Cyclodextrin-based controlled drug release system F...

LAdvanced Drug Delivery Reviews 36 (1999) 125–141

Cyclodextrin-based controlled drug release system*F. Hirayama, K. Uekama

Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Kumamoto 862-0973, Japan

Abstract

Because of their bioadaptability and multi-functional characteristics, cyclodextrins (CDs) are capable of alleviating theundesirable properties of drug molecules in various routes of administration through the formation of inclusion complexes.This article outlines the current application of natural and chemically modified CDs in the design of advanced dosage forms.In an oral drug delivery system (DDS), the hydrophilic and ionizable CDs can serve as potent drug carriers in the immediaterelease- and delayed release-formulations, respectively, while the release rate of water-soluble drugs can be retarded byhydrophobic CDs. Since CDs are able to extend the function of pharmaceutical additives, the combination of molecularencapsulation with other carrier materials will become effective and a valuable tool in the improvement of drug formulation.Moreover, the most desirable attribute for the drug carrier is its ability to deliver a drug to a targeted site; conjugates of adrug with CDs can be a versatile means of constructing a new class of colon-targeting prodrugs. On the basis of thisknowledge, the advantages and limitations of CDs in DDS are addressed. 1999 Elsevier Science B.V. All rights reserved.

Keywords: Cyclodextrin; Inclusion complex; Drug carrier; Oral drug delivery; Controlled release; Drug–cyclodextrinconjugate; Colon-targeting

Contents

1. Introduction ............................................................................................................................................................................ 1252. Controlled release in oral drug delivery systems ........................................................................................................................ 127

2.1. Immediate release ............................................................................................................................................................ 1282.2. Delayed release................................................................................................................................................................ 1292.3. Prolonged release ............................................................................................................................................................. 1302.4. Modified release .............................................................................................................................................................. 131

3. Cyclodextrin-based site-specific drug delivery ........................................................................................................................... 1333.1. CD–drug conjugates as colon-targeting prodrugs................................................................................................................ 1333.2. Brain targeting ................................................................................................................................................................. 1363.3. Specific cell targeting ....................................................................................................................................................... 136

4. Conclusions ............................................................................................................................................................................ 137References .................................................................................................................................................................................. 138

1. Introduction

* From the viewpoint of the optimization of theCorresponding author. Tel.: 1 81-96-371-4160; fax: 1 81-96-372-7023; e-mail: [email protected] pharmacotherapy, drug release should be controlled

0169-409X/99/$ – see front matter 1999 Elsevier Science B.V. All rights reserved.PI I : S0169-409X( 98 )00058-1

126 F. Hirayama, K. Uekama / Advanced Drug Delivery Reviews 36 (1999) 125 –141

in accordance with the therapeutic purpose and the is surrounded by the hydrophobic environment of thepharmacological properties of active substances. CD cavity. This can lead to alteration of physical,There has been growing interest in developing rate- chemical and biological properties of guest mole-or time-controlled oral preparations, because appro- cules, and can eventually have considerable pharma-priate drug release from dosage forms is of critical ceutical potential. Recently, a number of CD deriva-importance in realizing their therapeutic efficacy tives and CD polymers have been prepared to obtain[1,2]. In order to design more advanced dosage better inclusion abilities than found with parent CDsforms, various kinds of carrier materials are being [9,10] (Table 1). b-CD, the most common naturaldeveloped to deliver the necessary amount of drug to CD, has 21 hydroxyl groups, that is, seven primarythe targeted site for a necessary period of time, both and 14 secondary hydroxyls (Fig. 1). All of theseefficiently and precisely [3]. Cyclodextrins (CDs) are hydroxyl groups are available as starting points forpotential candidates for such a role, because they can structural modifications, and various functionalbe used either for complexation or as functional groups have been introduced into the macrocycliccarrier materials in pharmaceutical formulations [4– ring. Then the natural and chemically modified CDs8]. One of the important characteristics of CDs is have been extensively utilized to improve variousthat they form inclusion complexes both in solution drug properties, such as solubility, dissolution rate,and in the solid state, in which each guest molecule stability or bioavailability [11–17]. The works pub-

Table 1aPharmaceutically useful b-CD derivatives

Derivative Position of Substituentsubstituent

Hydrophilic derivativesMethylated b-CD 2,6-; 2,3,6- -O-CH3

Hydroxyalkylated b-CD Random -O-CH -CH(OH)-CH2 3

Branched b-CD 6- -Glucosyl: -maltosyl

Hydrophobic derivativesEthylated b-CD 2,6-; 2,3,6- -O-C H2 5

Peracylated b-CD 2,3,6- -O-CO(CH ) -CH2 n 3

Ionizable derivativesCarboxyalkyl b-CD Random -O-(CH ) -COONa2 n

Carboxymethyl; ethyl 2,6-; 3- -O-CH COONa; -O-C H2 2 5

Sulfates Random -O-SO Na3

Alkylsulfonates Random -O-(CH ) -SO Na2 n 3

aObtained by substitution of the OH groups located on the edge of the CD ring.

Fig. 1. Hydroxyls located on the edge of the b-CD ring.

