1331–1357.

31. Liu, J.-C.; Farber, M.; Chien, Y.W. Comparative release ofphenylpropranolamine HCL for long-acting appetite sup-pressant products: acutrim vs. dexatrim. Drug Develop. &Ind. Pharm. 1984, 10, 1639–1661.

32. Michaels, A.S. Device for Delivering Drug to BiologicalEnvironment. US Patent 4,180,073, Dec. 25, 1979.

33. Blackshear, P.J.; Rohde, T.D.; Grotting, J.C.; Dorman,F.D.; Perkins, P.R.; Varco, R.L.; Buchwald, H. Controlof blood glucose in experimental diabetes by means of atotally implantable insulin infusion device. Diabetes 1979,28 (7), 634–639.

34. Blackshear, P.J.; Rohde, T.D.; Varco, R.L.; Buchwald, H.One year of continuous heparinization in the dog using atotally implantable infusion pump. Surg. Gynecol. Obstet.1975, 141 (2), 176–186.

35. American pharmacy, implantable pump for morphine.NS24:20 1984.

36. Hsieh, D.S.T.; Langer, R. Zero-order drug delivery systemswith magnetic control. In Controlled Release Delivery Sys-tems; Roseman, T.J., Mansdorf, S.Z., Eds.; Marcel Dekker,Inc.: New York, 1983.

37. Kost, J. Ultrasound for controlled delivery of therapeutics.Clin. Mater. 1993, 13 (1–4), 155–161.

38. Tyle, P.; Agrawala, P. Drug delivery by phonophoresis.Pharm. Res. 1989, 6 (5), 355–361.

39. Bertolucci, L.E. Introduction of anti-inflammatory drugsby iontophophoresis: double blind study. J. Orthopaed. &Sports Phys. Ther. 1982, 4, 103.

40. Glass, J.M.; Stephen, R.L.; Jacobson, S.C. The quantityand distribution of radiolabeled dexamethasone deliveredto tissue by iontophoresis. Int. J. Dermatol. 1980, 19 (9),519–525.

41. Harris, P.R. Iontophoresis: clinical research in musculoske-letal inflammatory conditions. J. Orthopaed. & Sports Phys.Ther. 1982, 4, 109.

42. Controlled Release Suspensions, APhA/APS Midwest Reg.Meet, Chicago, Illinois, April, 1984.

43. Raghunathan, Y. Prolonged Release PharmaceuticalPreparations. US Patent 4,221,778, Sept 9, 1980.

44. Raghunathan, Y.; Amsel, L.; Hinsvark, O.; Bryant, W.Sustained-release drug delivery system I: coated ion-exchange resin system for phenylpropanolamine and otherdrugs. J. Pharm. Sci. 1981, 70 (4), 379–384.

45. Heller, J. Biodegradable polymers in controlled drug deliv-ery. Crit. Rev. Ther. Drug Carrier Syst. 1984, 1 (1), 39–90.

46. Morimoto, Y.; Fujimoto, S. Albumin microspheres as drugcarriers. Crit. Rev. Ther. Drug Carrier Syst. 1985, 2 (1),19–63.

47. Sezaki, H.; Hashida, M. Macromolecule-drug conjugates intargeted cancer chemotherapy. Crit. Rev. Ther. DrugCarrier Syst. 1984, 1 (1), 1–38.

48. Heller, J.; Pengburn, S.H. A triggered bioerodible naltrex-one delivery system. Proc. Int. Symp. Control. Rel. Bioact.Mater. 1986, 13, 35–36.

49. Heller, J.; Trescony, P.V. Controlled drug release by poly-mer dissolution. II: Enzyme-mediated delivery device.J. Pharm. Sci. 1979, 68 (7), 919–921.

50. Horbett, T.A.; Ratner, B.D.; Kost, J.; Singh, M. A biore-sponsive membrane for insulin delivery. In RecentAdvances in Drug Delivery Systems; Anderson, J.M.,Kim, S.W., Eds.; Plenum Press: New York, 1984; 209–220.

51. Kim, S.W.; Jeong, S.Y.; Sato, S.; McRea, J.C.; Feijan, J.Self-regulating insulin delivery systema—a chemicalapproach. In Recent Advances in Drug Delivery Systems;Anderson, J.M., Kim, S.W., Eds.; Plenum Press: New York,1983; 123.

52. Baker, R.W. Controlled release of biologically activeagents; J. Wiley & Sons: New York, 1987.

53. Jeong, S.Y.; Kim, S.W.; Eenink, M.J.D.; Feijen, J. Self-regulating insulin delivery systems. I. Synthesis and charac-terization of glycosylated insulin. J. Controlled Release1984, 1, 57–66.

54. Ringsdorf, H. Synthetic polymeric drugs. In PolymericDelivery Systems; Kostelnik, R.J., Ed.; Gordon and Brech:New York, 1978.

55. Chien, Y.W. Logics of transdermal controlled drugadministration. Drug Develop. & Ind. Pharm. 1983, 9,497–520.

56. Noonan, P.K.; Gonzalez, M.A.; Ruggirello, D.; Tomlinson,J.; Babcock-Atkinson, E.; Ray, M.; Golub, A.; Cohen, A.Relative bioavailability of a new transdermal nitroglycerindelivery system. J. Pharm. Sci. 1986, 75 (7), 688–691.

57. Chien, Y.W. Microsealed drug delivery systems: theoreticalaspects and biomedical assessments. In Recent Advances inDrug Delivery Systems; Anderson, J.M., Kim, S.W., Eds.;Plenum Press: New York, 1984; 367–387.

58. Chien, Y.W. Potential developments and new approaches inoral controlled release drug delivery systems. DrugDevelop. & Ind. Pharm. 1983, 9, 1291–1330.


DrugDelive

ryBucca

l–Mono

Drug Delivery: Fast-Dissolve Systems

Vikas AgarwalBhavesh H. KothariDerek V. MoeRajendra K. KhankariCIMA Labs, Inc., Brooklyn Park, Minnesota, U.S.A.

