Pharmaceutical Technology FEBRUARY 2001 1

he number of products based onnew drug delivery systems has sig-nificantly increased in the past fewyears, and this growth is expected

to continue in the near future. Recent advances in the field of genomics have accelerated research of biopharmaceuti-cals, and today a large number of compa-nies are busy developing protein- and peptide-based drugs. These biopharma-ceuticals present challenges to drug deliv-ery scientists because of their unique nature and difficulty in delivery throughconventional routes. Therefore, future re-search will focus on the delivery of thesecomplex molecules through differentroutes, including oral, nasal, pulmonary,vaginal, rectal, etc. This review is an up-date on some of the existing drug deliverytechnologies for oral controlled-release,delivery of large molecules, liposomes, tastemasking, fast-dispersing dosage forms, andtechnology for insoluble drugs. Nasal, pul-monary, vaginal, and rectal routes also arebriefly reviewed.

In the 21st century, the pharmaceuti-cal industry is caught between the down-ward pressure on prices and the increas-ing cost of successful drug discovery anddevelopment. The average cost and timefor the development of a new chemicalentity are much higher (approximately$500 million and 10–12 years) than thoserequired to develop a novel drug deliv-ery system (NDDS) ($20–50 million and3–4 years). In the form of an NDDS, anexisting drug molecule can get a new life,thereby increasing its market value andcompetitiveness and extending patent life.Limited formularies, patent expiry withsubsequent entry of generic competition,and vertical integration have the entirepharmaceutical industry (approximately

350 drug delivery companies and 1000medical device companies) focused ondesigning and developing new and bet-ter methods of drug delivery. There hasbeen a significant increase in approvalsof NDDSs in the past couple of years, andthis is expected to continue at an im-pressive rate in the near future. The saleof drug delivery products is valued atmore than $22 billion worldwide, andthis growth is expected to continue intothe present century. It is estimated thatthe drug delivery market will be at $120billion by 2007.

At present, there are so many existingdrug delivery technologies that a totalcompilation is not within the scope ofthis article. Yet an attempt is being madeto compile some of the most successfullymarketed drug delivery technologies.Most of the information is derived fromthe Internet sites of the major drug de-livery companies.

Current status of drug delivery technologiesIncorporating an existing medicine intoa new drug delivery system can signifi-cantly improve its performance in termsof efficacy, safety, and improved patientcompliance. The need for delivering drugsto patients efficiently and with fewer sideeffects has prompted pharmaceutical com-panies to engage in the development of newdrug delivery systems. Today, drug deliverycompanies are engaged in the developmentof multiple platform technologies for controlled release, delivery of large mole-cules, liposomes, taste-masking, oral fast-dispersing dosage forms, technology for in-soluble drugs, and delivery of drugs throughintranasal, pulmonary, transdermal, vagi-nal, colon, and transmucosal routes.

Rajan K. Verma is a PhD scholar and SanjayGarg* is assistant professor in the department of pharma-ceutics at the National Instituteof Pharmaceutical Educationand Research (NIPER), sector67, SAS Nagar, Punjab 160062, India, tel. 91 11 214682,fax 91 11 214692, e-mailgargsanjay@yahoo.com.

*To whom all correspondenceshould be addressed.

Current Status of

Drug Delivery Technologies and Future DirectionsRajan K. Verma and Sanjay Garg *

Evolution of an existing drugmolecule from a conventionalform to a novel delivery systemcan significantly improve itsperformance in terms of patientcompliance, safety, and efficacy.These days, drug deliverycompanies are engaged in thedevelopment of multipleplatform technologies to getcompetitive advantage, extendpatent life, and increase marketshare of their products.

T

Rajan K. Verma and Sanjay Garg, “Current Status of Drug Delivery Technologies andFuture Directions,” Pharmaceutical Technology On-Line, 25 (2), 1–14 (2001).

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Oral controlled releaseOral ingestion is the traditionally preferredroute of drug administration, providing aconvenient method of effectively achiev-ing both local and systemic effects. In con-ventional oral drug delivery systems, thereis very little control over release of the drug.The effective concentration at the target site can be achieved by intermittentadministration of grossly excessive doses,which, in most situations, often results inconstantly changing, unpredictable, andoften sub- or supra-therapeutic plasmaconcentrations leading to marked side effects. An ideal oral drug delivery systemshould steadily deliver a measurable andreproducible amount of drug to the targetsite over a prolonged period. Controlled-release (CR) delivery systems provide auniform concentration/amount of thedrug at the absorption site and thus, after absorption, allow maintenance of plasmaconcentrations within a therapeutic range,which minimizes side effects and also re-duces the frequency of administration. CRproducts are formulations that release ac-tive drug compounds into the body grad-ually and predictably over a 12- to 24-hourperiod and that can be taken once or twicea day. Typically, these products providenumerous benefits compared with im-mediate-release drugs, including greatereffectiveness in the treatment of chronicconditions, reduced side effects, greaterconvenience, and higher levels of patientcompliance due to a simplified dosingschedule. Because of the above advantages,such systems form the major segment ofthe drug delivery market.

A number of techniques are used toachieve controlled release of drugs via theoral cavity. Some of these techniques arereviewed briefly as follows.

Osmotic systems utilize osmotic pres-sure as the driving force for the deliveryof drugs. In its simplest design, it consistsof an osmotic core (a drug with or with-out an osmagent), which is coated with asemipermeable membrane, and a deliveryorifice is created with a mechanical or laserdrill. When the dosage form comes in con-tact with water, water is imbibed becauseof the resultant osmotic pressure of thecore and the drug is released from the ori-fice at a controlled rate. This system,known as elementary osmo-tic pump(EOP), was first developed by Felix

Theeuwes of AlzaCorporation (USA).A number of modifi-cations of this systemare available today,like the push-pull os-motic pump, whichis a bilayer tablet andis suitable for the delivery of highly orpoorly water-solubledrugs. The upperlayer consists of adrug along with os-motic agents. Thelower layer consists ofpolymeric osmoticagents. The tablet iscoated with a semi-permeable mem-brane, and a deliveryorifice is created sim-ilar to that of anEOP. Figure 1 showsthe schematic dia-gram of these two types of systems. AlzaCorporation is a leader in the field of oralosmotic systems, and some of the com-mercially marketed products based on thistechnology are listed in Table I.

MacroCap (Biovail Corporation Inter-national, Canada) utilizes a controlled-release pellet system, which is based onthe coating of pellets containing pharma-ceutical compounds with specialized poly-mers and plasticizers to control the rateand location of drug release in the gas-trointestinal (GI) tract. The MacroCapsystem uses the features of pH-activatedor pH- independent diffusion, osmoticdiffusion, or a combination of these mech-anisms. The pH-activated diffusion systemuses specifically designed coating polymersto control the delivery of drugs dependingon the pH environment of the GI tract.Under the osmotic diffusion system, therate of release of the drug from the pelletsis controlled by a combination of princi-ples involved in osmosis and diffusion.

Micropump Oral Controlled DeliverySystem (Flamel Technologies, France) issuitable for drugs that require an extended absorption time in the small in-testine. Each Micropump dosage form iscomposed of thousands of microparticlesranging in size between 200 and 400 mmand having a bioadhesive surface. Each

microparticle contains a drug crystal orgranule enclosed in a polymer coatingthat acts as a shell through which the drugcan be released under the effect of osmoticpressure. Modulating the thickness andcomposition of the polymer coating cancontrol the rate and duration of drug delivery.

MODAS or Multiporous Oral Drug Ab-sorption System (Elan Corporation, Ire-land) is surrounded by a non-disintegrat-ing, timed-release coating, which aftercoming in contact with gastrointestinalfluid is transformed into a semipermeablemembrane through which the drug diffusesin a rate-limiting manner. The tablet con-sists of a core of active drug plus excipients.This is then coated with a solution of in-soluble polymers and soluble excipients.After ingestion, the fluid of the gastro-intestinal tract dissolves the soluble excipients in the outer coating leaving justthe insoluble polymer, thereby forming anetwork of tiny, narrow channels con-necting fluid from the GI tract to the innerdrug core of water-soluble drug. This fluidpasses through these channels into thecore, dissolves the drug, and a resultantsolution of drug diffuses out in a con-trolled manner to the outside. The addi-tion of excipients, such as buffers can helpproduce a microenvironment within the

(a)

(b)

Osmotic drug core

Water

Delivery Orifice

Before operation During operationSemi-permeable

membrane

Osmotic drug core

Delivery orifice

Expanded push compartment

Polymeric push compartment

Figure 1: Schematic diagram of an elementary osmotic pump (a) anda push-pull osmotic pump (b).

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tablet that facilitates more predictable re-lease rates and absorption. Examples ofMODAS products developed by Elan in-clude Bron-12 (a 12-hour multicompo-nent over-the-counter [OTC] cough andcold product) and once-daily potassiumchloride.

