Journal of Drug Targeting, 2010; 18(9): 645–656

REVIEW ARTICLE

Cyclodextrins for drug delivery

A.L. Laza-Knoerr, R. Gref, and P. Couvreur
UMR CNRS 8612, Faculté de Pharmacie, Univ. Paris-Sud, 5 rue JB Clément, 92296 Châtenay-Malabry, France
Journal of Drug Targeting Downloaded from informahealthcare.com by Dalhousie University on 04/13/13

Abstract
Cyclodextrins (CDs) are macrocyclic oligosaccharides composed of α(1,4)-linked glucopyranose subunits.
These molecules possess a cage-like supramolecular structure, comparable with the structures of crown
ethers, cryptands, spherands, cyclophanes, or calixarenes. However, it took 50 years to establish the molecu-
lar structure of CDs. Owing to their capability to form inclusion complexes with a variety of guest molecules,
CDs are considered as the most important supramolecular host family among all supramolecular structures
mentioned above. They can form complexes with various types of molecules including inorganic, organic,
or organometallic that can be radical, cationic, anionic, or neutral molecules. This phenomenon bears the
name “molecular recognition,” while the selectivity in the formation of complexes with enantiomeric species
as guests is called “chiral recognition.” In addition, the properties of the molecules forming the complexes
with CDs can be modified significantly. As such, a large number of scientists have attempted to elaborate
and evaluate various CD derivatives that are able to complex a variety of drugs, enhancing by this way their
in vivo solubility and activity. Moreover, a large number of publications describe CD uses in other fields such
For personal use only.

as foods, textile, cosmetics, or agriculture. This review reports on the recent developments of CDs in drug
delivery using various routes of administration.
Keywords:  Cyclodextrin; drug delivery; inclusion complexes; targeting; toxicology

Introduction and history
The cyclodextrins (CDs) have been known for over 100
years. They were first discovered in 1891 by Villiers, a
French scientist (Villiers, 1891). He isolated about 3 g
of crystalline substance from 1000 g starch and deter-
mined its composition to be (C6H10O5)2·3H2O. Villiers has
named this product “cellulosine” because the substance
appeared to be resistant at acid hydrolysis and did not
have reducing properties.
In this so-called discovery period (Szejtli, 1998), a few
years later (1903), Franz Schardinger published an article
(Schardinger, 1903) suggesting that “crystalline dextrin”
would be a better name than “cellulosine” to identify
these molecules. Later, he changed the name “crystalline
dextrin” into “α- and β-CD.” However, in the followings
years, CDs were named “Schardinger CDs” in his honor.
In the second stage (from 1930s to the 1970s), the
structures of α- and β-CDs were first determined by
X-ray diffraction in 1942, followed by the γ-CD structure
in 1948. At the same time, structures of some inclusion
complexes of CDs were determined and in 1961, the nat-
ural existence of δ-, ζ-, ξ-, and even η-CD was reported
(Valle, 2004). The first patent in CDs was reported in 1953
(Freundenberg, Cramer, & Plieninger, 1953) and the first
fundamental review on CDs and derivatives was pub-
lished by French (1957).
Until the end of the 1960s, the CD structure, physical
and chemical properties, methods of preparation, and
corresponding inclusion complexes have been investi-
gated in detail by many authors (Higuchi and Connors,
1965; Cramer, Saenger, & Satz, 1967).
Summarizing the literature until the end of 1960s, CDs
were considered to be promising molecules, particularly
because of their industrial potential, but they remained
as expensive substances (fabrication in small quantities)
and their utilization in products for human use question-
able because of unknown potential toxic effect.
Following the last period from the 1970s until present,
after adequate toxicological studies, CDs are today used
as successful “new” pharmacological excipients. From
1981, when the first symposium on CDs was organized,

Address for Correspondence:  UMR CNRS 8612, Faculté de Pharmacie, Univ. Paris-Sud, 5 rue JB Clément, 92296 Châtenay-Malabry, France. E-mail: patrick.
couvreur@u-psud.fr

(Received 13 October 2009; revised 08 January 2010; accepted 13 January 2010)

ISSN 1061-186X print/ISSN 1029-2330 online © 2010 Informa UK, Ltd.