F. Hirayama, K. Uekama / Advanced Drug Delivery Reviews 36 (1999) 125 –141 127

lished thus far apparently indicate that the multi-functional characteristics of CDs may allow therational design of drug formulation and that thecombination of molecular encapsulation with othercarrier systems will become a very effective andvaluable method for the development of new drugdelivery systems [18–21]. Among the chemicallymodified CDs, the hydrophilic [22–27] or ionizableCDs [28–31] will enhance drug absorption, whilehydrophobic CDs may have broad applicability, andcould serve as novel slow-release carriers of water-soluble drugs, including peptide and protein drugs[32–38]. Moreover, the biodegradation property ofCD [39–41] is particularly useful as a colon-target- Fig. 2. Typical drug release profiles following oral administration.

(A) Immediate release; (B) Prolonged release; (C) Modifieding carrier, and the CD prodrugs will serve as arelease; (D) Delayed release.source of site-specific delivery of drugs to the colon

[42]. Thus, the objective of this contribution is tofocus on the potential use of natural and chemically trolled type is further classified into three types, i.e.modified CDs as high performance drug carriers in immediate release, prolonged release and modifiedthe development of advanced dosage forms with release types. On the basis of this knowledge,emphasis on the latest applications of CDs in site- various CD derivatives have been used in order tospecific delivery. modify drug release in oral preparations (Table 2).

The hydrophilic and hydrophobic CDs are usefulfor the immediate release and the prolonged release

2. Controlled release in oral drug delivery type formulations, respectively. The delayed releasesystems type formulation can be obtained by the use of

O-carboxymethyl-O-ethyl–b-CD (CME-b-CD).Fig. 2 shows typical drug release–time profiles Moreover, a combination of CDs and other carrier

after oral administration. The plasma drug levels– materials is useful for optimizing the release rate oftime profiles can be mainly classified into two drugs. Typical examples of the applications of CDcategories, i.e. the rate-controlled type and the time- derivatives in modified release and prolonged releasecontrolled type (delayed release type). The rate-con- formulations will be described next.

Table 2Modification of the drug release site and/or time profile by CDs

Release pattern Aim Use of CD

Immediate-release Enhanced dissolution and HP-b-CD, DM-b-CD,absorption of poorly water- SB-b-CDs,soluble drugs Branched b-CDs

Prolonged-release Sustained release of water- Ethylated b-CDs,soluble drugs Acylated b-CDs

Modified-release More balanced oral Simultaneous use ofbioavailability with prolonged different CDs and/ortherapeutic effects other excipients

Delayed-release (Enteric)pH-dependent release Acid protection of drugs CME-b-CDSite-specific release Colon-targeting Drug–CD conjugate


2.1. Immediate release epithelia or stratified cell layers and eventuallyentering the systemic circulation. In general, maxi-

Immediate release formulations of analgesics, mum absorption enhancement is obtained when justantipyretics, coronary vasodilators, etc. are particu- enough CD is used to solubilize all of the drug inlarly useful in emergency situations. Since the disso- solution. Further addition of CD to the drug solutionlution rate of the poorly water-soluble drugs is decreases the free fraction of the drug and, hence,mainly responsible for both the rate and extent of reduces the drug’s bioavailability. Practical formula-oral bioavailability of drugs, various hydrophilic tions usually contain a large quantity of pharma-materials are used to attain an immediate release ceutical excipients, which may compete with theformulation. The hydrophilic CDs have been exten- drug for the CD cavity. Such competition may alsosively used to enhance the oral bioavailability of occur with endogenous substances that exist at thesteroids, cardiac glycosides, nonsteroidal antiinflam- absorption site. The displacement of the drug frommatory drugs, barbiturates, antiepileptics, benzodi- the CD cavity by exogenous and endogenous sub-azepines, antidiabetics, vasodilators, etc. [4–11]. stances at the absorption site is responsible forThese improvements are mainly ascribable to the acceleration of drug absorption [43,44]. For instance,increase in solubility and wettability of drugs the overall process of drug absorption from a solidthrough the formation of inclusion complexes. The complex in the presence of competing agent iscommercial viability of CD-based oral formulations shown in Fig. 3 [12], where k is the dissolution rated

has been established with the marketing of more than constant, K is the stability constant of the complexc

ten products [17]. of the drug with the CD, K is the stability constanti

The rate and extent of oral bioavailability of a of the complex of the competing agent with the CDpoorly water-soluble drug from its CD complex can and k is the absorption rate constant of the drug. Aa

be optimized by adjusting various factors that affect high dissolution rate and relatively stable complexesthe dissociation equilibrium of the complex both in (K . K ) favor a free drug that is readily availablei c

the formulation and in the biophase in which the for absorption. By contrast, a free CD after thecomplex is administered [10,16]. Only a free form of dissociation of the complex removes some com-the drug, which is in equilibrium with the complexed ponents from the membrane surface, thereby modify-form of the drug in solution, is capable of penetrat- ing the transport properties of the membranes anding lipophilic barriers consisting of either mucosal facilitating drug absorption, especially for water-

