1.Introduction
A drug delivery system is expectedto deliver the required amount of drug to the targeted site for the necessaryperiod of time, both efficiently and precisely. Different carrier materials arebeing constantly developed to overcome the undesirable properties of drugmolecules (Szycher and Kim, 1991). Amongst them cyclodextrins (CDs) have beenfound as potential candidates because of their ability to alter physical,chemical and biological properties of guest molecules through the formation ofinclusion complexes. CDs were discovered approximately 100 years ago and thefirst patent on CDs and their complexes was registered in 1953 (Loftsson andBrewster, 1996). However, their large scale commercial utilization wasprevented mainly due to their high cost and concerns regarding their safety.Recent advancements have resulted in dramatic improvements in CD production,which have lowered their production costs. This has led to the availability of highlypurified CDs and CD derivatives which are well suited as pharmaceutical excipients. A lot of work has also beendone regarding the safety-assessment CDs and CD derivatives which has allayedthe fears which were initially raised regarding their safety. Because of theirstructure and physico-chemical properties, CDs as drug carriers provide anumber of advantages like:
1. They provide a number ofpotential sites for chemical modification.
2. CDs with different cavity sizesare available which makes it possible to entrap drugs of different moleculardimensions.
3. The microenvironment in theircavity is relatively non-polar and lipophilic.
4. They possess low toxicity and lowpharmacological activity.
5. They have a good aqueoussolubility.
6. They are rather resistant tohydrolysis by organic acids and many common alpha amylases, and completelyresistant to yeast fermentation and beta amylases.
7. They are not decomposed by hotalkali.
8. They exhibit a high thermalstability, with a decomposition temperature approaching 300°C.
9. They protect the included/conjugated drugs from biodegradation.
10. They can be used as process aidsto remove specific components from a mixture or minerals.
2. Cyclodextrins andComplexation Phenomenon
CDs are cyclic (a-1,4)-linkedoligosaccharides of a-D-glucopyranose containing a relatively hydrophobiccentral cavity and hydrophilic outer surface. Owing to the lack of freerotation around the bonds connecting the glucopyranose units, the CDs are notperfectly cylindrical molecules but are toroidal or cone shaped (Loftsson andBrewster, 1996). As a result of their molecular structure and shape, theypossess a unique ability to act as molecular containers by entrapping guestmolecules in their internal cavity. No covalent bonds are formed or brokenduring drug-CD complex formation, and in aqueous solution, the complexesreadily dissociate and free drug molecules remain in equilibrium with themolecules bound within the CD cavity.
The parent or natural CDs consist of6, 7 or 8 glucopyranose units and are referred to as alpha (a-), beta (b-) andgamma (g-) CD, respectively. CDs containing nine, ten, eleven, twelve andthirteen glucopyranose units, which are designated as d-, Î-, x-, h- and q- CD,respectively, have also been reported. Hundreds of modified CDs have beenprepared and shown to have research applications, but only a few of thesederivatives, those containing the hydroxypropyl (HP), methyl (M), andsulfobutylether (SBE) substituents have been commercially used as newpharmaceutical excipients.
3. Advantages ofCyclodextrin Inclusion Complexation
CDs have mainly been used ascomplexing agents to increase the aqueous solubility of poorly water-solubledrugs and to increase their bioavailability and stability. In addition, CDshave been used to reduce or prevent gastrointestinal or ocular irritation,reduce or eliminate unpleasant smells or tastes, prevent drug-drug ordrug-additive interactions, or even to convert oils and liquid drugs intomicrocrystalline or amorphous powders.
1. Enhancement of Solubility: CDsincrease the aqueous solubility of many poorly soluble drugs by forminginclusion complexes with their apolar molecules or functional groups. Theresulting complex hides most of the hydrophobic functionality in the interiorcavity of the CD while the hydrophilic hydroxyl groups on the external surfaceremain exposed to the environment. The net effect is that a water solubleCD-drug complex is formed.