DOI: 10.3109/10611861003622552 http://www.informahealthcare.com/drt
 646   A.L. Laza-Knoerr, R. Gref, and P. Couvreur

the total number of CD-related publications increased
over 15,000 by the end of 1997 (Szejtli, 1998). Every year,
CDs are the subject of approximately 1000 additional
research articles and abstracts, with a large number in
the pharmaceutical branch, and many CDs and deriva-
tives are included in the Handbook of Pharmaceutical
Excipients.
Considering the price of β-CD, while in 1970 1 kg
costed about 2000 euros, today it is only several euros
(∼450 euros) per kilogram. Thus, a large number of CD
derivatives are produced industrially and used in the
manufacture of drug carriers, cosmetics, or in catalysis,
agricultural, and food industries.
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hydrophobic cavity, CDs can form inclusion complexes
with a wide range of hydrophobic molecules as guests
(Figure 1A and B) (Ritter &Tabatabai, 2002). In aqueous
solution, the hydrophobic CD cavity is occupied by water
molecules bounded by “weak forces” (energetically
unfavored). Thus, water molecules can be substituted
by hydrophobic molecules such as drugs (“guests”)
with the formation of “host” (CD dissolved): “guest”
(drug molecules) complexes (Szejtli, 1998). Owing to
the size of the internal cavity, one or two hydrophobic
guest molecule(s) can be entrapped by one, two, or even
three CDs (Szejtli, 1998; Songa et al., 2009).
The stability of the complex formed depends on

how the “guest” molecule fits into the hydrophobic

Chemistry and properties
CDs are cyclic α-1,4-glucans composed of six to more
than 100 glucose units (Qi, Mokhtar, & Zimmermann,
2007). They are natural products resulting from intramo-
lecular transglycosylation reaction of starch degraded by
CD glucanotransferase (CGTase) enzyme (Szejtli, 1998).
The enzymatic product is generally a mixture of CDs
including α-, β-, and γ-CDs consisting of six, seven, or
For personal use only.
cavity (a whole molecule or part of it). The ratio of
host–guest complex is frequently 1:1, 2:1, 2:2, or 1:2.
The formed inclusion complexes can be isolated as
stable crystalline substances. The equilibrium estab-
lished between dissociated and associated species can
be characterized by the complex stability constant, Ka
(Szejtli, 1998).
In summary, many reviews and articles describe the
properties and structure of CDs and their complex forma-
tion with various drug molecules. A large number of CD

eight glucose units, respectively (Figure 1 and Table 1)
(Szejtli, 1998; Zhaofeng et al., 2007). They are the most
extensively studied and utilized products from the CD
family.
X-ray investigations on the structure of CD have
shown that due to their primary (C6) and secondary
hydroxyls group (C2 and C3) as well as due to their
derivatives have been reported in drug delivery, yielding
the improvement in bioavailability and the increase in
aqueous solubility and stability. Besides, CDs and CD
derivatives can also convert liquid drugs into microcrys-
talline powders, prevent drug–drug and drug–excipient
interactions, reduce ocular and gastrointestinal irritation,
or diminish bad taste and smell.

OH
OH
O
A OH O O
OH
O O OH
OH HO
O O O O
O HO OH O
O OH
HO HO OH HO
OHHO HO O
O O OH HO O O OH HO O
HO HO
OH HO OH HO HO
O OH OH OH OH
α-CD O O γ-CD
O β-CD
HO O HO O
OH HO OH HO OH HO
OH HO O
O O OH HO O O OH HO O
OHHO
HO HO HO
O OH HO OH
O O O HO OH
O O O
OH OH OH
HO O O O O
HO
O
HO
HO

B OH
H 6
4 5 O
H
HO H 1 H
3 2
OH
H O
7

Figure 1.  Chemical structures of α-, β-, and γ-CDs (A) (Zhaofeng et al., 2007) and (B).
 Cyclodextrins for drug delivery   647

Table 1.  Characteristics/properties of CDs.