SCOT or Single Composition OsmoticTablet System (Andrx Pharmaceuticals,USA) is also based on osmotic principlesand utilizes various osmotic modulatingagents as well as polymer coatings to pro-vide a zero-order release of a drug. PortabSystem (Andrx Pharmaceuticals) utilizesan osmotic core, typically containing awater-soluble drug. The core includes awater-soluble component and a continu-ous polymer coating. The purpose of thesoluble agent is to expand the core andthereby create microporous channelsthrough which the drug is released.

Zer-Os tablet technology (ADD DrugDelivery Technologies AG, Switzerland) isan osmotic system developed specificallyfor the delivery of lipophilic compounds.The tablet consists mainly of a core ofpoorly water soluble drug along with gel-

forming agents and standard excipients.The gel-forming agent, after coming incontact with water, forms a gel of an ap-propriate viscosity, and a suspension of apoorly water-soluble agent is formed andis pushed out of the orifice at a controlledrate. Tegretol XR, a successful product onthe US market, is based on this technol-ogy as well.

In addition to osmotic principles, nu-merous other approaches also exist for thedelivery of drugs in a controlled manner,some of which are briefly reviewed in thefollowing sections.

Ceform microsphere technology (FuiszTechnology Ltd., USA) allows the pro-duction of uniformly sized and shapedmicrospheres of pharmaceutical com-pounds. These microspheres are almostperfectly spherical, having a diameter thatis typically 150 to 180 mm, and allow forhigh drug content. The microspheres canbe used in a wide variety of dosage forms,including tablets, capsules, suspensions,effervescent tablets, and sachets. The mi-crospheres can be formulated for en-hanced absorption (Ceform EA) or taste

isolation (Ceform TI) and may be coatedfor controlled release (Ceform CR), pro-vided with an enteric coating (CeformEC), or combined into a fast/slow releasecombination (Ceform EA/CR).

CONSURF or Constant Surface AreaDrug Delivery Shuttle (Biovail Corpora-tion International) releases drug by theconcurrent swelling and dissolution of amatrix tablet. A constant surface area ispresented during the drug’s transitthrough the GI tract.

Contramid (Labopharm Inc., Canada)utilizes excipients (mainly starch) for thecontrolled delivery of drugs. The chemi-cal cross-linking of a starch consistingmainly of amylose leads to Contramid.During the cross-linking, bridges areformed between the polysaccharides. Vary-ing the quantity of cross-linking reagentused in the manufacturing process cancontrol the degree of the cross-linking.Once the Contramid dosage form is in thestomach, gastric fluids turn Contramid’ssurface to gel and the resulting semi-permeable membrane stabilizes rapidly.This membrane, which does not begin to

Table I: Some commercially marketed oral osmotic systems.Product name Chemical Developer/Marketer IndicationAcutrim Phenylpropanolamine Alza/Heritage Appetite suppressantAlpress LP Prazosin Alsa/Pfizer (France) HypertensionCalan SR Verapamil Alza/GD Searle & Co. HypertensionCardura XL Doxazosin mesylate Alza/Pfizer (Germany) HypertensionConcerta Methylphenidate Alza Attention Deficit

Hyperactivity DisorderCovera HS Verapamil Alza/G.D. searle HypertensionDitropan Oxybutynin Alza/UCB Pharma Overactive bladder

ChlorideDynaCirc CR Isradipine Alza/Novartis HypertensionEfidac/24 Pseudoephedrine Alza/Novartis Cold medication.Efidac 24 Chloropheniramine Alza/Novartis Anti-allergicChloropheniramineEfidac 24 Pseudoephedrine and Alza/Novartis Anti-allergic and cold

Pseudoephedrine/ Brompheniramine . treatmentBrompheniramine

Glucotrol XL Glipizide Alza/Pfizer Anti-diabeticMinipress XL Prazosin Alza/Pfizer HypertensionProcardia XL Nifedipine Alza/Pfizer Hypertension/anginaSudafed 24 hour Pseudoephedrine Alza/Warner Lambert Nasal decongestantTeczem Enalapril and Merck/Aventis Hypertension

DiltiazemTiamate Diltiazem Merck/Aventis HypertensionVolmax Albuterol Alza/Muro Pharmaceuticals Bronchospasm

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break down until it reaches the colon, en-sures that there is a regular release of theactive ingredients contained in the dosageform.

Dimatrix or Diffusion Controlled Ma-trix System (Biovail Corporation Inter-national) consists of either beads made byextrusion-spheronization or by pow-der/solution layering on nonpareil beadsor in the form of a tablet matrix. Themechanism of release is by diffusion ofdissolved drug molecules. Multipart orMultiparticle Drug Dispersing Shuttle(Biovail Corporation International) con-sists of a tablet that carries controlled-release beads or pellets through the GItract while maintaining their integrity andrelease properties. Release and distribu-tion of the beads is triggered by superdis-integration of the tablet.

DPHS or Delayed Pulsatile Hydrogel Sys-tem (Andrx Pharmaceuticals) is designedfor use with hydrogel matrix products thatare characterized by an initial zero-orderrelease of drug followed by rapid release.This release profile is achieved by theblending of selected hydrogel polymers toachieve a delayed pulse.

DUREDAS or Dual Release Drug Ab-sorption System (Elan Corporation) uti-lizes bilayer-tableting technology, whichhas been specifically developed to providetwo different release rates or dual releaseof a drug from a single dosage form. Thetablets are prepared by two separate direct-compression steps that combine animmediate-release granulate (for rapidonset of action) and a controlled-releasehydrophilic matrix complex within onetablet. The controlled-release matrix re-mains intact and slowly absorbs fluidfrom the GI tract, which causes the ma-trix to expand and transforms the hy-drophilic polymers into a porous, viscousgel that serves as a barrier between thedrug and the surrounding fluid. As thegel continues to expand, fluid penetratesfurther into the dosage form, dissolvingthe drug and allowing the resulting solu-tion to diffuse out in a controlled man-ner. A further extension of the Duredastechnology is the production of con-trolled-release combination dosage formswhereby two different drugs are incor-porated into the different layers, and thedrug release of each is controlled to max-imize therapeutic effect of the combina-

tion. Again both immediate- release andcontrolled-release combinations of thetwo drugs are feasible.

Gastric retention system (DepoMed Inc.,USA) consists of a drug containing poly-meric units that, if taken with a meal,remain in the stomach for an extended period of time to provide continuous, con-trolled delivery of an incorporated drug.

Geomatrix (Skye Pharma Plc., USA) is aplatform of oral controlled-release tech-nology that controls the amount, timing,and location of the release of drug com-pounds into the body. Geomatrix systemis a multilayer tablet with a matrix corecontaining the active ingredient and oneor more modulating layers (barriers) ap-plied to the core during the tabletingprocess. The function of these barriers isto delay the interaction of the core withthe dissolution medium. Eight Geomatrixtechnologies are designed to meet a widerange of therapeutic objectives: Zero-orderrelease provides a constant rate of drugrelease over a defined period of time; bi-nary release is used to provide the con-trolled release of two different drugs in asingle tablet; quick–slow release providesa quick burst of drug release followed bya constant rate of release over a definedperiod of time; slow–quick release pro-vides an initial constant rate of release fol-lowed by a quick burst of drug release ata predetermined time; positioned releasedelivers the drug to a predetermined po-sition in the digestive system before it be-gins to release the active drug compounds;accelerated release provides a constantlyaccelerating rate of drug release; delayedrelease provides a predetermined time lagbefore it begins releasing drug molecules;multiple pulse provides an initial quickburst of drug release followed by a prede-termined period of no release. Some ofthe drugs that are marketed based on thistechnology are diltiazem hydrochloride,nifedipine, and diclofenac sodium.

GMHS or Granulated Modulating Hy-drogel System (Andrx Pharmaceuticals)incorporates hydrogel and binding poly-mers with the drug, which is formed intogranules and then pressed into tablet form.

IPDAS or Intestinal Protective Drug Ab-sorption System (Elan Corporation) is amultiparticulate tablet technology, thathas been developed to enhance the gas-trointestinal tolerability of potentially

irritant or ulcerogenic drugs. Unlike othertablet formulations, IPDAS is composedof numerous high-density controlled-release beads. Each bead is manufacturedby a two-step process that involves the ini-tial production of a micromatrix of drugembedded in polymer and the subsequentcoating of this micromatrix with time-release coatings that are transformed intoa rate-limiting semipermeable membranein vivo. After ingestion, the tablet rapidlydisintegrates and beads are dispersed intothe stomach and subsequently pass intothe duodenum and along the GI tract ina controlled and gradual manner, inde-pendent of the feeding state. Drug releasefrom each bead occurs by a diffusionprocess through the micromatrix and sub-sequently through the pores in the rate-controlling semipermeable membrane.The intestinal protection of IPDAS is byvirtue of the multiparticulate nature ofthe formulation, which ensures wide dis-persion of irritant drug throughout theGI tract. The controlled-release charac-teristics of the individual bead avoids thehigh concentrations of drug being re-leased locally and absorbed systemically.An immediate-release granulate also canbe included in the tablet and may be re-quired for a fast onset of action. IPDASproducts are approved worldwide, andElan’s Naprelan product (once-daily na-proxen sodium) is sold in the US market.