Fig. 3. Overall process of drug absorption from an inclusion complex following dissolution and dissociation in the gastrointestinal tract.Modified from ref. [12]; k , dissolution rate constant of drug–CD complex; K , stability constant of drug–CD complex; K , stability constantd c i

of competing agent–CD complex; k , absorption rate constant of drug.a


soluble drugs. Thus, attention should be directed results were obtained for the sublingual administra-towards the dissociation equilibrium and stoichiome- tion of tablets containing complexes of steroids withtry of the complex in both body fluids and pharma- CDs [55–60]. HP-b-CD and b-CD polymers sup-ceutical formulations. ported the absorption of testosterone from the oral

As shown in Fig. 3, CDs are supposed to act only cavity and not from the gastrointestinal tract; theseas carrier materials and help to transport the drug solubilizers neither enter nor damage the oral tissuesthrough an aqueous medium to the lipophilic absorp- [61]. Inherently, the blood level of endogenoustion surface in the gastrointestinal tracts. Therefore, testosterone rises a few times a day in episodes thatsuch applications have been successful when the last approximately 1 h. Such pulsatile release ofrate-limiting step in drug absorption is dissolution of testosterone can be imitated by the sublingual ad-the drug itself and not absorption across the gastroin- ministration of its HP-b-CD complex, giving thetestinal tract. Recent studies have shown that com- desired pharmacological effects [57]. This formula-plexation of b-CD with imidazole antifungal agents, tion may be especially suitable for treatment of boyssuch as ketoconazole and econazole, provided an with delayed puberty and older men with an an-enhancement of oral bioavailability [45,46]. Other drogen deficiency [59].studies have demonstrated that a combination of Another approach is the use of amphiphilic CDs,a-CD with citric acid is effective in preventing gel such as b- or g-CD esterified on the secondaryformation of cefotiam hexetil hydrochloride, an hydroxyl groups by alkyl chains (from C to C ).6 14

orally active antibacterial agent, increasing the disso- They are capable of forming self-assembled nanos-lution rate and improving its oral bioavailability [47]. pheres that can be loaded with high amounts ofThe stabilizing effect of CDs on labile drugs is also poorly water-soluble drugs, such as indomethacinresponsible for the improvement of oral bioavail- and progesterone. The drug, being molecularly dis-ability. For example, a g-CD complex was found to persed in the nanospheres, is very rapidly released indecrease acid hydrolysis of cardiac glycosides and, aqueous medium, allowing for the administration ofhence, to improve the oral absorption of digoxin in poorly water-soluble drugs that can be bioavailabledogs [48]. rapidly [62].

Recently, highly hydrophilic CD derivatives, suchas 2-hydroxypropyl–b-CD (HP-b-CD) [49], 2.2. Delayed releasemaltosyl–b-CD (G -b-CD) [50], and2

sulfobutylether–b-CDs (SBE-b-CDs) [51] have been An enteric preparation can be classified as time-used to obtain an immediate release formulation that controlled release, since the drug is preferentiallyis readily dissolved in the gastrointestinal tract, released in the intestinal tract. Hydrophobic excipi-enhancing the oral bioavailability of poorly water- ents having a weak acidic group are preferablesoluble drugs. HP-b-CD is utilized to modify the because they are less soluble in water at low pH, butphysical properties of drugs in the solid state, such as soluble in neutral and alkaline regions due to theparticle size, the polymorphic transition and the ionization of the acidic group. Under the control ofconversion from the crystalline to an amorphous or this pH dependence, the delayed release dosageglassy state [52,53]. For example, the rapidly dis- form, which passes from the stomach into the highersolving forms of metastable and glassy states of pH environment of the upper small intestine, wouldnifedipine can be obtained by cooling the melts of a experience increased drug release. For this purpose,1:1 physical mixture of drug–HP-b-CD matrices CME-b-CD was developed to exhibit pH-dependent[54]. solubility for use in selective dissolution of the

Rapidly dissolving complexes of drugs with hy- drug–CD complex [28]. As shown in Fig. 4, CME-drophilic CDs are well suited for sublingual or b-CD displays limited solubility under acidic con-buccal administration. This type of drug entry not ditions, such as those found in the stomach, with theonly gives a rapid rise in systemic drug concen- complex solubility increasing as the pH passestrations but also avoids intestinal and hepatic first- through the pK (3.7) of the CME-b-CD. CME-b-a

pass metabolism of the drug. Other illuminating CD complexes have been used in in-vitro and in-vivo


effect under high gastric acidity was more pro-nounced under fasted conditions. As in the diltiazemstudies, a high degree of correlation was notedbetween the in-vivo studies and the in-vitro releasemeasured with the pH-changeable dissolution ap-paratus [64].

2.3. Prolonged release

Most of the slow-release preparations have beenaimed at achieving zero-order or pH-independentrelease of drugs to provide a constant blood level forFig. 4. Solubility of CME-b-CD as a function of pH in aqueous

solution at 258C. (see ref. [28]). a long period of time. This kind of formulation hasmany advantages, such as reducing the frequency ofdosing, prolonging the drug’s efficacy and avoiding

studies with diltiazem, a calcium-channel antagonist, the toxicity associated with the administration of aand molsidomine, a peripheral vasodilator. The simple plain tablet. For this purpose, hydrophobicdiltiazem studies were carried out in gastric acidity- CDs, such as alkylated and acylated derivatives, arecontrolled fasting dogs with the gastric pH being useful as slow-release carriers for water-solublecontrolled to less than two and greater than six. drugs. Among the alkylated CDs, 2,6-di-O-ethyl–b-Diltiazem absorption was slower at high gastric CD (DE-b-CD) and 2,3,6-tri-O-ethyl–b-CD (TE-b-acidity (t , 4.060.5 h) than at low gastric acidity CD) were the first slow-release carriers to be used inmax