Type of cyclodextrin
Characteristics α-CD β-CD γ-CD
Number of glucopyranose units 6 7 8
Molecular weight (g/mol) 972 1135 1297
Solubility in water at 25°C (%, w/w) 145 18.5 233
[α]D 25°C 150 ± 5 162.5 ± 5 177.4 ± 5
Internal diameter (Å) 4.7–5.3 6.0–6.5 7.5–8.3
External diameter (Å) 14.6 15.4 17.5
Volume of the cavity (Å3) 174 262 427
Approx. cavity volume in 1 mol CD (mL) 104 157 256
Cristal forms (from water) Hexagonal plates Monoclinic parallelograms Quadratic prisms
Cristal water (wt %) 10.2 13.2–14.5 8.13–17.7
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Diffusion constant at 40°C 3.443 3.224 3.000

Hydrolysis by A. oryzae α-amylase Negligible Slow Rapid
pK (by potentiometry) at 25°C 12,332 12,202 12,081

lowest water solubility. In α-CD molecule the hydrogen

bond belt is incomplete, because one glucopyranose
Hydrophobic cavity
unit is in a distorted position. As a result, of the six
6 (Å) possible bonds only four can be established. The γ-CD
molecule is a non-coplanar, flexible structure, the most
Hydrophilic soluble of three natural CDs (Szejtli, 1998).
7,9 (Å) outer shell A large number of CD derivatives have been synthe-
For personal use only.