Multipor technology (Ethical HoldingsPlc., UK) consists of a tablet core of an ac-tive drug, which is surrounded by a water-insoluble polymer membrane. The mem-brane consists of minute water-soluble par-ticles that, after coming in contact withwater, dissolve and form pores from whichthe drug is released. This technology alsocan be applied to pellets, granules, orminitablets. One or more drug substancesalso can be incorporated into the mem-brane, which can provide an immediate- release layer.

Pharmazome or Microparticulate DrugDelivery Technology (Elan Corporation)consists of combinations of polymers anddrugs in the size range of 5 to 125 mm.Each microparticle is a micromatrix ofdrug embedded uniformly throughout aninsoluble polymer and is produced by either a spray drying or emulsion tech-nique. By varying the amount and natureof the polymer used to form the micro-

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particle, this technology allows controlled-and/or delayed-release of drug from theformulation. In addition, this technologyalso can be used for taste masking becauseit acts as a means of physically preventinga drug from going into solution in themouth and coming into direct contactwith taste receptors. For the purpose ofpalatability, 125 mm is set as the upperlimit for Pharmazomes because these par-ticles have a gritty feeling that may be un-acceptable to consumers. Pharmazomescan be subsequently incorporated into avariety of delivery systems like chewabletablets, effervescent tablets, oral ready-made aqueous and non-aqueous suspen-sions, reconstitutable powders, and unit-dose sachet or sprinkle systems. Productsusing Pharmazome technology are cur-rently approved in Japan, Europe, andCentral and South America and includetwice-daily theophylline.

PPDS or Pelletized Pulsatile Delivery System (Andrx Pharmaceuticals) is de-signed for use with products that requirea pulsed release of the drug. This tech-nology uses pellets that are coated withspecific polymers and agents to controlthe release rate of the microencapsulateddrug. By varying the proportion and com-position of the polymer mixtures, for-mulations can practically control the re-lease rate of the drug. Peltab System(Andrx Pharmaceuticals) utilizes poly-mer-coated drug pellets or drug crystalsthat are manufactured into tablets. Inorder to provide controlled release, awater-insoluble polymer is used to coatdiscrete drug pellets or crystals that thencan resist the action of fluids in the GItract. This technology incorporates astrong polymer coating enabling thecoated pellets to be compressed into tabletswithout significant breakage.

PRODAS or Programmable Oral DrugAbsorption System (Elan Corporation) isa multiparticulate drug delivery technol-ogy that is based on the encapsulation ofcontrolled-release minitablets in the sizerange of 1.5 to 4 mm in diameter. Thistechnology represents a combination ofmultiparticulate and hydrophilic matrixtablet technologies and thus provides thebenefits of both these drug delivery sys-tems in one dosage form. Minitablets withdifferent release rates can be combinedand incorporated into a single dosage

form to provide the desired release rates.These combinations may include imme-diate-release, delayed-release, and/or con-trolled-release minitablets. In addition tocontrolled absorption over a specified pe-riod, PRODAS technology also enablestargeted delivery of drug to specified sitesof absorption throughout the GI tract.Combination products also are possibleby using minitablets formulated with dif-ferent active ingredients.

Reduced irritation system (DepoMed,Inc.) is designed to significantly reducelocal gastrointestinal irritation from theeffects of certain drugs. This system con-sists of an outer gelatin capsule that is de-signed to rapidly disintegrate upon in-gestion to deliver multiple small sphericalpellets. The spherical pellets are composedof an inert matrix of polymeric materialin which the active ingredient is homoge-neously dispersed in its solid state.

RingCap (Alkermes Inc., USA) combinesmatrix tablets and existing capsule band-ing processes to create controlled-releasesolid oral dosage forms. The RingCap sys-tem utilizes bands of insoluble polymeron a matrix tablet. The manufacturingprocess involves compressing the drug intocylindrical matrix tablets that are subse-quently film coated. Then, existing cap-sule-banding technology is used to applytwo or more polymeric rings around thecircumference of the matrix tablet. Thesebands lower the initial release of the drugby reducing the surface area exposed. Asthe matrix tablet erodes, new surface areasare created underneath and around thebands, thus increasing the rate of release.The release rate of the drug substance canbe designed to remain nearly constant oreven increase with time by adjusting thenumber and width of polymer bands.

SODAS or Spheroidal Oral Drug Ab-sorption System (Elan Corporation) is amultiparticulate drug-delivery technol-ogy and consists of controlled-releasebeads that can be produced in the rangefrom 1 to 2 mm in diameter. Each beadbegins as an inert core onto which thedrug is applied, followed by a number oflayers of soluble and insoluble polymerscombined with other excipients to pro-duce the rate-controlling layer. Drug release from these beads occurs by a dif-fusion process. Within the GI tract, thesoluble polymers dissolve, leaving pores

within the outer membrane. Fluid thenenters the core of the beads and dissolvesthe drug. The resultant solution diffusesout in a controlled, predetermined man-ner allowing for prolongation of the invivo dissolution and absorption phases.The immediate environment of the drugwithin the seed core can be manipulatedby use of excipients to ensure optimal sta-bility and solubility. These controlled-re-lease beads can be packaged into a capsuleor compressed into a tablet to produce thefinal dosage form. Products utilizingSODAS technology are approved and mar-keted throughout Europe, the US, andJapan and include once-daily diltiazemand once-daily verapamil. Cardizem SRand CD are twice- and once-daily formu-lations, respectively, of diltiazem hy-drochloride (based on SODAS technol-ogy) developed by Elan in partnershipwith Hoechst Marion Roussel. Verelan wasthe first verapamil controlled-release formulation (based on SODAS technol-ogy) in which the extent or rate of ab-sorption was not affected by food intake.In addition, the capsule could be openedand the beads sprinkled on soft food forthose patients unable to swallow tradi-tional dosage forms.

SMHS or Solubility Modulating Hydro-gel System (Andrx Pharmaceuticals) is de-signed for products utilizing a hydrogel-based dosage system that providessustained release without the need to usespecial coatings or structures, both ofwhich add to the cost of manufacturing.This technology avoids the initial burst effect commonly observed with other sus-tained-release hydrogel formulations.Diltia XT, marketed by Andrx Pharma-ceuticals, is based on this technology andis used for the treatment of hypertensionand angina.

SPDS or Stabilized Pellet Delivery Sys-tem (Andrx Pharmaceuticals) is designedspecifically for unstable drugs and incor-porates a pellet core of drug and protec-tive polymer outer layer(s).

SQZGel oral controlled-release system(Macromed, Inc., USA) is an oral deliv-ery system based on patented pH-sensi-tive hydrogels comprised of combinationsof FDA-approved generally recognized assafe (GRAS) polymers. In response to in-ternal or external pH levels, and by design,this system evenly releases a drug over an

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8- to 20-hour period based on the deliv-ery needs of the therapy. SQZGel is man-ufactured by an inexpensive standardtablet dosage form technique.

TIMERx (Penwest Pharmaceuticals Co.,USA) is a controlled-release drug deliverytechnology applicable to a broad range oforally administered drugs. This technol-ogy is based on an agglomerated hy-drophilic matrix. The matrix consists oftwo pharmaceutically acceptable polysac-charides, locust bean gum and xanthangum. Interactions between these compo-nents in an aqueous environment form atight gel with a slowly eroding core fromwhich the drug is released at a controlledrate for an extended period of time.Slofedipine XL (nifedipine) and CystrinCR (oxybutynin) are based on this tech-nology and are marketed in Europe.

KV Pharmaceuticals (USA) has devel-oped technologies for controlled deliveryof drugs that includes KV/24, which is amultiparticulate technology that can com-bine several different drug compounds,each requiring its own unique release pro-file, in a single tablet form that can betaken orally once every 24 hours. MeterRelease is a twice-a-day dosing, polymer-based drug delivery system that offers dif-ferent release characteristics than KV/24and is used for products that require adrug release rate of 8 to 12 hours. Syma-trix is a microparticulate formulation thatemploys smaller particles than KV/24 andMeter Release. Symatrix encapsulates ther-apeutic agents that improve a drug’s ab-sorption in the body when precise releaseprofiles are less important. Spheroid com-bines equipment technology with formu-lation expertise. Each particle has its ownmatrix as the rate-controlling mechanismfor the release of its contents. These parti-cles can be filled into hard gelatin capsulesor can be compressed into tablets. Orasertis designed as a solid oral dosage systemthat possesses bioadhesive and controlled-release properties. Orasite is a controlled-release muco-adhesive delivery system ad-ministered orally in solid or liquid form.

Triglas technology (Ethical HoldingsPlc.) is mainly for water-insoluble drugsand is based upon formulating drug withappropriate additives to form a solid so-lution of drug that can be coated onto thecarrier particles. These particles then canbe made into tablets. Rhotard (Ethical

Holdings Plc.) is based on double-matrixtechnology that involves two granulationstages during the manufacturing process.