(t 5 2.360.2 h) (Fig. 5). The in-vitro release data conjunction with diltiazem [33,65] and isosorbidemax

measured using a pH changeable dissolution ap- dinitrate [66] following oral administration of theparatus were in good agreement with the in-vivo data hydrophobic complexes to dogs. On the other hand,[63]. Molsidomine absorption from tablets contain- the peracylated CDs with medium alkyl chaining CME-b-CD was studied in gastric acidity-con- lengths (C –C ) are particularly useful as novel4 6

trolled dogs in the fasted and fed states. Under high hydrophobic carriers (Table 3), because of theirgastric acidity, molsidomine absorption was signifi- multifunctional and bioadaptable properties [32,67].cantly retarded relative to that found under low They have broad applicability in various routes ofgastric acidity conditions. The delayed absorption administration: for example, the bioadhesive proper-

ty of 2,3,6-tri-O-butyryl–b-CD (TB-b-CD) (C ) can4

be used in oral and transmucosal formulations, whilethe film-forming property of 2,3,6-tri-O-valeryl–b-CD (TV-b-CD) (C ) is useful in transdermal prepa-5

rations [68]. In oral applications, molsidomine wasused to design a sustained release formulation,because this drug is water-soluble and has a shortbiological half-life. The release rate of molsidominewas markedly retarded by complexation withperacylated b-CDs, in decreasing order of theirsolubility, in particular, by those longer than TB-b-CD [69]. When the complexes were administered

Fig. 5. Plasma levels of diltiazem after the oral administration of orally to beagle dogs, TB-b-CD suppressed a peaktablets containing CME-b-CD complex (equivalent to diltiazem at plasma level of molsidomine and maintained a30 mg/body) in gastric acidity-controlled dogs (see ref. [63]); s,

sufficient drug level for long periods, while thehigh gastric acidity dogs; d, low gastric acidity dogs. Each valuesingle use of other derivatives having shorter orrepresents the mean6standard error of four dogs. *, p , 0.05 vs.

high gastric acidity dogs. longer chains than TB-b-CD proved to be insuffi-


Table 3

Some physicochemical properties of acylated b-CDsa bCompound R Melting [M] SolubilityD

point (8C) (mg/dl)d

b-CD H 280 1 1850 119.0TA-; peracetyl–b-CD COCH 201–202 1 2522 823.03

TP-; perpropionyl–b-CD COC H 168–169 1 2450 423.52 5

TB-; perbutyryl–b-CD COC H 126–127 1 2607 219.83 7

TV-; pervaleryl–b-CD COC H 54–56 1 2640 283.04 9cTH-; perhexanoyl–b-CD COC H 2 1 2620 3.75 1 1c eTO-; peroctanoyl–b-CD COC H 2 1 2763 27 1 5c eTD-; perdecanoyl–b-CD COC H 2 1 2668 29 1 9c eTL-; perlauroyl–b-CD COC H 2 1 2829 21 1 2 3

a b c d eIn chloroform at 258C; In 80% (v/v) ethanol–water at 258C; Oily substance; In water; Could not be determined because of the lowsolubility.

cient (Fig. 6). Prolonged maintenance (at least 24 h) increased hydrophobicity and mucoadhesive prop-of higher and constant levels of salbutamol, a erties. Similarly, nanospheres formed by amphiphilicbronchodilator, in plasma was also obtained after CDs such as 2,3-di-O-hexanoyl–b-CD (DH-b-CD)oral administration of the TB-b-CD complex in may have bioadhesive effects on gastrointestinaldogs, where the plasma level of the major metabo- mucosa [62].lite, salbutamol glucuronide, was significantly lower The combined use of short and long chainthan that found after administration of the drug alone peracylated b-CDs in an appropriate molar ratio is[70]. This indicates that TB-b-CD may be a useful also effective in controlling the release rate of water-carrier for orally administered water-soluble drugs, soluble drugs [71]. For example, the release rate ofespecially for drugs that are metabolized in the diltiazem decreased with increasing hydrophobicitiesgastrointestinal tract. The superior sustaining effect of the carrier materials (Fig. 7). The change inexhibited with TB-b-CD may be a result of both release rate of the drug from the hydrophobic carriers

was clearly reflected in the drug levels found inblood after oral administration of the tablets to dogs.Although the drug–2,3,6-tri-O-acetyl–b-CD (TA-b-CD) (C ) system, at a molar ratio of 1:2, maintained1

plasma drug levels of over 30 ng/ml for at least 24h, a combination of TA-b-CD and 2,3,6-tri-O-octanoyl–b-CD (TO-b-CD) (C ) gave a constant8

plasma drug level (20–40 ng/ml) for more than 48h, with a significant increase in the extent ofbioavailability.