sized: 2-hydroxypropyl-β-CD (2-HP-β-CD) (Gould &

6,5 (Å)
15,4 (Å)
Figure 2.  Structure of β-CD.
Compared with α-CDs and β-CDs, γ-CD with a large
internal cavity and high solubility exhibits more favorable
properties. Therefore, many groups of scientists are inter-
ested in γ-CD (Takada et  al., 2003; Hirano et  al., 2005;
Jansook & Loftsson, 2008) and many attempts have been
made to modify the properties of CGTase to increase
the production of γ-CD (Biwer, Antranikian, & Heinzle,
2002).
The solubility of β-CD in water was determined to
be 18.6 mg/mL (Loftsson & Frioriksdottir, 1998). Such
relatively low water solubility limits β-CD applications
since the complex formation with lipophilic compounds
frequently results in the precipitation of solid cyclodex-
trin complexes. The aqueous solubility of the natural
CDs is often much lower than the comparable linear or
branched dextrins.
The C-2-OH group of one glucopyranoside unit can
form a hydrogen bond with the C-3-OH group of the
adjacent glucopyranose unit. In the CD molecule, a com-
plete secondary belt is formed by these H bonds; there-
fore, the β-CD has a rather rigid structure (Figure 2).
This intramolecular hydrogen bond formation is the
explanation for the observation that β-CD has the
Scott, 2005), methyl-β-CD (M-β-CD) (Uekama & Irie,
1987), or sulfated amphiphilic α-, β-, and γ-CDs (Dubesa
et  al., 2003) principally with the aim to improve the
apparent solubility or the biological activity of various
active molecules.
For example, the introduction of sulfate groups onto
the hydroxyl groups of CDs confers them a higher aque-
ous solubility and a wide range of biological activities
such as antiviral, anti-lipemic, anti-angiogenic, or anti-
inflammatory properties (Dubesa et al., 2003).
Amphiphilic CDs were also synthesized to increase
the contact of CDs (having high external hydrophilicity)
with lipidic biological membranes in vivo (Memisoglu-
Bilensoy et al., 2006). Depending on their structure, the
amphiphilic CDs have been named: “skirt”-CDs (Zhang
et  al., 1991), “lollipop”-CDs (Bellanger & Perly, 1992),
“bouquet”-CDs (Canceill et  al., 1992), and “cup-and-
ball”-CDs (Lin, 1995).
Recently, attention has been focused on the synthesis
and usage of CD polymers. Regarding the synthesis of
this type of water-soluble polymer, the general method
involves effective cross-linking agents like epichlorohy-
drin (Renard et  al., 1997), diisocyanates (Cadars et  al.,
2005), polycarboxylic acids (Martel et  al., 2005; Zhao
et al., 2009), or anhydrides (Gireka et al., 2005).
Epichlorohydrin is the most popular cross-linking
agent used in chemistry and industry for the synthesis
of β-CD polymers. A large quantity of epichlorohydrin
might be wasted in the reaction, because the reaction
between β-CD and epichlorohydrin requires a high
 648   A.L. Laza-Knoerr, R. Gref, and P. Couvreur
concentration of sodium hydroxide in order to activate
the hydroxyls of CD and to accelerate the hydrolyzation
of epichlorohydrin (Renard et al., 1997).
Unfortunately, most of the cross-linking agents
(epichlorohydrin, diisocyanates, anhydrides) utilized
in the synthesis of poly-CDs have a potential toxic effect
for human health and environment. Comparatively, citric
acid features a lower toxicity and is environment friendly.
The condensation between β-CD and citric acid has
been carried out at a temperature not higher than 170°C
and without any organic solvent (Martel et  al., 2005).
However, the drawback of this method lies in the weak
reactivity of citric acid compared with epichlorohydrin
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or diisocyanates.
CDs polymers in association with other polymers
constitute another area of current interest. For example,
promising results have been obtained by mixing hydro-
phobically modified dextrans bearing dodecyl moieties
with β-CD polymer. Owing to the inclusion of hydropho-
bic side chains of dextran into CD cavities, spontaneous
association occurs in solution (Daoud-Mahammed
et al., 2007a, 2007b; Gref et al., 2006). Encapsulation of
lipophilic drugs such as benzophenone and tamoxifen
in this type of system was achieved by their inclusion
For personal use only.
(complexation) in the remaining free cavities of CDs.
Toxicological consideration
The toxicity profiles of CDs first depend on the route of
administration used. After oral administration of CD,
a partial or complete hydrolysis of CDs was observed.
When used by the oral route, CDs can be hydrolyzed by
amylases from the digestive tract, similarly like starch
(Gerlóczy et al., 1985). γ-CD with a large internal cavity is
more easily hydrolyzed than α-CD which exhibits a small
internal cavity whereas β-CD is in between. Whether the
hydrolysis is partial or total, CDs are non-toxic when
administered through oral route. CDs can form inclusion
complexes with other compounds present in the diges-
tive tract (such as biliary salts) in a reversible manner
(Duchene, Bochot, & Loftsson, 2009).
It is reported that when administered in high doses in
animals by subcutaneous route, β-CD might cause neph-
rotoxicity, decrease in body weight, and decrease in liver
weight (Perrin et al., 1978). Intravenous administration
was shown to induce similar effects, due to the compl-
exation of some blood constituents, such as cholesterol.
By parental route, and especially the intravenous one,
β-CDs can destabilize the red blood cell membrane by
forming inclusion complexes with some of their constitu-
ents, leading to hemolysis (Duchene, Bochot, & Loftsson,
2009).
However, some derivatives of CDs can be used as
alternatives to the parent α-, β-, or γ-CDs because of their
lower toxicity. For example, 2-HP-β-CD is well tolerated
in animal tests (rats, mice, and dogs) particularly by oral
route (Gould & Scott, 2005). Furthermore, after intrave-
nous administration (mice, monkey, rats, dogs, or rab-
bits) 2-HP-β-CD revealed neither lethal nor carcinogenic
effects and did not show any consequence on embryo-
fetal development (rats or rabbits) (Gould & Scott, 2005).
Human experience with CD derivatives, especially SBE
β-CD (Captisol), a polyanionic variably substituted
sulfobutyl ether of β-CD and 2-HP-β-CD, indicates that
these two CDs are well tolerated in humans and have no
adverse effects on the kidneys or other organs following
either oral or intravenous administration (Stella & He,
2008).
Drug delivery
Owing to the remarkable ability of CDs to form inclusion
complexes with a variety of drug molecules, numerous
applications have been developed in the drug delivery
field using almost all routes of administration.
Nasal administration
Application of CD solution directly onto the mucosa
(nasal, buccal) is regarded as safe for hydrophilic and
natural CDs in a wide range of concentrations while for
methylated CD derivatives, the application time and the
concentration should be controlled (Asai et  al., 2002;
Boulmedarat et al., 2005).
In rats, the nasal absorption of insulin has been
notably improved by the use of CDs (Iriea et al., 1992).
It was reported that methylated CDs were more potent
enhancers of insulin adsorption than the parent CDs or
2-HP-β-CD. On the other hand, Asai et al. (2002) demon-
strated that 20% RM-β-CD (RM-randomly methylated)
causes serious damage to the rat nasal mucosa and 10%
solution causes irritation. In the same topic, Boulmedarat
et al. (2005) indicated that the application of 10% solu-
tion of RM-β-CD on epithelial cells presented toxic and
inflammatory effects, depending on the exposure time.
Nasal preparations must, however, be critically evalu-
ated for their possible effects on the mucociliary func-
tions (defence of the respiratory tract against bacteria,
allergens, etc.). In this view, on the contrary to steroids
free, the CD complexes did not present any effects on the
epithelial membranes probably because their cavities are
shielding the intrinsic toxicity of the included molecules
(Koizumi et al., 1987). Also, a nasal spray containing estra-
diol solubilized in 2,6-di-O-methyl-β-CD (DM-β-CD) was
found very well tolerated by patients over a period of 6
months (Hermes et al., 1992). In another study, Kondo,
Irie, and Uekama (1996a) have demonstrated that a
proper use of CDs in nasal morphine preparations may