Large-molecule deliveryResearch efforts in the field of genomicsare expected to accelerate the discovery ofnew therapeutic biomolecules, placing anincreased demand on the development ofdelivery systems for these drugs. This classof drugs is usually characterized by largesize, fragile nature, short biological half-life, and limited ability to cross cell mem-branes. These properties, along with themethods of administration of biophar-maceuticals, can limit their clinical appli-cations to certain disease states that war-rant the expense and inconvenience offrequent injection. At present, a large num-ber of companies are working in this area,as evidenced by the increasing number ofavailable technologies for delivering thesecompounds.

BEODAS or Bioerodable Enhanced OralDrug Absorption System (Elan Corpora-tion) is an oral microparticulate drug de-livery technology designed for the deliv-ery of macromolecules and is based on theentrapment of active pharmaceutical en-tities in a range of submicron sizes withinbiodegradable polymer matrices. Furthermodifications to the BEODAS platformtechnology have the potential for targeteddelivery and enhanced absorption of phar-maceutical entities that normally are notamenable to oral administration.

DepoFoam (DepoTech Corporation,USA) drug delivery system consists of mi-croscopic spherical particles composed ofhundreds to thousands of nonconcentricchambers (depots) encapsulating the drugto be delivered. The individual chambersare separated by a bilayer lipid membranemade up of synthetic duplicates of lipidsfound naturally in the body, resulting ina material that is both biodegradable andbiocompatible. The DepoFoam systemprovides either local site or systemic de-livery and can be administered by a num-ber of routes, including intrathecal, sub-cutaneous, intramuscular, and intra-articular. Typically, a DepoFoam particleconsists of less than 10% lipid and 90%aqueous drug solution, giving it a highloading factor. DepoFoam formulationsmaintain a drug in its therapeutic windowfor periods ranging from days to many

weeks, allowing lower initial drug levelsand significantly fewer doses. DepoFoamtechnology is applicable across a varietyof compounds, including small molecules,proteins, peptides, DNA, and vaccines.Some of the products like DepoCyt (cy-tarabine), DepoMorphine (morphine sul-fate), and DepoAmikacin (amikacin) arebased on this technology.

DUROS (Alza Corporation) is based onimplant technology, which provides an al-ternative for the delivery of a wide rangeof therapeutic compounds, including pep-tides, proteins, and other bioactive macro-molecules. These implants are miniaturetitanium cylinders designed to providecontinuous osmotically driven delivery ofdrugs within the body for up to one year.Following implantation, DUROS implantsenable continuous, precise delivery of thetherapeutic compound at rates as low as1% of a drop of water per day. The cylin-der is manufactured from titanium be-cause of the material’s tolerability tohuman tissue and its long use in medicaldevices such as implantable defibrillatorsand joint replacements. The cylinder pro-tects therapeutic agents from degradationin the body and enables a drug to remainstable for extended periods of time. Re-cently, Viadur (leuprolide acetate implant),which is based upon this technology, hasbeen approved for once-yearly palliativetreatment of advanced prostrate cancer.

LOCDAS or Localized Drug AbsorptionSystem (Elan Corporation) is a novel tar-geted oral drug delivery technology. Thistechnology utilizes targeting ligands, thatspecifically bind to certain absorption siteslocated on the apical surface of the epithelium cells of the human GI tract.These ligands are attached to coated mi-croparticles of protein and peptide drugsthat serve to protect their contents fromthe hostile environment of the GI tract.These are subsequently packaged in enteric-coated capsules that deposit the particlesat appropriate sites of absorption withinthe GI tract.

Macromol Systems (Cortecs InternationalLtd., UK) enable polypeptides and pro-teins to be administered by the oral routerather than by injection. Oral Mucosal Vac-cines (Cortecs International Ltd.) can beadministered by mouth and act by pre-senting the antigen to specialized cellswithin the intestine that pick up small par-

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ticles via the Peyer’s Patch and can processthem into the immune system to stimu-late a defensive response at mucosal sites.

Medipad (Elan Corporation) is a patient-friendly system that enables controlledparenteral delivery while minimizing dis-comfort. This system is designed for thedelivery of a broad range of compounds,from small molecules to proteins and pep-tides. Medipad is a low-cost, disposable,single-use system that combines uniquemicroinfusion technology with an inte-gral subcutaneous probe. An adhesivebacking fixes the system discreetly againstthe user’s chest or abdomen where it con-tinuously dispenses drug for up to 48hours. It is the only technology that cur-rently combines the simplicity of a patchwith the delivery capabilities of an infu-sion pump. The Medipad technology canbe tailored to a range of delivery volumes,delivery rates, and delivery profiles (bolus,extended bolus, continuous, or continu-ous plus bolus).

Oral vaccines: Elan Corporation and En-dorex Corporation, a US biotechnologycompany, have formed a joint venture todevelop a portfolio of technologies thatwill permit the oral administration of vac-cines. The technology focuses on two dif-ferent approaches for oral delivery of anti-gen through intestinal epithelial tissue.These are the production of micro- andnanoparticles of a defined size range con-taining antigens dispersed within a bio-erodable polymer matrix and polymer-ized liposomal vesicles in which antigensare enclosed in a stable membrane. Bothof these technologies protect antigens fromthe hostile environment of the GI tractand ensure that they are presented in anintact form to the mucosal surface forabsorption.

ProLease and Medisorb (Alkermes Inc.,USA) are two patented and proprietaryprocesses for creating injectable sustained-release products lasting from days tomonths. ProLease is specifically designed

for complex and fragile bioactive moleculessuch as proteins, and Medisorb is designedfor traditional small molecules and pep-tides. Both technologies are microsphere-based delivery systems composed of the de-sired bioactive molecule incorporated intoa matrix of poly-(DL-lactide-coglycolide),a common biodegradable medical poly-mer. Microspheres are packaged in vials asa dry free-flowing powder. Before admin-istration the microspheres are suspendedin an aqueous vehicle and administered bysubcutaneous or intramuscular injection.Release profiles can be adjusted by manip-ulation of formulation parameters and bycontrol of the fabrication process.

Transdermal and topical deliverySystemic delivery of drugs via transder-mal routes has generated considerable in-terest during the last decade. Transdermaldrug delivery systems (TDDS) deliverdrugs through the skin into the systemiccirculation at a predetermined rate,

Table II: Some of the commercially marketed transdermal systems.Product name Chemical Developer/Marketer IndicationAlora Estradiol TheraTech/Proctor and Gamble Postmenopausal syndromeAndroderm Testosterone TheraTech, Inc./GlaxoSmithKline Hypogonadism in malesCatapres-TTS Clonidine Alza/Boehinger Ingelheim HypertensionClimaderm Estradiol Ethical Holdings, Postmenopausal syndrome

Plc/Wyeth-AyerestClimara Estradiol 3M Pharmaceuticals/Berlex Labs Postmenopausal syndromeCombiPatch Estradiol/ Noven Pharmaceuticals, Inc. Hormone replacement

Norethindrone Aventis therapyDeponit Nitroglycerin Schwarz-Pharma Angina pectorisDuragesic Fentanyl Alza/Janssen Pharmaceutica Moderate/severe painEstraderm Estradiol Alza/Novartis Postmenopausal syndromeFematrix Estrogen Ethical Holdings/Solvay Postmenopausal syndrome

Healthcare Ltd.FemPatch Estradiol Parke-Davis Postmenopausal syndromeHabitraol Nicotine Novartis Smoking cessationMinitran Nitroglycerin 3M Pharmaceuticals Angina pectorisNicoderm Nicotine Alza/GlaxoSmithKline Smoking cessationNicotrol Nicotine Cygnus Inc./McNeil Smoking cessation

Consumer Products, Ltd.Nitrodisc Nitroglycerin Roberts Pharmaceuticals Angina pectorisNitro-dur Nitroglycerin Key Pharmaceuticals Angina pectorisNuvelle TS Estrogen/ Ethical Holdings, Plc./Schering Hormone replacement

Progesterone therapyProstep Nicotine Elan Corp./Lederle Labs Smoking cessationTestoderm TTS Testosterone Alza Corp. Hypogonadism in malesTransderm-Scop Scopolamine Alza/Novartis Motion sicknessTransderm Nitro Nitroglycerin Alza/Novartis Angina pectorisVivelle Estradiol Noven Pharmaceuticals, Inc./ Postmenopausal syndrome

Novartis

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thereby avoiding metabolism in the GItract and liver. Therefore, the amount ofactive ingredient required for transdermaldelivery can be significantly less than thatfor oral systems. TDDSs provide constantblood levels for 1 to 7 days and increasedpatient compliance. Table II lists some ofthe commercially marketed transdermalpatches.