INTRODUCTION

Orally disintegrating tablets (ODTs) rapidly disinte-grate in the mouth without chewing upon oral admin-istration and without the need for water, unlike otherdrug delivery systems and conventional oral solidimmediate-release dosage form.[1] ODT dosage forms,also commonly known as fast melt, quick melts, fastdisintegrating, and orodispersible systems have theunique property of disintegrating the tablet in themouth in seconds. For acute conditions, this dosageform is easier for patients to take anytime, anywherethose symptoms occur. For chronic conditions, it isassumed to improve compliance. Some importantadvantages of ODT drug delivery over others are easeof swallowing for patients and convenience of takingthe medication anytime without the need of water.Some limitations include difficulty in developingextremely high doses (typically in excess of 500mg),and sometimes-extensive taste masking of bitter tastingactives.

Orally disintegrating dosage forms are often for-mulated for existing drugs with an intention toextend the patent life of the drug through productdifferentiation. They are evaluated against the inno-vator drug in a bioequivalence study in humans toestablish comparability of pharmacokinetic para-meters. Although intuitive, at the present time nodata exists that ODTs improve compliance oversolid oral dosage forms.

MARKET NEEDS

The application of a drug delivery technology (DDT)to any molecule is based on market needs, product

differentiation, and patient compliance. Owing to theincreased costs of getting a product to market andfocus on clinical advancement, new chemical entities(NCEs) typically do not go through an extensiveevaluation of DDT. The goal is to get the productthrough the clinical studies with a stable formulationthat can achieve the safety and efficacy required forFood and Drug Administration (FDA) approval.The time to get the NCE to the market eats up amajority of the patent life cycle of the drug. Drugdelivery technologies are very helpful in addingvalue/timeline to the patent. They offer additionalbenefits such as patient compliance and ease ofadministration. Market data suggests that sales ofDDT-based products are increasing in general andwill continue to increase.

DRUG DELIVERY MARKET

Drug delivery systems are technologies that transportthe active drug into the body’s circulatory system.Drug can be delivered into the body by various means,depending on its physical and chemical properties.Some may alter the method of taking the drug, othersalter the desired therapeutic activity. The advent ofnew drug delivery systems can clearly differentiate adrug product in today’s highly competitive pharma-ceutical market. To better understand the concept ofthe drug delivery system, one needs to know how adrug delivery system can be a valuable and cost-effective life cycle management resource. Pharmaceuti-cal companies worldwide have recognized various drugdelivery systems as powerful marketing tools to differ-entiate products, extend product life cycles, and evenimprove the efficacy of a drug. Several examples

Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-120014098Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved.1104

DrugDelivery

Buccal–Mono

include Claritin ODTs, Actiq (transmucosal dosageform for patient compliance), and Cardiazem XL(osmotic dosage form for extended release).

The drug delivery market encompasses a wide arrayof technologies that cover various routes of administra-tion such as oral, nasal, transdermal, and inhalation.The oral route remains most popular owing to theease of administration, manufacturing, and regulatorystrategy.

The oral drug delivery market encompasses technol-ogies such as sustained and controlled release dosageforms, oral transmucosal technologies, targeted tech-nologies, pH-specific dosage forms, and orally disinte-grating dosage forms.

The increasing popularity of orally disintegratingdosage forms is in part owing to various factors such aspatient preference and life cycle management.[2] Somereasons for patient preference include fast disinte-gration, good mouth-feel, easy to handle, easy toswallow, and effective taste masking (for tablet basedtechnologies). A perceived benefit for ODT is the easeof administration to elderly and pediatric populationsand other patient populations that have difficultyswallowing traditional tablets or capsules.

A customer study funded by CIMA was done tomeasure consumer/patient reactions to fast dissolve.The population size was 5000 and spanned across adiverse age group. Patients were given a conventionaltablet and an ODT and asked various questions. Asignificant majority of the patients said they ‘‘wouldor might’’ prefer a fast dissolve dosage form over aregular tablet or liquid. Only 12% of the patientsrejected fast dissolve tablets. Most of the patients alsoindicated that they would ask their doctor for a fastdissolve version and would purchase a fast dissolve ifavailable.

Life cycle management allows for differentiation ofproduct in the market. According to datamonitor,drugs worth $37 billion will loose patent protectionbetween 2000 and 2010.

Development of an ODT formulation within thepatent expiration period can add significant patent lifeto the formulation as it cannot be substituted at thepharmacy counter until an equivalent ODT is availablein the market.

MANUFACTURING PROCESSES FOR ORALLY

DISINTEGRATING SOLID DOSAGE FORMS

This part of the article describes the main processes,which can be used to develop an ODT drug deliverysystem.[3,4] The processes described hereunder are uti-lized to develop ODTs, depending on its capabilitiesand limitations, in addition to developing the productwithin an acceptable period of time satisfying all the

specific needs of the product. Each technology utilizesone or more combinations of processes describedbelow to develop ODT drug delivery systems. ODTdevelopment consists of three parts:

1. Evaluating the need to taste mask the drug.2. Incorporating the taste masked/non-taste-

masked drug into the tablet matrix.3. Packaging.

TASTE-MASKING PRINCIPLE

Taste masking of drug may be achieved with prevent-ing the exposure of drug to the tongue through pro-cessing or adding competing taste-masking agents.Exposure of solubilized drug to the oral cavity canbe prevented by encapsulation in polymer systems orcomplexation.[5] The approaches are as follows:

� Layering the drug onto inert beads using a binderfollowed by coating with a taste-masking polymer.

� Granulating the drug and coating with a taste-masking polymer.

� Spray drying the drug dispersed or dissolved in apolymeric solution to get taste-masked particles.

� Complexation by the use of inclusion in cyclo-dextrins.

� Psychological modulation of bitterness.� Coacervation to form microencapsulated drug

within a polymer.� Formation of pellets by extrusion spheronization.

Layer/Coat Process

The layering process involves deposition of successivelayers of an active compound onto the granules ofthe inert starter seeds such as sugar spheres or micro-crystalline cellulose beads. Sugar spheres (Non Pareil)or microcrystalline spheres (Celpheres) can be usedas initial substrate in the preparation of beads by thelayering process. In the layering process, the bitter drugis dissolved or dispersed in an aqueous or non-aqueoussolvent, depending on its solubility characteristics andease of processing. Binder is added to the solution toform liquid bridges between the primary particles.Most commonly used binders are gelatin, povidone,carboxymethyl cellulose, hydroxypropyl methylcellu-lose (HPMC), hydroxypropyl cellulose (HPC), andmaltodextrin.[6] In solution form, the drug is com-pletely soluble in the solvent, while in dispersed form,the drug is either micronized before adding into thesolvent or the solvent containing dispersed drug issubjected to wet milling using a high-shear mixer tomicronize in solution. It is desirable that the ratio of

Drug Delivery: Fast-Dissolve Systems 1105

DrugDelive

ryBucca

l–Mono

particle size of the drug to the size of the beads is about1 : 10. In the layering process, drug layering up to100–150% in weight is achievable, beyond which druglayering may cause excessive grittiness because ofincreased particle size of the granules when incorpo-rated into a dosage form. A potential disadvantageencountered during drug layering process is the possi-bility of drug recrystallizing into different polymorphsupon completion of the process.