2.4. Modified release

Fig. 6. Plasma levels of molsidomine after oral administration of The conventional formulation of nifedipine, acapsules containing molsidomine or its peracylated b-CD complex typical calcium-channel antagonist, must be given(equivalent to 10 mg molsidomine) in dogs (see ref. [69]). d, drug

either twice or three times daily, because of the shortalone; n, TA-b-CD complex; j, TB-b-CD complex; x, TH-b-elimination half-life due to the considerable first-passCD complex. Each value represents the mean6standard error of

three–six dogs. *, p , 0.05 vs. drug alone. metabolism. Moreover, it has some pharmaceutical


Fig. 7. Release profiles of diltiazem from tablets containingFig. 8. Release profiles of nifedipine (5 mg) from plain tablet (F )diltiazem, diltiazem–TAb-CD and diltiazem–TA-b-CD–TO-b- 0

and seven double-layer tablets (F –F ) in water at 378C (see ref.CD systems (equivalent to 6 mg diltiazem) in water at 378C, 1 7

[75]).measured by the rotating basket method at 60 rpm (see ref. [71]).d, diltiazem alone; n, diltiazem–TA-b-CD complex (molar ratioof 1:1); m, diltiazem–TA-b-CD complex (molar ratio of 1:2); h,diltiazem–TA-b-CD–TO-b-CD complex (molar ratio of

ditions (608C, 75% relative humidity) [74]. Among1:2:0.25); j, diltiazem–TA-b-CD–TO-b-CD complex (molarthe seven formulations tested, the double-layer tabletratio of 1:2:0.5).

(F ), consisting of HP-b-CD with 3% HCO-60 /3

[hydroxypropylcellulose L (low viscosity grade)–hy-problems, such as low oral bioavailability due to droxypropylcellulose M (medium viscosity grade)] inpoor aqueous solubility, and a decrease in its dissolu- a weight ratio of 1 /(1.5:1.5) was selected as the mosttion rate during storage (due to crystal-growth) [72]. appropriate one, because it elicited a prominentTherefore, the release rate of nifedipine must be retarding effect with superior oral bioavailabilitymodified in order to obtain a more balanced oral compared with those of a commercially availablebioavailability with prolonged therapeutic effect. slow-release product [75] (Fig. 9). These facts

Wang et al. [73–75] have recently developed a suggest that a combination of HP-b-CD, HCO-60double-layer tablet, using HP-b-CD and pharma- and hydroxypropylcelluloses serves as a modified-ceutical excipients, and evaluated the drug’s release release carrier of nifedipine, and can be applied tobehavior. In these studies, an amorphous nifedipinepowder, prepared by spray-drying with HP-b-CD

and a non-ionic detergent, HCO-60 , was employedas a fast-release portion to attain initial rapid dissolu-tion and to prevent crystal growth during storage.Hydroxypropylcelluloses (HPCs) with different vis-cosity grades were employed as a slow-releaseportion to provide an appropriate level of sustainedrelease of poorly water-soluble nifedipine fromviscous matrices. Then, an optimal formulation ofthe double-layer tablet was surveyed by changing themixing ratio of the fast-release portion and the slow-release portion (Fig. 8).

The in-vitro release rate of nifedipine from theFig. 9. Plasma levels of nifedipine after oral administration of

double-layer tablet was little affected by the pH of tablets (20 mg as nifedipine) in dogs (see ref. [75]). s, double-the medium and the rotation speed of the paddle layer tablet (F ); m, double-layer tablet (F ); h, Adalat L-20.2 3

even after long-term storage under accelerated con- Each value represents the mean6standard error of four dogs.


other poorly water-soluble drugs with a short elimi- trast to those in HP-b-CD or sugars. The plasmanation half-life. drug profiles for OPTs following oral administration

When the stomach is one of the important absorp- to dogs were retarded, with a decreased in-vitro rate.tion sites, there should be no lag-time in drug release This technique has also been applied to chlor-from the dosage form. This type of dosage form is promazine [80], a weak basic drug, which exhibitsrequired for loop diuretics such as furosemide and pH-dependent solubility and is poorly soluble atpiretanide, in which the release of a certain amount neutral pH.of drug in the stomach is desired to give morebalanced bioavailability. To attain efficient bioavail-ability for such acidic drugs, double-layer tableting 3. Cyclodextrin-based site-specific drug deliverywas also useful, consisting of hydrophilic CDs as thefast-release portion and hydrophobic cellulose de- Recently, intensive efforts have been made torivatives as the slow-release portion [76]. In the case design a system that is able to deliver drugs moreof piretanide, a tablet consisting of a [DM-b-CD/ efficiently to specific organs, tissues and cells, etc.(hydroxypropylcellulose /ethylcellulose)] system, at a CD complexes are in equilibrium with guest and hostweight ratio of 1 /3(1 /3) provided sufficient slow molecules in aqueous solution, with the degree of therelease of the drug over 8 h and over a wide pH dissociation being dependent on the magnitude of theregion following initial rapid dissolution. stability constant of the complex. This property is a