Despite some of the advantages oftransdermal systems, delivery of certaindrugs can be difficult because of their poorpermeability across the skin. Use of pen-etration enhancers and prodrugs can in-crease the transdermal permeability ofdrugs. Recently there has been a lot of in-terest in physical techniques like ion-tophoresis, electroporation, sonophore-sis, and reverse iontophoresis as a meansof increasing the permeability of drugsacross the skin. Iontophoresis utilizes asmall voltage (typically 10 V or less) andcontinuous constant current (typically 0.5mA/cm2) to push a charged drug mole-cule into skin or other tissue. Electropo-ration utilizes a high-voltage (.100 V)pulse for a very short duration (ms to ms)to create new aqueous pathways (pores)across lipid-containing barriers, forcingthe drug molecule into systemic circula-tion. Sonophoresis is the application ofultrasound energy to enhance percuta-neous drug absorption. Some of the suc-cessful technologies in this field are as follows

Dermaflex (Elan Corporation) is a pas-sive transdermal patch employing a hydro-gel matrix in which a pharmaceutical compound is incorporated. Dermaflexregulates the availability and the absorp-tion of pharmaceutical compounds in amanner that may allow controlled and ef-ficient delivery.

Dermasite (KV Pharmaceuticals) is asemisolid site-release configuration fortopical applications to the skin.

D-trans (Alza Corporation) is a trans-dermal system that provides rate-controlledadministration of drugs through the skin.

These systems resemble small adhesive ban-dages and can offer multiday or weekly dos-ing and improved patient compliance.

E-trans (Alza Corporation) is an electro-transport system that uses low-powerelectric current to control drug adminis-tration through intact skin. E-trans sys-tems are being developed to provide continuous drug delivery as well as patient-controlled pulsatile delivery.

Microsponge systems (Advanced PolymerSystems Inc., USA) are based on micro-scopic polymer-based microspheres thatcan bind, suspend, or entrap a wide vari-ety of substances and incorporate theminto a formulated product, such as gel,cream, liquid, or powder. Microspongesystems are used primarily as reservoirsfor releasing active ingredients in an ex-tended period of time and as receptaclesfor absorbing undesirable substances, suchas excess skin oil. EveryStep (odor-fight-ing foot powder), Exact acne treatment (acream formulation of benzoyl peroxide),and Retino-A-Micro (tretinoin gel) arebased on this technology.

Polytrap systems (Advanced PolymerSystems Inc.) are designed to absorb skinoils and eliminate shine, provide a smoothand silky feel to product formulations, en-trap and deliver various ingredients in per-sonal care products, and convert liquidsinto powders.

TheraDerm-LRS (Theratech, Inc., USA) isa liquid reservoir system. Numerous drugformulations can be incorporated into aTheraDerm-LRS patch because the systemis not rate limiting to the administration ofthe drug and the drug reservoir is isolatedphysically from the adhesive within the sys-tem. TheraDerm-MTX (Theratech Inc.) isa matrix system based on an adhesive matrix patch design. The drug is incorpo-rated into the adhesive, resulting in a lightand flexible patch that conforms to the skinfor maximum adhesion and comfort.

TheraPatch (LecTec Corporation, USA)is a self-adhering patch that delivers med-ications topically into the skin for local-

ized pain relief and therapeutic treatment.Transdermal drug delivery systems

(Cygnus Inc., USA) provide the controlledrelease of drugs directly into the blood-stream through intact skin. By deliveringa steady flow of drugs into the bloodstreamfor an extended period of time, transder-mal systems can avoid the peak- and-effect of oral or injectable therapy and canenable more controlled effective treatment.

Liposomal deliveryLiposomes are microparticulate lipoidalvesicles and have been used as a carrier forthe improved delivery of a variety of drugssuch as chemotherapeutic agents, imag-ing agents, antigens, genetic materials, im-munomodulators, etc. Liposomes are afamily of vesicular structures based onlipid bilayers surrounding aqueous com-partments. In the majority of cases, lipidcomplexes and liposomal pharmaceuti-cals provide less toxicity and better effi-cacy than the active ingredient.

Conventional liposomes are typicallycomposed of only phospholipids (neutraland/or negatively charged) and/or cho-lesterol. These are characterized by a rel-atively short blood circulation time. Toovercome this problem, long-circulatingliposomes (also called stealth or stericallystabilized liposomes) have been developed.These stealth liposomes carry a polymercoating to obtain prolonged circulationtimes. Targeted liposomes (immunolipo-somes) may be either conventionally orsterically stabilized and have specific an-tibodies or antibody fragments on theirsurface to enhance target site binding.Cationic liposomes are still under devel-opment for improving the delivery of ge-netic material. A number of productsbased on liposomes have already been ap-proved for marketing (see Table III), andmore are awaiting approval. Companiessuch as ADD Drug Delivery TechologiesAG (Switzerland), DepoTech Corporation(USA), Nexstar Pharmaceuticals (USA),Novavax Inc. (USA), The Liposome Com-

Table III: Some of the commercially available liposomal/lipid-based products.Trade Name Chemical Manufacturer IndicationAmBisome Amphotericin B NeXstar Pharmaceuticals Systemic fungal infectionsAbelcet Amphotericin B The Liposome Company Systemic fungal infectionsAmphotec Amphotericin B Sequus Pharmaceuticals Systemic fungal infectionsDoxil Doxorubicin Sequus Pharmaceuticals Kaposi’s sarcomaDaunoXome Daunorubicin NeXstar Pharmaceuticals Kaposi’s sarcoma

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pany Inc. (USA), and Sequus Pharma-ceuticals Inc. (USA) are actively involvedin the development of liposomal-baseddrug delivery systems.

Novasome lipid vesicles (Novavax, Inc.,USA) are proprietary organized lipidstructures in which drugs or other mate-rials may be encapsulated for delivery intothe body topically or orally. Novasomelipid vesicles are made using Novavax’spatented manufacturing process from avariety of readily available chemicals calledamphiphiles, which include fatty alcoholsand acids.

Micellar nanoparticles (Novavax, Inc.) aresubmicron-sized, water-miscible lipidstructures that have different structuralcharacteristics and are generally smallerthan Novasome lipid vesicles. Micellarnanoparticles are derived from amphiphilemolecules.

Proliposomes (ADD Drug Delivery Tech-nologies AG) overcome the stability,entrapment, and production problems associated with conventional liposomalformulations. This approach avoids manydifficulties encountered with the manu-facturing of liposomes by forming lipo-somes at the point of delivery, presentingopportunities for novel delivery systemsdesigned for dermal, mucocutaneous, pul-monary, oral, and parenteral use.

Stealth liposomes (Sequus Pharmaceu-ticals Inc., USA) are stable in plasma andavoid rapid removal from the blood-stream. This is achieved by attaching poly-ethylene glycol to the surface of the lipo-somes to form long-circulating liposomes.Stealth liposomes are large enough thattypically they do not leak out of the blood-stream and into tissues through normal,healthy blood vessels. As a consequence,they continue to circulate intact until theyreach tissues where new blood vesselsform, such as tumors, sites of inflamma-tion, and sites of injury.

Taste maskingOral pharmaceuticals often impart an un-pleasant taste, primarily bitterness. Thedesire for improved palatability in theseproducts has prompted the developmentof numerous methods for taste masking,such as complexation of the drug withresins or cyclodextrins, use of microcap-sules, particle coating, etc. Many of thesecontributions have been successfully com-

mercialized in oral pharmaceutical prepa-rations that are available over the counteror by prescription.

Chewable tablets (Elan Corporation)consist of a mild effervescent drug com-plex dispersed throughout a gum base.The drug is released from the dosage form as a result of physical disruptionfrom chewing as well as chemical disrup-tion from the interaction between the fluids in the oral cavity with the efferves-cent material. The taste of the compoundis manipulated by a drug-coating tech-nique that provides a physical barrier between the drug particles and the tastereceptors of the mouth. These coatingtechniques are robust enough to with-stand the mechanical onslaught causedby chewing so that taste masking is notcompromised while patients take theirmedication.

KV Pharmaceuticals has developed anumber of taste-masked technologies, in-cluding Flavortech, a liquid formulationtechnology designed to reduce the bad tasteof therapeutic products. Micromask is ataste-masking technology that incorporatesa dry-powder, microparticulate approachto reducex objectionable taste by seques-tering the unpleasant drug agent in a specialized matrix. Liquette is a taste-mask-ing technology that incorporates unpleas-ant tasting drugs into a hydrophilic andlipophilic polymer matrix to suppress thetaste. Oraquick is a technology in whichthe bitter taste of a drug candidate is firstenhanced by neutralizing its negative tastecharacteristics and then developed into aquick-dissolving tablet formulation.

Tastemasking (Ascent Pediatrics Inc.,USA) technology is used to mask the ob-jectionable or unpleasant taste of variouscommon ingredients used in pediatricpharmaceuticals.

Oral fast-dispersing dosage formsA solid dosage form that dissolves or dis-integrates rapidly in the oral cavity, re-sulting in a solution or suspension with-out the need for the administration ofwater, is known as an oral fast-dispersingdosage form. These are also known as fast-dissolving, rapid-dissolve, rapid-melt,mouth-dissolving, and quick-disintegrat-ing tablets. Some of the advantages of oralfast-dispersing dosage forms include ad-ministration to patients who have diffi-

culty in swallowing, more rapid drug absorption, patient convenience, and com-pliance. These dosage forms are particu-larly helpful for pediatric and geriatric patients who have difficulty in swallowing(dysphagia) and also for traveling patients,for whom water may not be easily or read-ily accessible. The technologies, some ofwhich have been successfully marketed,mainly utilize conventional tabletingprocesses with slight modification, freeze-drying methods, and floss-formation tech-niques for manufacturing.