provide with adequate analgesia for chronic and acute
pain, offering a progress in patient comfort.
In the same topic, a nasal spray containing benzodi-
azepines solubilized in CD was reported by Loftsson et al.
(2001). It was possible to minimize the amount of CD
needed to solubilize the benzodiazepine drug by keep-
ing the drug/CD molar ratio close to one or by adding a
water-soluble polymer to the drug/CD complex.
Recently, Al Omaria et  al. (2009) described a novel
inclusion complex of ibuprofen (Ibu) with native CDs
and 2HP-β-CD. Without CD, Ibu exhibits an irritant effect
on the oral cavity, throat, and pharynx and this makes its
administration unpleasant. However, its complexation
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with natural or modified CDs helped circumventing these
inconveniences.
In conclusion, CDs may improve the drug bioavail-
ability and help bypassing the nasal barrier.
Ocular drug delivery
In the ophthalmology field, drug formulations are gener-
ally applied to the surface of the eye for two purposes: (1)
to provide intraocular treatment throughout the cornea
for diseases like glaucoma and (2) to treat the outside of
For personal use only.
the eye for infections (conjunctivitis, blepharitis, keratitis
sicca). Eye-drops are the conventional drug dosage forms
for 90% of currently used ophthalmic formulations. A
major problem in ophthalmic drug delivery is, however,
the rapid drug loss caused by drainage and high tear
fluid. Drug has to penetrate into the eye through con-
junctiva, cornea, and/or sclera membranes (lipophilic
membranes). These membranes are surrounded by an
aqueous tear fluid and by a mucin layer. Thus, ophthal-
mic drugs have to be water soluble (hydrophilic) to pen-
etrate the exterior surface of the eye (tear fluid and mucin
layer), but at the same time they have to display sufficient
lipophilicity to penetrate the ocular barrier into the eye.
As such, after ophthalmic application of drug formula-
tions, only less than 5% can penetrate the cornea and the
intraocular tissues (Lang, 1995).
In this context, CDs may represent an alternative
approach to increase the solubility and corneal perme-
ability of drugs.
Indeed, the inclusion complexes of ophthalmic drugs
with CDs were found to increase the drug aqueous solu-
bility without affecting their chemical structure and/or
activity (Loftsson & Järvinen, 1999; Loftsson & Stefánsson,
2002; Brewster & Loftsson, 2007; Alexanian et al., 2008;
Gaspar de Araújo et al., 2008; Granero et al., 2008; Araújo
et  al., 2009; Nagarwala et  al., 2009; Palma et  al., 2009).
Thus, CDs were found to be capable of delivering the
entrapped hydrophobic drugs directly to the ocular sur-
face, after the passage of the mucin layer. Some examples
are summarized in Table 2.
Cyclodextrins for drug delivery   649
Table 2.  Some examples of the use of CDs in ocular delivery.
CD derivatives
(abbreviation) Drugs References
HP-β-CD Acetazolamide (Fridriksdottir, Loftsson, &
Stefánsson, 1997; Granero
et al., 2008; Palma et al., 2009
Hydrocortisone Davies, Wang, & Tucker, 1997
Dipiverfrin Jarho et al., 1997
SBE-β-CD Dipiverfrin Jarho et al., 1997
Pilocaprine Järvinen et al., 1994
For example, the increase in water solubility and effi-
cacy of acetazolamide, a carbonic anhydrase inhibitor,
was observed in aqueous solutions of 2-HP-β-CD by the
formation of acetazolamide:2-HP-β-CD complex. This
derivative of CD was found to be non-toxic toward the
ocular tissue (because it was unable to penetrate biologi-
cal membranes such as the eye cornea) and its aqueous
formulation was well tolerated (Fridriksdottir, Loftsson,
& Stefánsson, 1997; Granero et  al., 2008; Palma et  al.,
2009).
Promising results were also obtained by mixing 2-HP-
β-CD with hydrocortisone (HC) (Davies, Wang, & Tucker,
1997) to formulate a stable topical ophthalmic solution. A
soluble 1:1 inclusion complex was formed with enhanced
chemical stability and water solubility.
CD derivatives were successfully used to increase
the aqueous stability of dipivefrin too (dipivalyl epine-
phrine, DPE) (Jarho et  al., 1997). The effect of 2-HP-
β-CD or sulfobutyl ether β-cyclodextrin (SBE-β-CD) in
the presence of DPE was studied with isolated rabbit
cornea. The authors reported the formation of strong
inclusion complexes (SBE-β-CD/DPE and HP-β-CD/
DPE) together with a dramatic increase in the aqueous
stability of DPE (at room temperature and at pH values
of 5 and 7.4).
Järvinen et  al. (1994) reported the complexation of
a large number of β-CD with pilocarpine ophthalmic
drug. The authors highlighted that the aqueous stabil-
ity of pilocarpine increased at pH 7 in the presence of
SBE-β-CD. Further, the same author (Järvinen, Järvinen,
& Urtti, 1995) showed that SBE-β-CD solution improved
ocular absorption by adding poly(vinyl-alcohol) (PVA)
which increased the viscosity and also reduced eye irrita-
tion. Consequently, CDs may be useful in the formulation
of ophthalmic suspension by complexation with a large
number of ophthalmic drugs.
Oral drug delivery
At present, oral administration of inclusion complexes
of CDs with many poorly water-soluble drugs is possible
because of the natural α- and β-CDs, unlike γ-CD (very
large cavity) are not hydrolyzed by human saliva.
 650   A.L. Laza-Knoerr, R. Gref, and P. Couvreur