After the drug is layered over an inert startingmaterial, it is then coated with a polymer that retardsdissolution in the oral cavity. Two mechanisms to pre-vent dissolution are predominantly used, either a poly-mer that slows down dissolution across all pHs or apolymer that does not dissolve in the pH of the salivabut dissolves rapidly in the gastric fluid of the stomach.The various polymers used for taste-masking purposeare Eudragit E 100, ethylcellulose, HPMC, HPC poly-vinyl alcohol, and polyvinyl acetate. The polymer isdissolved in an aqueous or non-aqueous solventdepending on its solubility characteristic and antitackagents such as talc, magnesium stearate, and cab-o-silare added to improve processing and prevent agglom-eration. Sometimes taste masking is possible bycombining layer/coat in a single process, i.e., incorpor-ating the drug in solution/suspension form containinga polymer that serves both as a binder and as ataste-masking agent and then depositing the drug ontobeads.

Granulation

Taste masking by granulation is achieved by decreas-ing the surface area of the drug by increasing itsparticle size. The additional benefit obtained is easeof processing for tablet compression as the majorityof drugs have a low bulk density. Additionally, poly-mers that serve as binders and taste-masking agentsmay be incorporated, which reduce the perceptionof taste. Granulation may be achieved with or with-out the use of a solvent. Dry granulation involvesthe use of forming compacts/slugs that are milledfor blending. Wet granulation can be achieved byusing the fluid bed process or high-shear granulation.In the fluid bed process, the drug is suspended in thebed with air, and a binder is sprayed from the top.The granules formed are porous and not amenableto further processing like coating. In high-sheargranulation, the granule formation occurs by sprayinga liquid binder onto drug/mixture of drugs with exci-pients that are being agitated by combined action ofan impeller and chopper. The granules obtained aredense and may be used directly or coated further ina fluid bed. This approach is suitable for high-dosedrugs (>50mg) with unpleasant taste.

Spray Drying

For taste-masking application, the drug is either dis-solved or dispersed along with bulking agent (polymer)and, occasionally, a binding agent is also added ifrequired, in a suitable solvent. Spray drying consistsof four stages: atomization of feed into a spray,spray–air contact (mixing and flow), drying of spray(moisture/volatiles evaporation), and separation ofdried product from the air.[7] The solvent used forspray drying process may be aqueous or non-aqueous.Product obtained upon spray drying yields high-porosity granules or beads containing encapsulateddrug. Some unintended effects include formation ofsolid dispersions of the drug owing to recrystallizationand thermal degradation for temperature-sensitivedrugs.

Complexation

Taste masking by inclusion complexation is possible byphysically entrapping the drug in cone-shaped struc-tures called cyclodextrins.[8] Cyclodextrins are bucket-shaped oligosaccharides produced from starch. Owingto their peculiar structure and shape, they possessthe ability to entrap guest molecules in their internalcavity. Drug inclusion complexes can be formed bya variety of techniques that depend on the propertyof the drug, the equilibrium kinetics, other formu-lation ingredients, processes, and the final dosageform desired. In all these processes, a small amountof water is required to achieve thermodynamic equi-librium. The initial equilibrium to form the complexis very rapid, the final equilibrium takes a longer time.The drug, once inside the cyclodextrin cavity, makesconformational changes to itself so as to attach itselfto the complex and to take maximum advantage ofthe weak van der waals forces.

Complexation is also possible through the use ofion-exchange resins. Both anionic and cationic typesare available.[9] The preparation of the taste-maskedcomplex involves suspending the resin in a solvent inwhich the drug is dissolved. For liquid preparations,the drug–resin complex can be used as is. For soliddosage forms, the complex may be processed by fil-tration or direct drying. Drug loading up to 50% ispossible with this process. Some commercially avail-able ion-exchange resins that may be used for tastemasking are based on methacrylic acid and divinylbenzene and styrene divinyl benzene polymer.[10]

Psychological Modulation of Bitterness

Taste masking with addition of competing agentsinvolves modulating the psychological perception of

1106 Drug Delivery: Fast-Dissolve Systems

DrugDelivery

Buccal–Mono

bitterness. To understand this better, the theory ofperception of taste is in order. The biochemical andphysiological basis of bitterness has been summarizedrecently.[11,12] There are two theories. One theory con-tends that receptors for common taste stimuli such assalt, bitter, and sweet are present in specific locationsof the tongue. The second theory contends that tastebuds respond to all stimuli to a different extent.Regardless of the mechanism, taste masking isachieved by the addition of specific inhibitors to sup-press the stimuli. This approach is likely to involvethe use of an inhibitor specific to the taste maskingof the drug in question. In the authors’ knowledge,there is no specific universal inhibitor available, whichwill mask all the taste stimuli.

Coacervation

Coacervation leads to formation of a microencapsu-lated form of drug. The process primarily consists offormation of three immiscible phases, formation ofthe coat, and deposition of the coat. The formationof the three immiscible phases is accomplished by dis-persing the core particles in a polymer solution. A phaseseparation is then induced by changing the temperatureof the polymer solution, addition of a salt and non-solvent, or by inducing a polymer–polymer interaction.This leads to deposition of the polymer coat on the corematerial under constant stirring. The core particlescoated by the polymer are then separated from theliquid phase by thermal, cross-linking, or desolvationtechniques leading to rigidization of the coat.[13]

Extrusion Spheronization

The process begins with the blending of dry powdersfollowed by granulation. The granulation is differentfrom conventional granulation as the end point isdetermined by the consistency of the paste suitable forpassing through an extruder. After passing through theextruder, the granulate is in the form of rods. The rodscan then be passed through a spheronizer to form pellets,which are then dried. An advantage touted for extrusionspheronization is the formation of more spherical pelletscompared to wet granulation.[14]

Hot-melt extrusion involves passing a molten soliddispersion of the drug through a extruder to obtainpellets. The hot-melt extrudate consists of drug dis-persed in a molten hydrophilic matrix, which is thenpassed through an orifice in the extruder. The extruderpaste can then be passed through a spheronizer toobtain pellets that are subsequently cooled. This processis primarily used for increasing the solubility of poorlysoluble drugs as it leads to formation of amorphous

form of the drug; however, the appropriate choice ofpolymers could lend itself to taste masking. The advan-tage touted for this is better control of particle size of thepellets and absence of the use of solvents.