EFVDAS or Effervescent Drug Absorp-tion System (Elan Corporation) is a drugdelivery technology that has been used inthe development of a number of bothOTC and prescription medications. Thisis particularly advantageous for conditionssuch as colds and flu, for which Elan hasmodified its EFVDAS technology to de-velop hot drink sachet products that com-bine medicines and vitamins for OTC use.The granular contents of the sachets canbe added to boiling water to producepleasant-flavored solutions. In these casesthe effervescence of the granulate mixtureis modified to accommodate the use ofheated water. Examples of products thatElan has developed include effervescentibuprofen, paracetamol (acetominophen),cimetidine, naproxen, and a paracetamoland codeine combination product.

Fast Melt (Elan Corporation) is a highlyporous, microfine matrix tablet. Onceplaced on the tongue, this matrix rapidlyabsorbs liquid and disintegrates. The drug,in a stabilized, size-reduced form to en-sure optimal solubility, dissolves rapidly.The combination of a mild effervescentbase and drug processing ensures that thedosage form goes into solution in ap-proximately 15 to 30 seconds. The drug isreleased rapidly within the oral cavity,where it dissolves to form a drug solutionthat is then swallowed. This is particularlyadvantageous in cases like migraine wherea fast onset of clinical effect is required. Aportion of the drug solution may be ab-sorbed locally in the oral cavity and there-fore may avoid first-pass metabolism inthe liver that limits the bioavailability ofmany drugs. The fast-melt system rapidlydisintegrates in the oral cavity; hence,patients do not have to swallow large cum-bersome dosage forms, which discouragesmany from taking their medication. Thus,

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the fast-melt dosage form combines thebenefits of liquid formulations with thoseof a solid oral dosage form.

Flashdose (Fuisz Technologies, USA) uti-lizes shearform technology to form a ma-trix known as floss. The floss is a fibrousmaterial similar to cotton candy fibers andis commonly made from saccharides suchas sucrose, dextrose, etc. The candy flosscan then be milled and blended with active ingredients and other processingaids and subsequently compressed intofast-dissolving tablets.

Flashtab (Prographarm, France) is acombination of taste-masked multipar-ticulate active drug substances with spe-cific excipients compressed into tablets.This orodispersible tablet is placed in themouth, where it disperses rapidly beforethe patient swallows. Some of the drugsthat are marketed using this technologyare acetaminophen (pediatric and adult),ketoprofen, and ibuprofen.

Multiflash (Prographarm) is a multi-unittablet composed of coated microgranulesand fast-disintegrating excipients. Thismultiparticulate tablet quickly disinte-grates in the esophagus after being swal-lowed with a minimum amount of water.This tablet avoids mucosal adhesion, andcoated pellets can match various dissolu-tion rates.

Orasolv (Cima Labs Inc., USA) is ob-tained by direct compression and utilizeseffervescent materials (for faster disinte-gration) and taste-masking agents. Thetechnique involves the formation of mi-crocapsules by a novel technique involv-ing the dispersion of active ingredient intoa suitable polymer along with other excipients such as mannitol and magne-sium oxide. The active agents and man-nitol are added to the polymeric disper-sion (ethyl cellulose, acrylates, etc.) understirring, followed by the addition of mag-nesium oxide. Magnesium oxide and man-nitol are added to promote the release ofthe active agent. The mixture is dried forone hour at 50 ºC, delumped, and driedfor another hour at the same temperature.The material is then screened (8-mesh)and dried for one hour at 60 ºC. Theformed microcapsules, effervescent mix-tures, and other standard excipients aremixed and compressed to form tablets.The tablets have a hardness of about 1–2

kp and an in vivo disintegration time of,1 min.

Wowtab tablets (Yamanouchi PharmaTechnologies, USA) are usually made byconventional tableting methods and havefast disintegration (1–40 s). The formula-tion usually consists of a mixture of fast-disintegrating but poorly compressible sac-charides (e.g., mannitol, lactose, glucose,etc.) and a slowly disintegrating saccharidethat shows good hardness upon com-pression (e.g., maltose, sorbitol, etc.). Themixture is compressed after undergoing ahumidification and drying process result-ing in tablets that show adequate hardnessand rapid disintegration.

Zydis (R.P. Scherer, UK) uses freeze-drying technology in the manufacture offast-disintegrating dosage forms. Theseformulations are combinations of water-soluble matrix material along with thedrug and some functional excipients thatare formed in the blister pockets andfreeze-dried to remove the water by sub-limation. The resulting structures are veryporous in nature and rapidly disintegrateor dissolve upon contact with water.Some of the drugs that are being mar-keted in the form of Zydis products areoxazepam, lorazepam, piroxicam, lop-eramide, famotidine, loratidine, enalapril,phenylproponalamine/brompheniramine,and selegiline.

LYOC (Farmalyoc, France) and Quicksolv(Janssen Pharmaceutica, USA) also utilizefreeze-drying technology to produce oralfast-dispersing tablets.

Technology for insoluble drugsDrug solubility may be the rate-limitingstep in absorption (e.g., in drugs belong-ing to Class 2 or drugs having good per-meability but poor solubility) and there-fore may affect the bioavailability of thedrug. More than 40% of potential drugproducts suffer from poor water solubil-ity. This frequently results in potentiallyimportant products not reaching the mar-ket or not achieving their full potential. Agood deal of research has been done inthis area, and currently a number of tech-nologies are available to address the poorsolubility of drugs.

INDAS or Insoluble Drug AbsorptionSystem (Elan Corporation) addresses theproblem of poor solubility by manipulat-ing the physicochemical characteristics of

a drug to create a high-energy adsorbatethat demonstrates enhanced solubility.This high-energy adsorbate is subse-quently combined with Elan’s other con-trolled absorption technologies to deliverthe required plasma profile. The drug inquestion, usually crystalline in nature, isconverted into an amorphous form by acombination of energy, excipients, andunique processing procedures. Once thedrug is converted to the desirable physi-cal form, an adsorption process utilizinga novel polymer cross-linked technologyprevents recrystallization and stabilizesthe resulting high-energy complex. Thecombination of the change in the physi-cal state of the drug coupled with the sol-ubilizing characteristics of the excipientsemployed ensures that the solubility of theactive ingredient is enhanced. Nifelan, aonce-daily nifedipine formulation, is based on this technology and is marketed in Europe and Southeast Asia.

Liquid-Oros technology (Alza Corpo-ration) is designed for controlled deliveryof insoluble drug substances or peptides.This system is based on osmotic princi-ples and is a self-emulsifying formulationsystem. It consists of an osmotic layer,which expands after coming into contactwith water and pushes the drug formula-tion through an orifice in the capsule.

NanoCrystal technology (Elan Corpo-ration) reduces a drug to extremely smallparticles (, 400 nm in diameter) using aspecialized milling technique. A suspen-sion of the insoluble drug in a stabilizingsolution, consisting of GRAS stabilizersand other excipients, is used for the millingprocess to prevent aggregation of the re-sulting nanoparticles and also serves toincrease the dissolution rate of thenanoparticles by acting as a surfactantwithin the GI tract. Additionally, Nano-Crystal technology serves as a platformfor targeting drugs to specific anatomicalsites or to control delivery over time. Oncethe NanoCrystal form of the insolubledrug has been transformed into a morephysically stable form, it can be incorpo-rated into other drug delivery systems suchas oral controlled-release or highly con-centrated parenteral solutions. Recently,Elan obtained marketing approval fromFDA for a tablet form of American HomeProducts Corporation's drug Rapamune,which represents the first approval for a

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drug presentation containing NanoCrys-tal technology. Rapamune is indicated forthe prevention of organ rejection in kid-ney transplant patients, and the new tabletprovides easier administration and stor-age than the currently marketed Rapa-mune oral solution.

SoftGel (R.P. Scherer) is a soft gelatincapsule formulation that contains a highconcentration of a hydrophobic drug insolution (or fine particles of drug in sus-pension) in a hydrophilic or lipophilic liq-uid. This technology has been specificallydeveloped to improve the solubility, sta-bility, bioavailability, and rate of absorp-tion of drug molecules. ACT-3 (ibupro-fen) marketed in Australia by WhitehallLaboratories (Australia), and Fortovase(saquinavir) marketed by Roche Labs, Inc.(USA) are some of the products based onthis technology.

ADD Drug Delivery Technologies AGutilizes solubilizing properties of patentedblends of phospholipids to increase solu-bility and bioavailability of poorly water-soluble drugs.