CDs (α-CD, β-CD, γ-CD) and their derivatives
[sulfated-α-CD, sulfated-β-CD, carboxymethyl-β-CD
(CM-β-CD), and 2-HP-β-CD] have been utilized in oral
hygiene products to bind large sized malodorous com-
pounds residing in the mouth (organic acids, amines,
amino acids) (Lantz et al., 2006). The authors highlighted
the high affinity of lactic and succinic acids for CM-β-CD
and a slightly higher binding to sulfated-β-CD than to
native β-CD (Table 3). The explanation lies in the pres-
ence of carboxylic groups in the structure of both lactic
and succinic acids which interact with hydrogen bond
donor/acceptor sites in carboxylate and sulfate groups
attached to both CD derivatives (CM-β-CD, sulfated-
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• The formation of a “host–guest” complex CD mol-
ecule (with bad tasting), impeding its reaction with
the taste buds.
• The interaction of the CDs with the so-called gate-
keeper proteins localized in the taste bud paralyzing
them.
The bitter taste of coffee results from overcooking,
extended standing in either cold or hot state, which are
effectively reduced by mixing 0.1 until 10.2% (w/v) β-CD.
CDs form complexes with polyphenols and chlorogenic
acid, preventing by this way the bad sensation in the
mouth (Hamilton & Healy, 1970).

β-CD). An important tool in this regard is the use of CDs and

Very important characteristics of CDs and deriva-
tives for oral delivery purposes stems from their ability
to modify the bioavailability of drugs by increasing the
time period of drug release and the drug dissolution rate
(Loftsson, Matthíasson, & Másson, 2003) whereas at the
same time CDs may decrease local GI tract irritation or
bitter taste of drugs (Sjejtli & Szente, 2005). Following
interactions are possible in order to eliminate the bitter
taste:
For personal use only.
their derivatives via dynamic complex formation so that
the complexes overcome undesirable physicochemical
properties including low aqueous solubility, poor dis-
solution rate, and limited drug stability. CDs have been
utilized extensively in pharmaceutical formulations to
enhance drugs’ bioavailability (Loftsson et  al., 2005;
Carrier, Miller, & Ahmed, 2007; Mallick et  al., 2007).
In this topic, many recent reviews deal with the use of
CDs as excipients for the oral delivery of various drugs
(Soares, Carvalho, & Veiga, 2007; Stella & He, 2008;