INCORPORATION OF TASTE-MASKED

DRUG/NON-TASTE-MASKED DRUG

INTO THE TABLET MATRIX

After evaluating the need to taste mask the drug, thedrug is then incorporated in the final dosage form.Final dosage forms for ODTs can be achieved usingfreeze drying, molding, and direct compression. Freezedrying based ODT technology is a single-step process.Taste masking, if achieved, and formation of thematrix can be achieved in one step. Alternatively, thedrug may be incorporated in the freeze-drying processin a taste-masked form. Molding and compression-based technologies mostly involve taste masking as aseparate processing step. Each process has its ownadvantages and disadvantages and are discussed below.

TABLET MATRIX PRINCIPLE

Freeze Drying

Freeze drying, also known as lyophilization, is a pro-cess in which water is sublimated from the productafter freezing. This process can be used in many differ-ent ways to achieve the same end point. In one of thefreeze-drying formulation methods, drug is physicallytrapped in a water-soluble matrix (water-soluble mix-ture of saccharide and polymer, formulated to providerapid dispersion, and physical strength), which is freezedried to produce a product that dissolves rapidly whenplaced in the mouth. The ideal candidate for this kindof manufacturing method would be a molecule that ischemically stable and water insoluble, with a particlesize lower than 50 mm.[15] In another method, lyophili-zation of an oil-in-water emulsion (porous solid galenicform) is placed directly in the blister alveolus.[16] Oneother method for ODT manufacture using freeze dry-ing involves the formation of a porous solid formobtained by freezing an aqueous dispersion or solutionof the active containing matrix, then drying the matrixby removing the water using an excess of alcohol(solvent extraction). The ideal candidates for this kindof method should be insoluble in the extraction ofsolvent. The advantage of this process is that drugsubstances that are thermolabile in nature can be for-mulated at non-elevated temperature, thereby eliminat-ing adverse thermal effects, and stored in a dry statewith few shelf life stability problems.[17]


DrugDelive

ryBucca

l–Mono

Molding

Compression molding is a process in which tablets areprepared from soluble ingredients such as sugars bycompressing a powder mixture previously moistenedwith solvent (usually ethanol or water) into moldplates to form a wetted mass.[18]

In hot-melt molding, molded forms are prepareddirectly from a molten matrix in which drug is dis-solved or dispersed (heat molding) or by evaporatingthe solvent from a drug solution or suspension in thepresence of nitrogen gas at standard pressure (no-vacuum lyophilization). Tablets produced by this typeof molding are solid dispersions categorized as hotmelt. In molding, the drugs physical characteristicdepend onwhether its dissolves or disperse in themoltencarrier. The drug can exist as discrete particles dispersedall over the matrix or dissolved in the matrix. Whenthe drug is dissolved in the matrix, it forms a solid sol-ution. The characteristic of the tablets (such as disinte-gration time, drug dissolution rate, and mouth feel) willdepend on the state of the drug whether dispersion ordissolution. As the molded tablets dispersion matrixin which the drug gets dispersed or dissolved are madeof water-soluble sugars, tablet disintegration is morerapid when tablets are more porous.

Direct Compression

A direct compression method uses conventional equip-ment, commonly available excipients, and a limitednumber of process steps. This process may involvegranulation prior to final blend. The direct compressiontablet’s disintegration and solubilization are based onthe single or combined action of super disintegrants,water-soluble excipients, and effervescent agents.[19] Inmany cases, the disintegrants have a major role in thedisintegration and dissolution process of ODT tech-nology made by direct compression. The choice of a suit-able type and an optimal amount of disintegrants isparamount for ensuring a rapid disintegration rate.

Several different formulation routes are followed toachieve an optimal disintegration time in ODT drugdelivery systems made by direct compression.

PACKAGING

Upon prototype selection, selection of a packagingconfiguration is a crucial part of an ODT dosage form.Unlike conventional tablets, where packaging providesa means of administration/transport, ODTs mayrequire specialized packaging configurations owing totheir relative high moisture sensitivity and fragility.

In fact, the cost of packaging can be significant forcommercialization.

One approach used to overcome the moisture andphysical issues with ODTs is to select a rigid, multi-layer foil-based barrier material to protect the dosageform, with the blister actually forming during the tab-let formulation process. In many cases, ODT are veryfragile, and regular push through blister packagingmay break the tablet upon removing from the blister,so the packaging requires a peelable closure. Packagingmade from formable and flexible material can offerprotection from water, oxygen, or ultraviolet barrier,as well as providing some physical protection.

The most common packaging configurationincludes blister packaging and bottle packaging. Blister-packaged ODTs require specialized packaging equip-ment. In case of CIMA’s PakSolv Technology, tabletsare picked and placed in individual blister pockets ‘‘oneat a time’’ using a robotic hand. In the case of freezedrying technology, each blister needs to be filledindividually with the solution or suspension beforesubjecting it to freeze drying.

The final packaged dosage form has to be evaluatedto verify packaging integrity. One way to perform thisis by immersing blisters in water and subjecting themto a vacuum for a specified period of time. The blistersare then opened manually and checked for presence ofwater droplets. Additionally, blisters and bottlesshould be monitored in simulated shipping testsaccording to American Society for Testing Materials(ASTM) standards.

An additional issue with blister packaging is theevaluation of child resistance. The Consumer ProductSafety Commission regulates this. The blisters areevaluated for ‘‘F ’’ value, and appropriate designsneed to be in place for child resistance and seniorfriendliness. The F requirement is determined fromthe toxicity of the drug. In the case of tablets, thiswould be the number of tablets that when ingestedmay produce a serious injury or serious illness basedon a 25-pound child. A package passes a certain Frating, if 90% of the children from an initial 50-childtest are not successful in accessing the required Fnumber of tablets. As an example, if it is determinedthat an F ¼ 3 package is required and during testingwith 50 children, 4 children are able to access threeor more cells during the test, an F ¼ 3 rating isobtained at 92%.