2. Enhancement of Bioavailability:When poor bioavailability is due to low solubility, CDs are of extreme value.Preconditions for the absorption of an orally administered drug is its releasefrom the formulation in dissolved form. When drug is complexed with CD,dissolution rate and consequently absorption is enhanced. Reducing thehydrophobicity of drugs by CD complexation also improves their percutaneous orrectal absorption. In addition to improving solubility, CDs also preventcrystallization of active ingredients by complexing individual drug moleculesso that they can no longer self-assemble into a crystal lattice.
3. Improvement of Stability: CDcomplexation is of immense application in improving the chemical, physical andthermal stability of drugs. For an active molecule to degrade upon exposure tooxygen, water, radiation or heat, chemical reactions must take place. When amolecule is entrapped within the CD cavity, it is difficult for the reactantsto diffuse into the cavity and react with the protected guest. In the case ofthermal or radiation induced degradation, the active must undergo molecularrearrangements. Again, due to the stearic constraints on the guest moleculewithin the cavity, it is difficult for the entrapped molecule to fragment uponexposure to heat or light or if it does fragment, the fragments do not have themobility needed to separate and react before a simple recombination takesplace. Volatile components can be stabilized against loss by reducing thevolatility in case of liquids and by reducing the tendency of some solidproducts to sublimate. The deliquescence of hygroscopic substances is alsoreduced by complexation with CDs. Physical changes like sedimentation andcaking in suspension or recrystallization of drugs to less soluble butthermodynamically more stable polymorphic crystal forms, etc., can also beprevented or reduced by complexation with CDs.
4. Reduction of Irritation: Drugsubstances that irritate the stomach, skin or eye can be encapsulated within aCD cavity to reduce their irritancy. Inclusion complexation with CDs reducesthe local concentration of the free drug below the irritancy threshold. As thecomplex gradually dissociates and the free drug is released, it gets absorbedinto the body and its local free concentration always remains below levels thatmight be irritating to the mucosa.
5. Prevention of Incompatibility:Drugs are often incompatible with each other or with other inactive ingredientspresent in a formulation. Encapsulating one of the incompatible ingredientswithin a CD molecule stabilizes the formulation by physically separating thecomponents in order to prevent drug-drug or drug-additive interaction.
6. Odor and Taste Masking:Unpleasant Odor and bitter taste of drugs can be masked by complexation withCDs. Molecules or functional groups that cause unpleasant tastes or odors canbe hidden from the sensory receptors by encapsulating them within the CDcavity. The resulting complexes have no or little taste or odor and are muchmore acceptable to the patient.
7. Material Handling Benefits:Substances that are oils/liquids at room temperature can be difficult to handleand formulate into stable solid dosage forms. Complexation with CDs may convertsuch substances into microcrystalline or amorphous powders which can beconveniently handled and formulated into solid dosage forms by conventionalproduction processes and equipment.
4. Applications ofCyclodextrins in Drug Delivery Systems
The multifunctional characteristicsof CDs have enabled them to be used in almost every drug delivery system be itoral drug delivery or transdermal drug delivery or ocular drug delivery. Thecommercial viability of CD-based oral formulations has been established withthe marketing of more than 20 products world-wide.
A number of excellent reviews haveappeared in the literature in the last few years describing the applications ofCDs in various drug delivery systems (Table 1). We present below an update onthe recent work done in the different fields.
4.1Oral Drug Delivery System:
Since time immemorial, out of allthe sites available for delivering drugs, oral route has been the most popularroute for designing a drug delivery system. In the oral delivery system, therelease of the drug is either dissolution controlled, diffusion controlled,osmotically controlled, density controlled or pH-controlled.
CDs have been used as an excipientto transport the drugs through an aqueous medium to the lipophillic absorptionsurface in the gastro-intestinal tract, i.e., complexation with CDs has beenused to enhance the dissolution rate of poorly water-soluble drugs. HydrophilicCDs have been particularly useful in this regard. Table 2 lists the variousdrugs that have been evaluated for their ability to form complexes with CDs andthe improvement afforded by such complexation.