Table 3.  Some examples of the use of CDs in oral delivery. Shimpi, Chauhan, & Shimpi, 2004; Stickley, 1994; Fahr
CD derivatives & Liu, 2007; Challa et al., 2004). Thus, the usefulness of
(abbreviation) Active molecules References CDs has been demonstrated in the case of various drugs
α-CD Peptides Haeberlin et al., 1996 such as cilostazol (Patel & Rajput, 2009), piroxicam
CM-β-CD Lactic acid and Lantz et al., 2006 (Lister, Acerbi, & Cadel, 1993), flurbiprofen (Tokumura,
succinic acid Muraoka, & Machida, 2009), paclitaxel (Agüeros et al.,
β-CD Nicotine Carlsson & Andersson, 2009), andragrapholide (Ren et  al., 2009), gefitinib
1991
(Phillip Lee et  al., 2009), various peptides (Haeberlin
Polyphenols and Hamilton & Healy, 1970
chlorogenic acid
et al., 1996), efavirenz (Sathigari et al., 2009), diclofenac
Peptides Haeberlin et al., 1996 (Miro et  al., 2009), flavonoid dioclein (Rezende et  al.,
Flavonoid dioclein Rezende et al., 2009 2009), triclosan (Dinge & Nagarsenker, 2008), and many
Cilostazol Patel & Rajput, 2009 others.
Flurbiprofen Tokumura, Muraoka, &
Machida, 2009
Gefitinib Phillip Lee et al., 2009 Dermal drug delivery
Piroxicam Lister, Acerbi, & Cadel,
Dermal drug delivery has gained popularity in the past
1993
Efavirenz Sathigari et al., 2009
decade. Many drugs have been successfully formulated
γ- CD Peptides Haeberlin et al., 1996
by this route. The transdermal drug transport and release
Cilostazol Patel & Rajput, 2009 is restricted by the stratum corneum which represents
HP-β-CD Peptides Haeberlin et al., 1996 the main barrier toward the administration of active
Triclosan Dinge & Nagarsenker, compounds by this route. Therefore, many methods to
2008 increase drug absorption have been tested.
Cilostazol Patel & Rajput, 2009 Four different approaches have been proposed to
Diclofenac Miro et al., 2009 enhance drug delivery through the skin (Matsuda &
Efavirenz Sathigari et al., 2009 Arima, 1999):
Paclitaxel Agüeros et al., 2009
Andragrapholide Ren et al., 2009 (1) Enhancement in the release of drugs from the
Gefitinib Phillip Lee et al., 2009 transdermal pharmaceutical preparation bases.
DM-β-CD Peptides Haeberlin et al., 1996 (2) Improvement of drug retention in the skin or of the
Cilostazol Patel & Rajput, 2009 flux of drug through the skin.
 Cyclodextrins for drug delivery   651

(3) Increase in the tissue targeting (localized drug
delivery).
(4) A combination of (1), (2), and (3).
In order to meet these criteria, many scientists have uti-
lized surfactants, liposomes, permeation enhancers, ion
pairs, etc.
In the past decade, various kinds of chemically modi-
fied CDs too have been prepared in order to optimize
the dermal delivery of drugs (both for systemic and local
use).
Some representative examples are summarized in
Table 4. In general, CD derivatives improve the solubil-
Journal of Drug Targeting Downloaded from informahealthcare.com by Dalhousie University on 04/13/13
HP-β-CD enhanced the dermal delivery into the skin
(proved by the increase of their stability constants). PVP
acted as a co-enhancer. More recently, Lopez et al. (2000)
reported a protective effect of 2-HP-β-CD ascribed to an
increase in the solubility of dexamethasone without the
need of any tertiary agent.
Furthermore, the combined effects of CD complexa-
tion and entrapment into liposomes was investigated
and highlighted for the first time by McCormack and
Gregoriadis (1994). This method revealed an increased
drug solubility and stability as well as a better controlled
in vivo release.
For example, Maestrellia et  al. (2006a) developed