Commercialization of ODTs have to go through thefinal evaluation of long-term stability of the tabletmatrix and packaging components per InternationalConference on Harmonisation guidelines. As themajority of ODT dosage forms on the market aresensitive to moisture, evaluation of moisture vaportransmission rate is an important parameter for asses-sing the shelf life of the product.


DrugDelivery

Buccal–Mono

Some ODTs are sensitive to moisture to such anextent that, even during processing or formulationdevelopment stages, temperature and humidity haveto be controlled to avoid long-term stability issuesand may require special packaging. Long-term stabilitystudies done with several ODT products have indicatedthat the foil–foil blister PakSolv blister design leads toa mere 0.1% increase in moisture level compared tostart over six months at 40�C/75% RH. The increasein moisture level for high density polyethylene (HDPE)bottles is about 0.5% under the same stability con-ditions at the end of six months based on CIMAin-house experience on all bottled products.

IN PROCESS CHALLENGES

The final product containing taste-masked drug, andmatrix is typically evaluated for sensory characteris-tics, disintegration time, and compared for dissolution.

Sensory characteristics of prototypes includeevaluation in taste panels in humans. Some of the char-acteristics tested are flavor acceptance, bitterness per-ception, sweetness, and after taste. Evaluation inhuman panels is not entirely possible all the time owingto the cost and timing associated with human testing.Some alternate methods include dissolution testing insmall volume[20] and electronic evaluation of tastereferred to as an electronic tongue.[21] It consists ofcoated probes that are immersed in a liquid-containingdissolved solids. The potentiometric response of theprobe is compared for the active and placebo usingprincipal component analysis mapping. The responseof the product containing the active that is closest toplacebo is regarded as the best formulation.

Disintegration

Disintegration is an important characteristic of anODT. According to the Center for Drug Evaluationand Research Data Standards Manual, the definitionof an ODT is ‘‘A solid dosage form containing med-icinal substances which disintegrates rapidly, usuallywithin a matter of seconds, when placed upon thetongue.’’[22] According to the European Pharmacopoeia(EP), ‘‘Orodispersible tablets are uncoated tabletsintended to be placed in the mouth where they disperserapidly before being swallowed.’’[23] The test criteriaoutlined by EP is ‘‘Orodispersible tablets shoulddisintegrate within 3min when examined by the testfor disintegration of tablets and capsules.’’ In vitrodisintegration testing is sometimes performed by thestandard United States Pharmacopoeia (USP) methodand often times by more discriminating methods in an

attempt to mimic in vivo performance. As with manyanalytical methods, there is no definite correlationbetween in vitro and in vivo data. In vitro disinte-gration tests serve as an important quality control testthroughout the development of the product. A disinte-gration time specification is considered standard onfinal product specification for ODTs, unlike conven-tional tablets.

Hardness and Friability

Many ODTs, in an effort to decrease disintegrationtime, are highly porous soft-molded tablets compressedat low compression force.[24] Sometimes if the formu-lation and processing parameters are not optimized,the tablets can exhibit higher friability irrespectiveof any hardness changes. Also, problems like capping,picking, and chipping are observed during formulationdevelopment if the formulation and processingparameters are not optimized. Several of the com-pressed ODTs are more robust and can withstand therigors of bottling.

Dissolution

Dissolution testing of ODTs has been reviewedrecently.[25] As ODTs sometimes contain taste-maskedactive, it adds an added layer of complexity to thedevelopment of a dissolution method for tablets. Thetaste masking plays a significant role in dissolutionmethod development, specifications, and testing. TheUSP 2 paddle apparatus is the most suitable and com-mon choice for ODTs. USP 1 is not appropriate owingto rapid disintegration in the screen, leaving signifi-cantly less perturbation of the product in the media.Discriminating, robust dissolution methods has valuein monitoring process optimization, changes duringscale-up of taste-masked bulk drug and tablet manu-facture and routine quality control testing. This isimportant as the barrier properties of the scaled-uptaste-masked product may change, leading to leachingof the drug in the oral cavity that may effect taste oreven bioequivalence.

Upon selection of a prototype based on the evalu-ation techniques described above, the individualprocesses are scaled up against FDA guidelines andevaluated for stability and bioequivalence.

REGULATORY

The FDA’s approval process for any applicationwhether it is a new drug application (NDA), abbreviatednew drug application, or over-the-counter is a closely


DrugDelive

ryBucca

l–Mono

monitored government activity. The FDA has set reg-ulations for filing a petition of a Supplemental NDAfor a drug that has the same strength and routeof administration as a drug listed in the FDA’spublication entitled ‘‘Approved Drug Products withTherapeutic Equivalence Evaluations,’’ but differ indosage form. This petition generally can be filedpursuant to section 505(b) (2) of the Federal Food,Drug and Cosmetic Act and 21 CFR x 314.93. Mostof the ODT drug delivery systems fall under this cate-gory. Depending on the bioequivalence study, certainproducts can get approval under this clause or other-wise will need to establish safety and efficacy of theproduct by conducting further clinical trials. As ODTproducts do not require administration of water, itmay be required to perform bioequivalence studieswith and without water depending upon the natureof the drug. This will depend upon the difference ofabsorption of drug in the fed and fasted state and inaddition may lead to a fed and fasted study.

ORALLY DISINTEGRATING TECHNOLOGIES

OraSolv�, DuraSolv�, and PakSolv�

OraSolv and DuraSolv are CIMA’s core ODT tablet-based technologies. The ingredients contained in thetechnology include polyols as fillers, disintegrant,which may include an effervescence couple, flavor,sweetener, and lubricant. The drug may be tastemasked if required typically utilizing a fluid bed coat-ing process. The tabletting process includes direct com-pression, and can accommodate a wide range ofpotency from less than 1mg to as high as 500mg.

Tablets manufactured with OraSolv technologyshould contain an effervescence couple along withmicroparticles of drug within a rupturable coat.[26]

The tablets manufactured are compressed at a lowhardness that promotes fast disintegration. The dosageforms need to be packaged in foil–foil aluminum blis-ters with a dome shape that impact physical protectionand impermeability to moisture. This constitutes thePakSolv Techonology.[27]

Tablets manufactured with DuraSolv technologycontain a non-directly compressible filler and a lubri-cant. They may or may not contain effervescence,and the drug need not be taste masked.[28] DuraSolvtablets are compressed at higher hardness comparedto OraSolv that allows for packaging in bottles or pushthrough blisters.