Rapid dissolving complexes with CDshave also been formulated for buccal and sublingual administration. In thistype of drug delivery system, a rapid increase in the systemic drugconcentration takes place along with the avoidance of systemic and hepaticfirst pass metabolism (Jain et al, 2002).
4.2.Rectal Dug Delivery System:
Recent studies have shown thatrectal mucosa can be used as a potential site for delivering drugs, which havea bitter and nauseous taste, have a high first-pass metabolism and degrade inthe gastro-intestinal pH. It is an ideal route to deliver drugs to theunconscious patients, children and infants. However, rectal mucosa offers avery limited area for drug absorption resulting in an erratic release of drugs.To overcome these problems, a number of excipients have been used and amongstthem, CDs have been found to be quite useful.
CDs, to be used as excipient inrectal drug delivery system should have the following characteristics:
1. They should be non-irritating tothe rectal mucosa.
2. They should inhibit the reversediffusion of drugs into the vehicle.
3. They should have a low affinityfor the suppository base.
Complexation of hydrophobic drugswith CDs have resulted in a significant increase in the rectal absorption ofthese drug (Table 3). The reason for the enhanced release has been attributedto the formation of a hydrophilic complex, which has a low affinity for thebase and rapidly dissolves in the rectal fluids. It has been reported that thecomplexation enhances the dissolution of lipophilic drugs at an interfacebetween the molten base and the surrounding fluid and inhibits the reversediffusion of the drug into the vehicle. Recently the absorption of humanchorionic gonadotropin (hCG) was found to increase by about four times in malerabbits when co-administered with a-CD (Kowari et al., 2002)
CDs have also been studied as rectalpermeation enhancers. They have been found to increase the permeation of drugsthrough rectal epithelium cells. It has been reported that complexation ofmorphine HCl with a and b-CD resulted in an increase in the bioavailability ofmorphine when it was formulated as a suppository. The complexation increased onlythe bioavailability and did not alter the release rate of morphine from thevehicle. (Kondo et al, 1996; Uekama et al, 1995) CDs have also been used toprevent the local irritation of drugs on the rectal mucosa.
4.3.Nasal Drug Delivery System:
The use of nasal mucosa fortransporting drugs is a novel approach for the systemic delivery of highpotency drugs with a low oral bioavailability due to extensivegastro-intestinal breakdown and high hepatic first-pass effect. CDs have theability to enhance drug delivery through biological barriers without affectingtheir barrier function, a property which makes CDs ideal penetration enhancersfor intranasal drug delivery. CDs can also act as solubilizers for lipophilicwater-insoluble drugs, making it possible to formulate such drugs in aqueousnasal spray formulations. Furthermore, CD complexation can stabilize drugswhich are chemically unstable in aqueous solutions, and decrease drugirritation after nasal application.
CDs, when used as excipients innasal drug delivery system should have the following characteristics:
1. They should not have any local orsystemic effect.
2. They should not interfere withthe nasal muco-ciliary functions.
3. They should not show ciliostaticeffect.
4. They should be non-irritating andnon-allergenic.
5. They should enhance thepermeation of drugs across nasal epithelium in a reversible manner.
The absorption enhancement affordedby CDs can be attributed primarily to their ability to reduce the physical ormetabolic barriers to drugs. Another potential barrier to the nasal absorptionof drugs is the limitation in the size of hydrophilic pores through which theyare thought to pass. The hydrophilic CDs solubilize some specific lipids frombiological membrane through the rapid and reversible formation of inclusioncomplexes, leading to an increase in the membrane permeability. Of all the CDsavailable, HP-b-CD and methylated b-CDs have been used mainly as solubilizersand absorption enhancers in nasal drug delivery system.