Poorly water-soluble drugs often demonstrate er- desirable quality, because the complex dissociates toratic oral bioavailability that is further exacerbated give free CD and drug at the absorption site, andwhen attempts are made to develop controlled re- only the drug in free form enters into the systemiclease dosage forms. A porosity-controlled osmotic circulation. A typical example of this is the applica-pump tablet (OPT) is one coated with a semiperme- tion of HP-b-CD to the chemical delivery systemable membrane containing leachable pore-forming developed by Bodor [81], which will be describedmaterials. The idea was first developed formally by below. However, the inclusion equilibrium is some-Zentner et al. [77]. In this system, drug, after times disadvantageous when drug targeting is to bedissolution, is released from the tablet by hydrostatic attempted, because the complex dissociates before itpressure through pores created by the dissolution of reaches the organs or tissues to which it is to bepore formers incorporated into the membrane. Hy- delivered. One of the methods to prevent dissociationdrostatic pressure is created by an osmotic agent, e.g. is to bind a drug covalently to CDs. In this section,the drug itself or a tablet component, after water is recent results on site-specific delivery using CDs areimbibed across the semipermeable membrane. This described.system is generally applicable for only highly water-soluble drugs. Because poorly water-soluble drugs 3.1. CD–drug conjugates as colon-targetingdissolve slowly, it is not possible to completely prodrugsdeliver drugs with poor solubility from such devicesand tablets in general. This problem can be over- Colon targeting is essentially classified as a de-come by adding (SBE) –b-CD (there are about layed release with a fairly long lag-time (Fig. 10),7 m

seven degrees of substitution of the sulfobutyl ether because the time required to reach the colon aftergroup on b-CD hydroxyls and these can act as both a oral administration is expected to be about 8 h insolubilizer and as an osmotic agent) [78]. Recently, man [82,83]. When a CD complex is given orally, itOkimoto et al. [79] developed a novel OPT for will readily dissociate in the gastrointestinal fluid,prednisolone using (SBE) –b-CD, which acts as a depending on the magnitude of the stability constant.7 m

solubilizer and an osmotic agent. Core tablets, in an This indicates that CD complexes are not suitable forOPT containing the drug and osmotic agents, were colon-specific delivery due to release of the drugfilm-coated with cellulose acetate. In-vitro release (because of dilution and/or competitive inclusionstudies revealed that prednisolone was completely effects) before it reaches the colon. On the otherreleased from OPTs with (SBE) –b-CD, in con- hand, the physicochemical and biopharmaceutical7 m


Fig. 10. Release profiles of drug from various dosage forms following oral administration.

properties of CD–drug conjugates, in which a drug is observed for the a-CD conjugate may be due to thecovalently bound to CD, must differ greatly from fact that a-CD cavity is too small to accommodatethose of the inclusion complex. One of the advan- the BPAA moiety. The release profiles of the drugtages of CD–drug conjugates is that they can survive after incubation of the ester conjugates in rat gas-passage through the stomach and small intestine, trointestinal tract contents, intestine and liverhowever, drug release will be triggered by enzymatic homogenates, and blood in isotonic buffer solutions,degradation of CDs in the colon. Taking these were then compared with those of ethyl biphenylylfactors into account, we [42,84] have designed acetate (EBA), a simple ethyl ester of BPAA. EBAamide- and ester-type conjugates of the antiinflam- was easily hydrolyzed in liver and gastrointestinalmatory drug biphenylylacetic acid (BPAA) with three tract homogenates, and also in blood, however, itnatural CDs, anticipating a new candidate for a was stable enough in the cecal and colonic contents.colon-targeting prodrug (Fig. 11) [82,83]. In sharp contrast, the a- and g-CD ester conjugates

Interestingly, the solubility of the CD-based pro- released BPAA significantly in cecal and colonicdrugs is related to the cavity size of CD. For contents, while no appreciable drug release from theexample, the extremely low solubility of the b-CD conjugates was observed on incubation with otherconjugate was ascribed to the intermolecular associa- contents or fluids. When the ester conjugates weretion between the drug moiety and the neighboring incubated with rat cecal contents, a- and g-CDCD cavity. On the other hand, the highest solubility conjugates produced BPAA quantitatively, while the

b-CD conjugate released BPAA in only smallamounts, despite the significant disappearance of theb-CD conjugate. Although the drug release patternsof the three CD conjugates are different from eachother, the in-vitro data clearly suggest that esterconjugates are first subject to the ring-opening of CDby bacterial enzymes, to give the triose and maltoseconjugates through to longer linear oligosaccharideconjugates. Thus, the ester linkage of the smallsaccharide–BPAA conjugates could be highly sus-ceptible to hydrolysis. On the other hand, the amideconjugates hardly released the drug at all, despiteFig. 11. Structures of biphenylylacetic acid (BPAA) and its

cyclodextrin conjugates. fermentation to small saccharide–BPAA conjugates.


of bioavailability for the a- and g-CD conjugateswere about four and five times larger, respectively,than that for BPAA alone. In-vivo studies furtherrevealed that BPAA is released and absorbed in thececum and colon after oral administration of the estertype conjugates in rats, which may consequentlyprovide the long lag time. The antiinflammatoryeffects of the g-CD ester conjugate and b-CDcomplex were evaluated using the model of car-rageenin-induced acute edema in rat paw [85]. In thecase of the b-CD complex, a rapid antiinflammatoryresponse was observed, compared to that of BPAAalone, because the drug was mainly absorbed fromFig. 12. Serum levels of BPAA after the oral administration of

suspensions containing BPAA, b-CD complex or CD ester conju- the small intestine after fast dissolution of thegates (equivalent to 10 mg/kg BPAA) in rats (see ref. [42]). s, complex. In sharp contrast, the g-CD ester conjugateBPAA alone; d, b-CD complex; x, a-CD ester conjugate; m,

needed a fairly long lag time to exhibit the drug’sb-CD ester conjugate; h, g-CD ester conjugate. Each value

activity, because BPAA was produced after it hadrepresents the mean6standard error of two–four rats.reached the cecum and colon. On the basis of the