The advantages of tablet-based technology includelow cost of goods, standard manufacturing technology,standard packaging format and materials, and low-development costs and risks. Disadvantages includeslightly longer disintegration time.

Lyoc�

Lyoc technology is owned by Cephalon Corporation.CIMA is a subsidiary of Cephalon, and currently man-ages the Lyoc R&D efforts. This was the first freeze-drying-based technology introduced for ODTs. Theprocess involves preparation of a liquid solution orsuspension of the drug containing fillers, thickeningagents, surfactants, non-volatile flavoring agents, andsweeteners.[29] This homogenous liquid is thendeposited in blister cavities and subjected to freeze dry-ing. Advantages of Lyoc compared to other freeze-dried dosage forms include absence of preservatives.

Zydis�

Zydis technology is owned by RP Scherer, a subsidi-ary of Cardinal Health. This drug delivery systemconsists of freeze-dried tablets having active drugdesigned to rapidly disintegrate in the mouth.[30]

The freeze-dried tablet is made by lyophilizing a sus-pension or solution of drug containing various excipi-ents such as polymer, polysaccharides, preservatives,pH adjusters, flavors, sweeteners, and colors, whichis then filled in blisters. Freeze drying occurs in theblisters, which are then sealed and further packaged.Some of the advantages of the Zydis system includefast disintegration time. Some of the disadvantagesinclude low throughput, high cost of goods, and lim-ited taste masking.

Flashtab�

Flashtab tablet matrix consists of a swellable agent(modified starch or microcrystalline cellulose) and asuper disintegrant (crospovidone or croscarmellose).The system may also contain, depending on the need,a highly water-soluble polyol with binding propertiessuch as mannitol, sorbitol, maltitol, or xylitol, insteadof the swellable agent as mentioned before.[31] Theactive is taste masked by direct coating. Tablets manu-factured using this technology produce durable tabletsin which the excipients are first granulated using wet ordry granulation process, then the coated drug is mixedwith the excipient granules and compressed into tabletsthat can be handled and packaged using conventionalprocessing equipment. Tablets for blister packagingcan withstand the pressure used to push the tabletout of the lidding foil of the blister card. Tabletscontaining hygroscopic material can also be blisterpackaged, by using high-quality polyvinyl chloride oraluminum foils, which provide a higher degree ofmoisture protection than ordinary polyvinyl chlorideor polypropylene foils.


DrugDelivery

Buccal–Mono

FlashDose�

Fuisz technologies is the inventor of the FlashDose-technology.[32] It is now owned by Biovail. FlashDosetablets are manufactured utilizing SHEARFORM�

matrix in which material containing substantialamounts of fibrous polysaccharides, which are pro-cessed by simultaneous action of flash melting and cen-trifugal force, are compressed to form fine sugar fibers.FlashDose tablets containing a matrix of these sugarfibers disintegrates very rapidly upon contact with sal-iva, with disintegration times of a few seconds. Thetablets produced by FlashDose are hydrophilic andhighly porous, owing to relatively low compressionduring the pressing of the tablets. For taste masking,Fuisz uses its own patented, single-step, solvent-freeprocess, termed ‘‘CEFORMTM technology,’’ whichproduces uniform microspheres with a very narrowparticle size distribution. The resulting tablets pro-duced by this process are soft, friable, and highlymoisture sensitive. They require specialized packagingmaterials and processes to protect them from externalhumidity and mechanical abrasion.

WOWTAB�

WOWTAB tablets are developed by YamanouchiPharma Technologies.[33] The main ingredients in thetablets include low- and high-moldable sugars. Thelow-moldable sugars promote quick dissolution andinclude mannitol, lactose, and glucose. High-moldablesugars promote good hardness upon compaction andinclude maltose, sorbitol, and maltitol. The activeand other excipients are granulated with a solutioncontaining both the sugars in a fluid bed granulator.The granules obtained are blended with lubricantsand flavors and then compressed to form tablets. Thetablets are then stored in a controlled humidity andtemperature system for conditioning and then pack-aged in blisters or bottles. Taste masking of the activemay be achieved by the use of cyclodextrins.

ODT Technologies in Development

KryotabTM

Biotron designs and develops freeze-dried tablets andmicroparticles using low-temperature and cryogenic-processing technologies.[34] The products developedmay be used for different dosage forms such as oral,parenteral, pulmonary, and transdermal delivery.Kryotab technology’s two version used to develop dif-ferent dosage form are Kryotab-MIM and Kryotab-CD. Unlike RP Scherer’s Zydis technology, in this

technology, the unit doses are not initially formed fromliquid dispersions, but from the tabletted articlesubjected to freeze drying. The water needed to beremoved during freeze drying is introduced into thetablets in the form of ice particles and mixed alongwith excipients and active and subsequently com-pressed at low temperature. The porosity in the tabletis determined and controlled by the number and sizeof ice particles. Microencapsulated liquid or gelled bin-der is incorporated in the tabletting mixture to obtainrigid tablets with high tensile strength. During com-pression, the microcapsules disintegrate and releasethe binder, which improves the adhesion between thecompressed drug and excipient particles

OraQuickTM

KV Pharmaceutical’s two proprietary taste-maskingtechnologies, FlavorTech� and MicroMask�, are uti-lized for developing OraQuick tablets. MicroMaskprovides taste masking by incorporating a druginto matrix microspheres. The first step involved informulating the tablet include dissolving the sugar(sucrose, mannitol, sorbitol, xylose, dextrose, fructose,or mannose), and protein (albumin or gelatin) in a suit-able solvent, such as water, ethanol, isopropyl alcohol,and ethanol–water mixture.[35] The porosity of the pro-duct is determined by the quantity of solvent used inthe formulation. The solution of the matrix is thenspray dried, yielding highly porous granules. Thematrix granules are mixed with other excipients suchas binder, lubricant, sweeteners, flavors, coloringagent, fillers, disintegrants, surfactants, etc. The drugcan be added at this stage in the form of taste-maskedgranules, other wise added first in the matrix granule.The granules or powder obtained is then compressedat low compression force to form tablets that are softand friable but highly porous. After the tablets arecompressed, they are subjected to a sintering step.Tablets are sintered in an oven, typically at tempera-ture of about 50�C to 100�C for few minutes to severalhours or at 90�C for about 10min. During this step,the compressed tablets containing binder (polyethyleneglycol) in the earlier step melts and binds particles toform stronger tablet.