Colon-specific deliveryAlthough the small intestine is the pri-mary site for drug absorption and is there-fore a preferred area of the GI tract to target with various controlled-release tech-nologies, considerable interest has beenshown in the past few years in colon tar-geting of drugs. The main reasons for thisinterest are the reduced proteolytic activ-ity in the colon, which may be advanta-geous in targeting certain drugs such asproteins and peptides that are enzymati-cally degraded in the stomach or small in-testine, and the topical treatment of car-cinomas and inflammatory bowel diseases.In the past few years many colon-specificdosage forms have been developed, in-cluding prodrugs, cross-linked hydrogels,matrices, and coated dosage forms. Coateddosage forms are preferred because ofinnovations in the coating technology andwide flexibility in the design. These coateddosage forms are mainly based upon oneof the following:● The pH-controlled release coatings that

are insoluble at the lower pH of thestomach and dissolve in the lumen ofthe small intestine. To achieve release inthe colon, the start of the drug release iscontrolled by increasing the thickness

of the coating, allowing a pH- and time-controlled polymer dissolution and drugrelease. These pH-sensitive enteric poly-mers dissolve in a pH between 6 and 7and thus release the drug as soon as thepH of the intestine reaches 6 or 7. Someof these enteric polymers are celluloseacetate phthalate, HPMC phthalate, andEudragit L and S.

● Time-controlled release coating in whichthe lag time depends upon coating thick-ness and drug release can be accom-plished by changes in osmotic pressureor disruption of the coating by swellingof the core.Oros-CT (Alza Corporation) is a system

that can be used as a once- or twice-a-daycolon-targeted dosage form and is basedon the principles of osmotic pressure.Oros-CT can be a single osmotic unit orcan be comprised of as many as five to sixpush-pull osmotic units filled in a hardgelatin capsule. Each bilayer tablet consistsof an upper compartment (drug alongwith osmotic agents) and a lower com-partment (polymeric osmotic agent), sur-rounded by a semipermeable membrane.An orifice is created in the membrane nextto the drug layer. After coming into con-tact with the GI fluids, the gelatin capsuledissolves and the enteric coating preventsentry of water from the stomach. As thesystem enters into the small intestine, theenteric coating dissolves and water is im-bibed into the core, thereby causing thepush compartment to swell. At the sametime, flowable gel is formed in the drugcompartment, which is pushed out of theorifice at a rate that is precisely controlledby the rate of water transport across thesemipermeable membrane.

Pulsincap (R.P. Scherer) consists of awater-insoluble capsule body and a water-soluble cap. The drug formulation is con-tained inside the capsule. The soluble capdissolves in the intestine, thereby allow-ing the hydrogel plug to swell and expand.Ejection of the swollen plug occurs aftera lag time that depends on the hydrogelplug, the length of the plug, and the fitratio (plug diameter to body diameter).

Colon Specific Systems (Advanced Poly-mer Systems, Inc.) uses Microsponge sys-tems to protect the active agent from theenvironment of the stomach and deliv-ers the drug to the colon in a controlledfashion.

Intranasal deliveryIntranasal delivery of certain drugs offerssignificant advantages. The nasal cavitycan be used for the delivery of severalcompounds and offers rapid absorptioninto the systemic circulation, providingrapid onset of desired therapeutic effect,lower required dosages, fewer side effects,and improved patient compliance. More-over, this route may also permit the de-livery of challenging molecules such asproteins and peptides.

In the past drops were instilled in thenose, but with the advent of insufflatortechnology, drops are seldom used now.Nasal dosage forms consist mainly ofpreparations containing dispersed or dis-solved drugs placed in a container that issqueeze- or spray-activated. Alternatively,liquid solutions can be delivered using me-tered atomizing pumps or metered-dosepressurized nasal inhalers. Butorphanol(Stadol NS Nasal Spray, Bristol MyersSquibb Co., USA), calcitonin (MiacalcinNasal Spray, Novartis), dihydroergotamine(Migranal Nasal Spray, Novartis, Inc.),sumatriptan (Imitrex Nasal Spray, Glaxo-SmithKline), and desmopressin (DDAVPNasal Spray, Aventis Pharma, USA) aresome of the drugs marketed in the formof a nasal spray. Cromolyn sodium (Nasal-crom Nasal Solution, Fisons Pharmaceu-ticals) is available in a solution form.Budesonide (Rhinocort Nasal Inhaler,Astra) and beclomethasone diproprion-ate (Rino Clenil, Chiesi Farmaceutici) aremarketed in the form of metered-dosepressurized aerosols. Beclomethasonediproprionate is also available in the formof a metered-dose manual spray unit (Be-conase AQ, Glaxo-SmithKline, and Van-cenase AQ, Schering Plough Corporation).

Nasal powders are an alternative dosageform and may show improved stability.Administration of powders requires nasalinsufflators that are either mechanicallyor respiration actuated. In mechanical de-vices, a rubber bulb is connected throughthe dose reservoir to a nasal adapter.Squeezing the rubber bulb provides astream of air that is capable of emittingthe loaded powder in the insufflator.Rinoflatore (Fisons, Italy), Miat Nasal Insufflator (Miat, Italy), and Puvlizer (Teijin, Japan) are some of the marketedinsufflators for nasal administration of

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powders. Respiration-actuated devices area nose-adapted version of dry powder in-halers (DPIs). With both types of devices,the drug is loaded in a gelatin capsule thatis pierced just before activation. The cap-sule is located between the air jet producerand the nose adapter, and the flowingairstream creates turbulence inside thecapsule, which aerolizes and releases thepowder from the capsule.

Nasal gels also can be used to providean enhanced bioavailability comparedwith oral delivery. EnerB (Nature’s Bounty,Inc.), a vitamin B-12 dietary supplement,is available in gel form.

Pulmonary deliveryUntil now, pulmonary delivery has beenused primarily for the treatment of respi-ratory disease. More recently, the lung’snatural ability to transfer molecules intothe bloodstream has been utilized for de-livering drugs to the systemic circulation.This method is a noninvasive alternativeto painful injections and can lead to therapid onset of action and good bioavail-ability. Inhalation devices broadly fall intothree categories: pressurized metered-doseinhalers (MDIs), nebulizers, and DPIs.MDIs contain the drug as a solution or asuspension of fine particles in a liquefiedpropellant held under high pressure. Thedrug is emitted through an orifice from ametering valve. Nebulizers, on the otherhand, do not require propellants and cangenerate large quantities of small dropletscapable of penetrating into the lung. Re-cently, a great deal of work has been donein the field of DPIs. In DPIs, the drug isstored in a dry state, thereby ensuringlong-term stability and sterility.

Some of the single dose breath-drivenDPIs that are currently marketed are Rotahaler (GlaxoSmithKline), Flowcaps(Hovione), and Cyclohaler (Pharma-chemie). Diskhaler and Accuhaler (Glaxo-SmithKline) are multidose factory-me-tered inhalers. In addition, severalmultidose patient/device-metered DPIsare available; Clickhaler (M L Labs), Easy-haler (Orion), Pulvinal (Chiesi), Turbo-haler (AstraZeneca), and Ultrahaler (Aven-tis Pharma).

AERx system (Aradigm Corporation,USA) is based on aerosol-generation tech-nology capable of producing low-velocitysmall particles suitable for efficient and

reproducible pulmonary delivery. The sys-tem aerosolizes liquid formulations thatare prepackaged in unit-dose packets forinhalation. Each unit-dose packet consistsof a small blister package that stores a liq-uid drug formulation and an aerosoliza-tion nozzle with a membrane incorpo-rating an array of micro-machined holes.The AERx device creates a respirableaerosol by releasing a mechanical actua-tor that is activated automatically whenthe patient’s inhalation is optimal for drugdelivery. The actuator compresses the blis-ter packet, thereby forcing open the sealedchannel and extruding the liquid drugthrough the aerosolization nozzle. Theaerosolized drug produced by this processis inhaled through the mouthpiece of theAERx device. The aerosolization of the liq-uid drug via the disposable nozzle takesabout 1 s and produces a low-velocity,fine-particle aerosol necessary for opti-mized deposition within the lungs.

Spiros (Dura Pharmaceuticals Inc.,USA) is designed to deliver a relativelyconsistent drug dose to the lungs over awide range of inspiratory flow rates. Thecore technology contained in Spiros is anaerosol generator that uses electro-mechanical energy to disperse drug pow-der to form an aerosol for inhalation. Themain components of the aerosol genera-tor include the impeller, the motor, thebreath-actuated switch, and the dosingchamber. When the switch is activated, theelectric circuit is completed and the im-peller rotates. The action of the impelleron the dry powder formulation suppliesthe energy to disperse the drug and pro-vides a zero-velocity cloud of aerosolizeddrug for inhalation. The cloud ofaerosolized drug is suspended in the dos-ing chamber and is delivered to the lungsonly as the patient inhales.

Vaginal/rectal deliveryThe vagina has been studied as a favorablesite for the local and systemic delivery ofdrugs, and this route offers certain ad-vantages such as the avoidance of the gutand hepatic first-pass metabolism, reduc-tion in gastrointestinal and hepatic sideeffects, and local targeting of drugs to thereproductive organs. Vaginally adminis-tered agents and formulations are beingdeveloped mainly to provide dual pro-phylaxis for contraception and protection

against microbial infections, includingAIDS and other sexually transmitted dis-eases. This route also has potential foruterine targeting by the so-called first uter-ine pass effect of active agents such asprogesterone and danazol .