Fig. 12 shows the serum levels of BPAA after oral above-mentioned results, the release mechanism ofadministration of three ester conjugates, compared BPAA from its g-CD prodrugs, as an example, in ratwith the drug alone and a b-CD complex in rats. As cecum and colon, could be as proposed in Fig. 13. Inexpected, the fast-dissolving form of CD complex the case of ester-type conjugates, drug release isshows a rapid increase and decrease in the serum triggered by the ring-opening of CDs, which conse-drug levels, compared with that of drug alone. In the quently provides site-specific drug delivery in thecase of b-CD conjugate, a slight increase in serum colon. On the other hand, the amide conjugates dodrug levels was observed, probably due to the slower not release the drug even in the cecum and colon,drug release. However, the serum drug levels of the despite the ring-opening of CDs. The amide linkagea- and g-CD conjugates increased after a lag time of of the small saccharide–drug conjugates may beabout 3 h, and reached maximum levels at about 9 resistant to the bacterial enzymes and poorly absorb-and 8 h, respectively, accompanied by a significant able from the intestinal tract due to high hydro-increase in the extent of bioavailability. The extent philicity. Therefore, the ester-type conjugate is pre-

Fig. 13. Release mechanism of drug from g-CD–drug conjugates in rat cecum and colon. Modified from ref. [85].


ferable as a delayed release-type prodrug that can examples is the b-CD conjugates with d-opioidrelease a parent drug selectively in the cecum and receptor peptides, N-leucine-enkephalin and its

4 2 5colon. cyclic analogue [ p-I-Phe , D-Pen , D-Pen ]en-kephalin, where the carboxyl group of the C-terminal

3.2. Brain targeting leucine was coupled with 6-amino-6-deoxy–b-CDand in the latter conjugate, all hydroxyl groups of

When a drug is covalently coupled to 1-methyl- CDs were further methylated to increase the lipo-1,4-dihydronicotinic acid through an enzymatically philicity [92,93]. Although the potency of the latterlabile linkage, its lipophilicity increases and allows conjugate decreased in the receptor binding assayselective delivery of drug molecules into the brain and in the in-vitro guinea pig intestine and mouseacross the blood–brain barrier, which is character- spermatic duct bioassay systems, it showed potentized by the endothelial cells of cerebral capillaries antinociceptive properties when given i.c.v and i.v.that have tight continuous circumferential junctions, in the mouse tail flick test and exhibited no toxicity.thus restricting the passage of polar drugs to the Furthermore, it showed prolonged action in thebrain [86]. After entry into the brain, the dihydro- bioassay. Although the detailed transport mechanismpyridine moiety is oxidized by oxidoreductase to of these conjugates to the brain has not been fully1-methyl-pyridinium cation. Thus, the polar drug–1- elucidated, this methodology can be applied to othermethylpyridinium derivative is trapped in the brain neuropharmaceuticals such as morphine. The b-CDdue to the presence of the blood–brain barrier. conjugate with N-leucine-enkephalin is of interest,Subsequently, the parent drug is released from the because it has a vacant cavity and can include aprodrug by the action of other enzymes. This is an neurotropic drug, dothiepine. In general, the sub-essential concept of Bodor’s chemical delivery sys- stituents introduced at primary hydroxyl groups oftem and is applied to brain targeting of drugs such as CDs, through a spacer of appropriate length, aresteroids, antitumor agents and calcium-channel an- self-included within the cavity. However, the en-tagonists [87]. The problem, however, is that the kephalin conjugate can accommodate other guestprodrugs of the chemical delivery system are poorly molecules, probably because the self-inclusion iswater-soluble due to the presence of the lipophilic restricted due to a steric hindrance. This inclusionmoiety. HB-b-CD solved this solubility problem by property of conjugates may be useful from themeans of soluble complex formation, together with viewpoint of drug formulation, since two differentenhancing the chemical stability of the drugs can be incorporated into the CD molecule.dihydronicotinic acid in aqueous solution. For exam-ple, the i.v. administration of estradiol chemical 3.3. Specific cell targetingdelivery systems (5 mg/kg) solubilized in 20% HB-b-CD produced a higher concentration of the pro- b-Lactam antibiotics exert their lethal effect bydrug in rat brain, which was almost the same as that inhibiting the synthesis of bacterial peptidoglycan,produced by the administration of the prodrug (15 thereby disrupting the cell morphology and eventual-mg/kg) solution in dimethylsulfoxide [88]. It is ly resulting in cell lysis and death [94]. Since theapparent that HB-b-CD has an advantage over antibacterial effect of b-lactam is affected by thedimethylsulfoxide from a safety point of view. The permeability of the outer membrane of bacteria, it isimprovement in chemical delivery systems using important in the evaluation of drug efficacy toHB-b-CD was reported for testosterone [89], dexa- measure the diffusion rate of drugs across themethasone [90] and benzyl penicillin [91]. membrane. However, the b-lactamase enzyme ex-