Quick-DisTM

Lavipharm Laboratories is the inventor of Quick-Distechnology. Quick-Dis technology refers to thin, easilydispensed, flexible, and rapidly dissolving films for thelocal or systemic delivery orally.[36] Quick-Dis disinte-grates rapidly upon wetting when placed under thetongue. This drug delivery of Lavipharm has the


DrugDelive

ryBucca

l–Mono

capability of being printable, non-tacky in nature whiledry, with a low-residual water content, easy to process.The film thickness ranges from 1 to 10mils, and surfacearea can be 1–20 cm2 for any geometry. Lavipharmmanufactures its oral films by a solvent-casting pro-cess, using water as the preferred solvent followed bya drying step. The coating thickness range is typicallyfrom 5 to 20mils with aerated oven drying. The filmscan also be processed alternatively using cold- orhot-melt extrusion technique.

AdvatabTM

Eurand is the owner of Advatab drug delivery system.Eurand is known for its Microcaps� technology, whichinvolve taste-masking drug particles using microencap-sulation process based on coacervation/phase separ-ation technique.[37] Eurand applied Microcapstechnology to design ODTs (Advatab), which containstaste-masked active ingredients. The primary ingredientsin the dosage form include sugar alcohols and sacchar-ide with particle size less than 30 mm along withdisintegrant and lubricant. The lubricant used in theformulation is added as an external lubricant com-pared to conventional formulations, which containan internal lubricant. The company claims that thisallows the tablets to be stronger compared to conven-tional tablets as internal lubricants are hypothesized todecrease binding of the drug particles. The dosageforms are manufactured using conventional tablettingand packaging equipments. The tablets, which can

handle high drug loading and coated particles, can bepacked in both bottles and pushed through blisters.

QdisTM

Phoqus owns the Qdis technology. The dosage formscomprises of ODTs containing agglomerates greaterthan 50 mm in size that comprises at least 10% or moreof superdisintegrants without drug. The agglomeratesare blended with excipients, and drug particle sizeranging in size from 50 to 300 mm. The resulting softtablets are coated using an electrostatic dry-powderdeposition technology. This coating strengthens thetablet while still providing rapid disintegration.[38]

FrostaTM

Akina owns Frosta technology. The technology incor-porates manufacture of highly plastic granules using aplastic material, a material enhancing water pen-etration, and a wet binder.[39] These granules can thenbe compressed into tablets at low pressure, thusenabling fast disintegration upon administration.

Miscellaneous

Owing to the increasing popularity of ODTs, somerecent trends are of notable mention. One of them isthe use of highly plastic granules to compress intotablets at low pressure to enable it to melt faster,

Table 1 ODT technologies and corresponding commercial products

Technologies Company name Products on market

DuraSolv�, OraSolv� CIMA Tempra� Quicklet/Tempra� FirsTabs, Trimainic�

Softchews (several formulations), Remeron�

SolTabs, Zomig� Rapimelt, Nulev�, Alavert�,FazaClo, Parcopa, Niravam, Clarinex Redi Tabs

FlashDose Biovail Neruofen

Flashtab Ethypharm Nurofen

Kryotab Biotron None

OraQuick KV Pharmaceutical None

Quick-Dis Lavipharm Lab Film none

RapitrolTM Shire Lab None

Slow-DisTM Lavipharm Lab Film none

WOWTAB Yamanouchi Benadryl Fastmelt

Advatab Eurand None

Zydis Cardinal Health Maxalt MLT, Claritin Reditabs, Zyprexa Zydis,Zofran ODT

Lyoc Cephalon Proxalyoc (piroxicam), Paralyoc (paracetamol),SpasponLyoc (loperamide)


DrugDelivery

Buccal–Mono

thereby enhancing the dissolution profile. The plasticgranules are made of three components namely: a plas-tic material, a material enhancing water penetration,and a wet binder.[39]

Excipient manufacturers are now supplying excipi-ents specifically geared toward manufacture of ODTs.One of them is spray-dried mannitol. The properties ofthis excipient suitable for ODTs include good compress-ibility at low hardness and fast disintegration, desirableproperties for the manufacture of ODTs. The twobrands commercially available include Pharmaburst bySPI Pharma[40] and Pearlitol by Roquette.[41] The hopeis that it will stimulate the development of ODTs inhouse for pharmaceutical companies not traditionallyinvolved with manufacture of ODTs.

Companies are offering taste-masking capabilitiesfor drugs. Some of them are Particle Dynamics,[42]

The Coating Place,[43] and Particle and CoatingTechnologies.[44] The rationale here is outsourcing oftaste-masking abilities of drugs, which can then becombined, with the use of excipients such as spray-driedmannitol to develop ODTs in-house. One company hasgone a step further. SPI Pharma has a business agree-ment with Particle and Coating Technologies to tastemask drugs for their clients or offer the ability for manu-facture of free-dried ODTs through their agreementwith Oregon Freeze Dry Company.[45] This allows devel-opments of an ODT of both compressed or freeze-drieddosage form for a client without having any in-houseresources.

Table 1 outlines some of the ODT technologies andcorresponding commercial products, if any.

CONCLUSIONS

As discussed in this article, drugs can be administeredinto humans by various drug delivery systems. A largenumber of companies are in the ODT drug deliverymarket, which is evident from the number of productslaunched as ODT and patents approved. Amongstother drug delivery companies, those in the ODT mar-ket possess tremendous potential of extending the drugproduct life cycle, reducing the attrition rate during thedrug development stage, and extending the profita-bility of existing products. Owing to its flexible nature,molecules of a wide variety of doses and chemicalcharacteristics can be incorporated into an ODT. Thedifferent technologies such as fine particle layering/coating or adding flavors/sweeteners into tablet matrixfor taste masking, spray drying, granulation, freezedrying, molding are now widely accepted applicationsin the industry for developing an ODT. As pharmaceu-tical companies are now starting to recognize theneed for more technological advances to meet thenew challenges in the future, DDT continues to have

a significant impact and contribution in meeting thosedemands and challenges.

ARTICLE OF FURTHER INTEREST

Hot Melt Extrusion Technology, p. 2004.

REFERENCES

1. Habib, W.; Khankari, R.; Hontz, J. Fast-dissolve drugdelivery systems. Crit. Rev. Thera. Drug Carrier Syst.2000, 17, 61.