Hycore-V (Core Group Plc, Scotland)uses hydrogel polymer technology to ab-sorb fluid and swells without losing itsphysical form. As the hydrogel swells, thedrug is released in a controlled manner.Drug release can be controlled over a pe-riod of a few hours to several days by vary-ing the shape and the physical and chem-ical properties of the polymer. Hycore-Vis delivered through the vagina in the formof a pessary. Hycore-R (Core Group Plc)uses similar technology and delivers thedrug through the rectum in the form of asuppository.

Vagisite (KV Pharmaceuticals) is a semi-solid system intended for drug adminis-tration within the vaginal vault. Biosert(KV Pharmaceuticals) is a bioadhesivecontrolled-release system that is a solidrectal or vaginal suppository at room tem-perature and, after insertion, becomes abioadhesive long-acting cream.

Site-specific drug deliveryOne of the goals of effective drug deliveryis to control and optimize the localized re-lease of drug at the target site and rapidlyclear the nontargeted fraction. In the pastfew years, there has been considerable interest in the development of a deliverysystem that will release the drug locally ina highly selective fashion. Some of thebenefits of this type of delivery system arethe delivery of a calculated amount ofdrug at the site of action and limited ac-cess to other organs. The amount of drugreaching the systemic circulation theoret-ically will be less, thereby resulting in fewerside effects. At present, a number of tech-nologies are available for site-specific delivery.

Atrigel (Atrix Laboratories, Inc., USA)comprises biodegradable polymer formu-lations that are administered as flowablecompositions (solutions, gels, pastes, andputties) that solidify in situ upon contactwith body fluids to form biodegradable im-plants. The Atrigel system is designed toprovide extended localized or systemic drugdelivery in a single application without theneed for surgical implantation or removal.

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Durasite (Insite Vision Inc., USA) is aneye drop formulation comprised of across-linked carboxyl-containing polymerthat incorporates the drug to be deliveredto the eye.

Matrix Delivery System (Matrix Pharma-ceuticals, USA) is an aqueous-based pro-tein system in which a chemotherapeuticdrug is combined with a protein matrixand a vasoconstrictor to create an in-jectable gel. This gel enables targeted de-livery of water-soluble drugs by direct in-jection into solid tumors and skin lesions.The Matrix delivery system localizes therelease of the drug, maintaining high drugconcentrations at the tumor or lesion siteand increasing the duration of exposureof the targeted tissue to the therapeuticagent.

Microsphere Delivery System (Core GroupPlc) uses biodegradable polymers and a method that facilitates the microencap-sulation of water-insoluble and water-soluble compounds. Potential applicationsof this technology include the long-termcontrolled delivery of injectable com-pounds, the delivery of active agents tosites poorly accessible from systemic circulation, and site delivery of highly potent agents.

Oligosphere Injectable Microspheres(Macromed, Inc.) is a proprietary polymericmicrosphere technology based on FDA-approved PLGA polymers. MacroMed’spatented processing uses aqueous cosol-vents providing a drug-friendly loading en-vironment. MacroMed’s process also cre-ates a homogenous drug/polymer matrix.This enables a constant release profile withlittle or no initial burst. Oligosphere is in-jected parenterally and is designed for drugrelease profiles of greater than one month.

ReGel Injectable Controlled-Release System(Macromed, Inc.) is designed to deliveractive agents systemically or locally forperiods of one to six weeks. MacroMedformulates these systems with its propri-etary thermosensitive and biodegradableclass of hydrogels. These formulations area liquid at or below room temperatureand are injectable through a small 25-gauge needle. Upon injection as a liquid,the product quickly becomes a gel at bodytemperature, forming a depot that slowlydegrades over a period of four to sixweeks. The ReGel System is biodegrad-able and is made from GRAS components.

ReGel’s solubilizing characteristics havebeen shown to increase syringability andconsistency of dose.

Retinal delivery system (Insite Vision,Inc.) is a device that provides controllednonsurgical delivery of ophthalmic drugsto the retina and other tissues in the pos-terior chamber of the eye.

Oral transmucosal deliveryOral transmucosal systems address the

need for a convenient noninvasive drugdelivery vehicle that provides rapid onsetof therapeutic action and allows the pa-tient to control drug administration untilthe desired effect is achieved. The drug isreleased in the mouth, allowing rapid ab-sorption through the oral mucosal tissues.

Bioadhesive Delivery System (ColumbiaLaboratories, Inc., USA) consists of apolymer, polycarbophil, and an active in-gredient. This system is based on the prin-ciple of bioadhesion, a process by whichthe polymer adheres to epithelial surfacesand to mucin, a naturally occurring se-cretion of the mucus membranes. Thepolymer remains attached to epithelialsurfaces and the mucin and is dischargedupon normal cell turnover or upon thedetachment of the mucin from the mucusmembranes, a physiological process that,depending on the area of the body, occursevery 12 to 72 h.

Oral transmucosal delivery (Theratech,Inc.) may enable the delivery of manylarge-molecule drugs, including peptidesand polysaccharides that cannot readilybe delivered orally or transdermally.TherTech’s oral transmucosal delivery sys-tems are solid dosage forms that will ad-here to various surfaces in the oral cavityand deliver drugs within a period of time.

Future directions and conclusionsAs discussed in this article, drugs can bedelivered to a patient by many differentdelivery systems, including oral, transder-mal, injection, implants, etc. Most of thedrugs are amenable to these types of de-livery systems. With the sequencing of thehuman genome, biotechnology companiesare rapidly developing a large number ofpeptide- and protein-based drugs. It is ex-pected that in the next 10 to 20 years, pro-tein- and peptide-based drugs will consti-tute more than half of the new drugsintroduced into the market, and more than

80% of these protein drugs will be anti-bodies. These biopharmaceuticals (pro-teins, peptides, carbohydrates, oligo-nu-cleotides, and nucleic acids in the form ofDNA) present drug delivery challenges be-cause these are often large molecules thatdegrade rapidly in the blood stream. More-over, they have a limited ability to cross cellmembranes and generally cannot be de-livered orally. Such molecules will be muchmore difficult to deliver via conventionalroutes, and injections may be the onlymeans of delivery (at least as of today).

The routes of administration will be dic-tated by the drug, disease state, and desiredsite of action. Some sites are easy to reachsuch as the nose, the mouth, and thevagina. Others sites are more challengingto access, such as the brain. Gene therapyis also likely to be one of the most excitinggrowth sectors as biotech companies be-come involved in drug delivery. Currently,no product in this category, which includesgenetically engineered cells, has reachedthe market but several are in Phase III clin-ical trials. By 2005, some of these productswill reach the market, and their value hasbeen estimated to be close to $5 billion.

In conclusion, the market for drug de-livery systems has come a long way andwill continue to grow at an impressive rate.Today’s drug delivery technologies enablethe incorporation of drug molecules intonew delivery systems, thus providing nu-merous therapeutic and commercial ad-vantages. A large number of companiesare involved in the development of newdrug delivery systems, which is evident byan increased number of products in themarket and the number of patents grantedin the recent past. Tomorrow’s drugs def-initely will be more challenging in termsof the development of delivery systems,and pharmaceutical scientists will have tobe ready for a difficult task ahead.

AcknowledgmentsR.K. Verma acknowledges CSIR, India, forawarding him financial assistance in theform of a Senior Research Fellowship.

Suggested reading1. S. Engel, “Delivering Results,” R&D Direc-

tions, 5 (2), 48–64 (1999).2. S. Engel, “Smashing the Barriers,” R&D Di-

rections, 4 (4), 44–67 (1998).3. S.V. Sastry, J.R. Nyshadham, and J.A. Fix,“Re-

cent Technological Advances in Oral Drug

www.pharmaporta l .com

www.pharmaporta l .com

Delivery — A Review,” Pharm. Sci. Technol.Today, 3 (4), 138–145 (2000).

4. G. Storm and J.A. Crommelin, “Liposomes:Quo Vadis?,” Pharm. Sci. Technol. Today, 1(1), 19–31 (1998).

5. C.S. Leopold, “Coated Dosage Forms forColon-Specific Drug Delivery,” Pharm. Sci.Technol. Today, 2 (5), 197–204 (1999).

6. R.K. Verma, B. Mishra, and S. Garg, “Os-motically Controlled Oral Drug Delivery,”Drug Dev. Ind. Pharm., 26 (7), 695–708(2000).

7. R.K. Chang, et al., “Fast Dissolving Tablets,”Pharm. Technol., 24 (6), 52–5, (2000).

8. I. Ashurst, et al., “Latest Advances in the De-velopment of Dry Powder Inhalers,” Pharm.Sci. Technol. Today, 3 (7), 246–256 (2000).

9. Encyclopedia of Controlled Drug Delivery, Vols.1 & 2, J.E. Mathiowitz, Ed.(John Wiley &Sons, Inc., New York, 1999). PT

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