The specific delivery of potential neurophar- pressed at the cell surface interferes with this mea-maceuticals to the brain is obstructed by the presence surement. In order to solve this problem, a b-lactam-of the blood–brain barrier. One of the strategies to ase inhibitor that is water-soluble and could reach theovercome this transport problem is to prepare pro- cell membrane, but not penetrate it, must be pre-drugs with high lipophilicity that pass through the pared. Kurunaratne et al. [95] chose b-CD as a bulkyblood–brain barrier. Unfortunately, the applications moiety for the prevention of drug entry acrossof CDs to brain targeting are few. One of the channels in the bacterial outer membrane; thus, they


prepared b-CD conjugates linked to an antibiotic, reported for CD conjugates with oligonucleotide andmethicilline, at the molecular terminus through spac- doxorubicin [103,104].

˚ ´ers of different lengths (4.7–23.7 A) [95]. The extent Recently, Pean et al. [105,106] reported that b-of inhibition of the surface b-lactamase of P. and g-CD derivatives coupled to the neuropeptideAeruginosa in the presence of 10 mM of each of the substance P bind to the neurokinin 1 receptorconjugates was as follows: 6% using the conjugate (substance P receptor) of rat brain and cultured

˚with the spacer length of 12.0 A, 20% using the 14.0 Chinese hamster ovary (CHO) cells transfected with˚ ˚A conjugate, 43% using the 16.8 A conjugate, 77% the human neurokinin 1 receptor gene, in vitro.

˚ ˚using the 20.0 A conjugate, 91% using the 22.6 A Furthermore, in vivo intracerebral injection of the˚conjugate, and 100% using the 23.7 A conjugate. substance P–g-CD conjugate in the rat striatum

They concluded that the length of the spacer should induced a massive internalization of the receptor,˚be greater than 16 A for optimum inhibition of which was monitored by immunofluorescene after

b-lactamase in the outer membrane. Kim et al. [96] labeling of the receptor with a fluorescent polyclonalreported that the a-CD conjugate with antitumor antibody. Therefore, the immunoreactivity is translo-sulfonylurea selectively blocks NADH oxidase ac- cated from plasma membrane to endosomes intivity at the external plasma membrane surface of dendrites and cell bodies. These results indicate thatHeLa cells. the substance P moiety bound to g-CD recognizes

Intercellular recognition events are fundamental to the neurokinin receptor-bearing neurons. Schaschkemany biological processes in which oligosaccharides et al. prepared the b-CD conjugates linked cova-on cell surface glycoproteins or lectins have been lently to tetra- and hepta-peptide analogues of gastrinresponsible for cell–cell recognition and adhesion, through succinyl amide bond and investigated theiretc. [97]. Therefore, CD derivatives bearing small binding characteristics of G-protein-coupled CCK-B/saccharides may be useful as a carrier for transport- gastrin receptor expressed in CHO cells [107]. Theing active drugs to sugar receptors such as lectins receptor affinity of the heptapeptide-b-CD conjugatelocated on the cell surface. In accordance with this was identical to that of the unconjugated tetrapep-concept, several CD conjugates with mono- and tide, although it was weaker than that of the corre-disaccharides, such as glucose, galactose, mannose, sponding unconjugated heptapeptide. However, thefucose, etc., have been prepared and investigated for functional assay monitored by inositol phosphatebinding characteristics to sugar-specific receptors production was potent as the corresponding parent[98–100]. The b-CD conjugates with galactose peptides. They concluded by using docking experi-exhibited higher recognition by the galactose-specific ments of the conjugates into the receptor model thatK. bulgaricus cell wall lectin (KbCWL); i.e., they the high hormonal potency of the heptapeptideinhibited flocculation of K. bulgaricus cells induced conjugate may be ascribed to a synergetic effect ofby the isolated KbCWL lectin and their inhibition the specific intermolecular interaction of the peptideactivity was higher than that of galactose, whereas with the receptor and unspecific interaction of thethe glucose derivatives showed no inhibition effect. b-CD moiety with the receptor surface. These resultsa-Glucosylgluconoamide–b-CD showed a high af- suggest that rationally designed CD conjugates of

21finity (association constant, 8730 M ) to the bioactive components will provide an attractiveglucose-binding protein concanavalin A, a repre- means for the targeting of specific cells such assentative of a large family of lectins [101]. It is tumor cells.reported that some galactose and fucose conjugateshave a significant cytotoxic effect on the humanrectal adenocarcinoma cell line, with P-glycoprotein- 4. Conclusionspositive multidrug resistance [102]. The sugar-substi-tuted CD derivatives may offer a new way of The purpose of this contribution was to outlinedelivering drugs selectively to specific cell surfaces how well the CDs satisfied the requirements for aof organs such as liver and colon, although the drug carrier in drug delivery systems (DDSs). Auptake of drugs into cells may decrease due to the desirable attribute for the drug carrier is the ability topresence of a bulky, hydrophilic CD moiety, as control the rate and time of drug release; peracylated


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