The concept of pulsed estrogentherapy has recently been exploited by the introduction of a nasal spraydelivery system containing CD (Al-Azzawi, 2002). The administration ofestradiol via the nasal mucosa was made possible by the use of randomlymethylated alpha-CD, which increased the solubility of estradiol. The newformulation provided reliable dose-dependent exposure to estradiol, avoidingthe hepatic first-pass effect and demonstrated good biological and clinicalefficacy. Bioavailability and clinical evaluation of a CD based intranasalformulation of midazolam also showed results comparable to an intravenousformulation with respect to the speed of absorption, serum concentration andclinical sedation effect (Gudmundsdottir, et al., 2001; Loftsson et al., 2001)Table 4 lists the various drugs evaluated for their complexation ability withCDs and incorporated into nasal drug delivery systems.
The safety of CDs as nasalabsorption enhancers has also been studied extensively. It has been found thattoxicity can occur at two stages. First, when the CD is in direct contact withthe nasal mucosa, i.e., local toxicity and secondly, when the CD complex has beenabsorbed through the nasal epithelium, i.e., systemic toxicity. From theliterature review, it has been found that local toxicity of CDs on nasalmucosa is not significant. However, the risk of systemic side effects of CDsafter nasal administration depends on how much CD has been absorbed and it hasbeen found that after nasal administration of a drug CD formulation, only thedrug is absorbed by the nasal epithelium but not the highly water soluble CD.The CD portion not absorbed is removed by the nasal muco-ciliary clearancesystem, which transports the unabsorbed CD towards the oesophagus, from whereit is swallowed. (Marttin et al., 1997b; Marttin et al., 1998). Asai et al(2002) have recently shown that 30 or 60 min exposure to 10% w/v HP-b-CD or randomlymethylated b-CD resulted in no obvious mucosal damage to the nasal mucosa ofrats.
4.4.Transdermal Drug Delivery System :
Transdermal drug delivery system isa sophisticated and more reliable means of administering the drug through skin,for local and systemic action. It offers the advantages of minimization of sideeffects due to the optimization of the concentration profile of drug in bloodwith time, avoidance of first-pass metabolism, easy termination of therapy bymere removal of patch, predictable and extended duration of action and greaterpatient compliance due to reduction in the frequency of dosing. However, themost important limitation of this drug delivery system is the limitedpermeation of drugs through human skin. The human skin is composed ofunvascularized epidermis and highly vascularized dermis below it. The externallayer of epidermis called stratum corneum is less permeable as compared to theother layers beneath it. Before a topically applied drug can act either locallyor systemically, it must penetrate the stratum corneum, the permeation barrier.A number of studies have been carried out to find safe and suitable permeationenhancers to promote subcutaneous absorption of drugs.
Use of CDs as permeation enhancershas gained tremendous popularity over the past few years. The rate ofpermeation of the drug through the skin is affected by partition coefficient ofthe drug between the skin and vehicle and the thermodynamic activity of drugsin vehicle.
CDs to be used as excipients intransdermal drug delivery system should possess the following characteristics:
1. They should be therapeuticallyinert.
2. They should not interfere withthe normal functions of the skin such as protection from heat, humidity,radiation and other potential insults.
3. They should not alter the pH ofthe skin.
4. They should not interact with anycomponent of the skin.
5. They should not cause skinirritation.
In transdermal drug delivery system,hydrophilic, hydrophobic as well as ionizable CDs have been used as carriersfor drugs. Hydrophilic CDs like 2,6 dimethyl-b-CD and hydroxypropyl-b-CD havebeen used to improve the solubility and dissolution characteristics ofinsoluble drugs. Hydrophobic CDs such as 2,6 diethyl-b-CD have been used to retardthe dissolution rate of water soluble drugs and ionizable CDs likecarboxymethyl-b-CD, sulfated and sulfobutylether-b-CD have been used to improveinclusion capacity and reduce side effects associated with drugs.