2. Cremer, K. Orally disintegrating dosage forms. Pharma-ceutical technology. Formulation and solid dosage 2003,supplement, 22–28.

3. Dobetti, L. Fast-Melting tablets: developments and tech-nologies. Pharm. Tech. 2001, Supplement, 44–46.

4. Lieberman, H.; Lachman, L. Particle-coating methods. InPharmaceutical Dosage Forms: Tablets; Marcel Dekker,Inc.: New York, 1982; Vol. 3, 120–144.

5. Pondell, R. Taste masking with coatings. Coating Tech-nology. 1996, October 2–3.

6. Busson, P.; Schroeder, M. Process for Preparing a Pharma-ceutical Composition. US Patent 6,534,087, March 18,2003.

7. Masters, K. Spray Drying Fundamentals: Process stagesand Layouts. Spray Drying Handbook, 5th Ed.; LongmanScientific & Technical: New York, 1991; 23–64.

8. Prasad, N.; Straus, D.; Reichart, G. Cyclodextrin flavordelivery systems. US Patent 6,287,603, September 16, 1999.

9. www.rohmhaas.com/ionexchange/pharmaceuticals/index.htm (accessed March 27, 2006).

10. Hughes, L. Selecting the right ion exchange resin. PharmaQuality 2005, 1 (1), 54–56.

11. Brown, D. Orally disintegrating tablets—taste over speed.Drug Delivery Technology 2003, 3 (6), 58–61.

12. Stier, R. Masking bitter taste of pharmaceutical actives.Drug Delivery Technology 2004, 4 (2), 52–57.

13. Lachman, L.; Lieberman, H.; Kanig, J. The Theory andPractice of Industrial Pharmacy, 3rd Ed.; Lea and Febiger;1986, 420.

14. O’Connor, R.; Schwartz, J. Extrusion and spheronizationtechnology. In Pharmaceutical Pelletization Technology;Marcel Dekker Inc., 1989; Vol. 37, 187.

15. Blank, R.G.; Mody, D.S.; Kenny, R.J.; Aveson, M.C. FastDissolving Dosage Form. US Patent 4,946,684, August 7,1990.

16. Green, R.; Kearney, P. Process for Preparing Fast Disper-sing Solid Dosage Form. US Patent 5,976,577, November 2,1999.

17. Lawrence, J.; Posage, G. Biconvex Rapidly Disintegra-tingDosage Forms.US Patent 6, 224, 905,December 3, 1998.

18. Ford, J. The current status of solid dispersion. Pharm.Acta. Helv 1986, 61, 69–88.

19. Roser, B.J.; Blair, J. Rapidly Soluble Oral Dosage Forms,Methods of Making Same, and Composition Thereof. USPatent 5,762,961, June 9, 1998.

20. Hughes, L.; Gehris, A. A new method of characterizing thebuccal dissolution of drugs, rohm and haas research labora-tories. Spring House.

21. http://www.alpha-mos.com/en/technology/tecprinciple.php (accessed March 27, 2006).

22. http://www.fda.gov/cder/dsm/DRG/drg00201.htm(accessed March 27, 2006).

23. Orodispersible tablets. European Pharmacopoeia. 2004,5 (1), 628.

24. Sparks, R.; Jacobs, I.; Mason, N. Method of ProducingPorous Tablets with Improved Dissolution Properties. USPatent 6,544,552, April 8, 2002.


DrugDelive

ryBucca

l–Mono

25. Klancke, J. Dissolution testing of orally disintegratingtablets. Dissolution Technologies 2003, 10 (2), 6–8.

26. Wehling, F.; Schuehle, S.; Madamala, N. EffervescentDosage Form with Microparticles. US Patent 5,178,878,January 12, 1993.

27. Katzner, L.; Jones, B.; Khattar, J.; Kosewick, J. BlisterPackage and Packaged Tablet. US Patent 6,155,423,December 5, 2000.

28. Khankari, R.; Hontz, J.; Chastain, S.; Katzner, L. RapidlyDissolving Robust Dosage Form. US Patent 6,024,981,February 15, 2000.

29. Laboratoire Lafon. Galenic Form for Oral Administrationand its Method of Preparation by Lyophilization of anOil-in-Water Emulsion. European Patent 0,159,237, 1985.

30. Kearney, P.; Wong, S.K. Method for Making Freeze DriedDrug Dosage Forms. US Patent 5,631,023, May 20, 1997.

31. Pebley, W.S.; Jager, N.E.; Thompson, S.J.; Rapidly Disin-tegrating Tablets. US Patent 5,298,261, March 29, 1994.

32. Robinson, J.; McGinity, J. Effervescent Granules andMethod for Their Preparation. US Patent 6,488,961,December 3, 2002.

33. Mizumoto, T.; Masuda, Y.; Fukui, M. Intrabuccally Dis-solving Compressed Moldings and Production ProcessThereof. US Patent 5,576,014, November 19, 1996.

34. Lagoviyer, Y.; Levinson, R.S.; Stotler, D.; Riley, C.T.Means for Creating a Mass Having Structural Integrity.US Patent 6,465,010, B1, October 15, 2002.

35. http://www.uspharmacist.com/oldformat.asp?url¼newlook/files/Feat/FastDissolving.htm&pub_id¼8&article_id¼842accessed March 27, 2006).

36. Flanner, H.; Chang, R.; Pinkett, J.; Wassink, S.; White, L.Rapid Immediate Release Oral Dosage Form. US Patent6,384,020, May 7, 2002.

37. Cremer, K. Fast dissolving technologies in detial. Orallydisintegrating dosage forms. Pharma Concepts GmbH &Co. KG 2001, 62–97.

38. Tian, W.; Leighton, A.; Langridge, J. Fast DisintegratingTablet. European Patent ZA200406193, October 6, 2005.

39. Jeong, S.H.; Fu, Y.; Park, K. Frosta�: a new technologyfor making fast-melting tablets. Expert Opinion on DrugDelivery 2005, 2 (6), 1107–1116.

40. http://www.spipharma.com (accessed March 27, 2006).41. http://www.roquette.com (accessed March 20, 2006).42. http://www.particledynamics.com (accessed March 20, 2006).43. http://www.encap.com/ (accessed March 20, 2006).44. http://www.pctincusa.com (accessed March 20, 2006).45. http://www.abfingredients.com/?page=press (accessed

March 27, 2006).


encyclopedia of pharmaceutical technology, third edition

Documents