Table 5 lists the drugs which havebeen complexed with CD successfully in dermal preparation to minimize systemicside effects, improve patient compliance for long term therapy, increasesolubility and retard release of drug substances.
4.5.Ocular Drug Delivery System :
In an ocular drug delivery systemthe most preferred dosage form is the eye drop due to easy instillation in theeye. But the major disadvantage of this dosage form is its inability to sustainhigh local concentration of drug. The other dosage form for ocular treatmentincludes oily drops, gels, ointments, suspensions and inserts but theseformulations suffer from the drawback of causing irritation and blurred vision.There is therefore a need of an agent, which can overcome these problems whileformulating an ocular dosage form. In ocular drug delivery CDs have been usedto increase the solubility and/ or stability of drugs and to prevent sideeffects of drugs such as irritation and discomfort.
CDs have been used to solubilizepoorly water soluble drugs and enhance ocular bioavailaibility of lipophillicdrugs by keeping the drugs in solution and increasing their availaibility atthe surface of the corneal barrier. Hydrophillic CDs such as HP-b-CD andsulphobutyl-b-?CD have been used for the purpose mainly due to their non-toxicityand hydrophilicity. CDs to be used as an excipient in ocular drug deliverysystem should possess the following characteristics:
1. They should be non-irritating tothe ocular surface, as irritation can cause
reflex tearing and blinking resulting in fast washout of instilled drug.
2. They should be non-toxic and welltolerated.
3. They should be inert in nature.
4. They should enhance thepermeability of the drug through the corneal mucosa.
Numerous studies have shown that CDsare useful additives in ophthalmic formulations for increasing the aqueoussolubility, stability and bioavailability of ophthalmic drugs, and to decreasedrug irritation. Table 6 lists the drugs which have been evaluated for theircomplexation ability and incorporation into ophthalmic drug delivery system.
4.6Controlled and Targeted Drug Delivery System:
Whereas most of the earlier workdone on CDs concentrated on their property to enhance the release rate ofdrugs from dosage forms, some recent work has also been done to evaluate CDs ascarriers in controlled release drug delivery systems (Hirayama & Uekama,1999). Of the various CD derivatives, hydrophobic CDs such as alkylated andacylated derivatives have been used to prolong the release rate of drugs whilehydrophilic derivatives have been used to enhance the release rate. Recently,Kumar et al (2003) prepared a bilayered tablet of melatonin whereby the releaserate of drug was increased in the fast-release portion by the use of CDs whileit was retarded in the slow-release portion by the use of cellulosic polymers.
One of the most recent applicationsof CDs has been their incorporation in liposomes and neosomes. The main purposehas been to combine the advantages of CDs (such as increase solubility) withthe advantages of liposomes and neosomes (such as their precision andtargeting). Complexation with CD has also been used for brain targeting andspecific cell targeting. Table 7 enlists the drugs formulated as controlled andtargeted delivery systems using different CDs.
5. Future Prospects ofCyclodextrins
The future prospects of CD and itsderivatives are quite bright since they possess remarkably unique properties offorming inclusion complexes with drugs. An increasingly number of drugs beingdeveloped today have problem of poor solubility, bioavailability andpermeability. CDs can serve as useful tools in the hands of pharmaceuticalscientists for optimizing the drug delivery of such problematic drugs and alsofor drugs having other undesirable properties such as poor stability,objectionable taste and odor and irritation potential.
Although, presently onlyconventional formulations such as tablets, capsules, solutions and ointmentshave been commercialized using CDs, these are extensively being studied fortheir utilization in novel formulations such as nanoparticles, liposomes, nasal,ophthalmic and rectal formulations, transdermal products and targeteddrug delivery systems and the time is not far when such productswill become commercially available.
6.Acknowledgements
Grateful acknowledgement is made toUGC (for research grant to S. Baboota), CSIR (for research associateship to R.Khanna) and to AICTE (for emeritus fellowship to S. P. Agarwal).