ity and stability of hydrophilic drugs in dermal aqueous
solution preparations as well as in other type of dermal
preparations (ointments).
For example, Kawahara et al. (1992) reported that the
release rates of indomethacin from gel ointment and
hydrophilic petrolatum were accelerated by complexa-
tion with diethyl-β-CD. In rats, the in vivo absorption of
indomethacin from gel ointment was also accelerated by
complexation with diethyl-β-CD.
Siguroardottir and Loftsson (1995) reported the effect
of the addition of a polymer (tertiary agent) to a solution
For personal use only.
by this way an efficient formulation of ketoprofen.
Ketoprofen is an analgesic used for the treatment of
osteoarthritis but it presents a low water solubility. When
administered by the oral route, it presents a gastrointesti-
nal irritation. For this reason, transdermal administration
has been used as an interesting alternative.
Permeability studies across artificial membranes sim-
ulating the skin behavior with the complex ketoprofen–
2-HP-β-CD incorporated in liposome have showed a
prolonged release effect. The entrapment efficiency of
ketoprofen–2-HP-β-CD in liposomes has been found

containing a corticoid and CDs on the delivery of the to depend on both liposome preparation and complex
drug through hairless female mice skin. The results sug- concentration in the aqueous phase used for liposome
gested that the addition of a small quantity of hydroxy- preparation.
propylmethylcellulose (HPMC) or polyvinylpyrrolidone Regarding the CD polymers, Szeman et al. (1987) high-
(PVP) to the suspension containing dexamethasone–2- lighted that the plasma concentrations of the antifungal
agent tolnaftate was increased by complexation with the
β-CD polymer via dermal delivery. To evaluate the percu-
Table 4.  Some examples of the use of CDs in dermal delivery.
CD derivatives
taneous absorption of this formulation, the experiences
(abbreviation) Drugs References were conduced by topical application of the drug powder
α-CD Miconasole Tenjarla et al., to the skin of mice.
1998 Some types of CDs (parent and derivatives) may
β-CD Betamethasone Otagiri et al., affect the permeability of drugs through the skin via
1984 the interactions with some components of skin (choles-
4-Biphenylacetic Arima et al., 1996 terol or proteins). Thus, the effects of β-CD, randomly
acid
methylated β-CD (RAMEB) and 2-HP-β-CD on the skin
Chloramphenicol Rahman et al.,
1991
have already been investigated (Legendre et  al., 1995).
DM-β-CD Butylparaben, Okamoto et al.,
RAMEB was reported to decrease the transdermal flux
indomethacin, sulfanilic 1986 of piribedil due to the formation of an inclusion complex
acid RAMEB:piribedil as shown by RMN. On the other hand,
4-Biphenylacetic acid Arima et al., 1996 the penetration of S-9977 hydrochloride was increased
M-β-CD, CM-β-CD, Hydrocortisone Siguroardottir & twofold with the addition of RAMEB, in spite of the fact
maltosyl-β-CD Loftsson, 1995 that this drug did not interact with this CD derivative.
HP-β-CD Dexamethasone Lopez F.P. Renata Therefore, inclusion of skin components into CD have
et al., 2000
to be taken in consideration since it may influence skin
Ketoprofen Maestrellia et al.,
2006
penetration of the drugs in various ways.
Miconasole Tenjarla et al., Among the three derivatives of CDs (β-CD, RAMEB,
1998 and 2-HP-β-CD), only RAMEB extracted significant
β-CD polymer Tolnaftate Szeman, Ueda, & amounts of the major lipid classes from isolated stratum
Szejtli, 1987 corneum (SC). In conclusion, some β-CDs (parent and
Indomethacin Kawahara et al., derivatives) are capable of modifying the skin barrier
1992 function. As long as the drug molecules do not form an
 652   A.L. Laza-Knoerr, R. Gref, and P. Couvreur

inclusion complex with CDs, this results in an enhance- Table 5.  Some examples of the use of cyclodextrin in rectal delivery.
ment of the drug diffusion through the skin. CD derivatives
Finally, with or without tertiary agent, CDs (parents (abbreviation) Drugs References
or derivatives) are good agents for the delivery of dermal α-CD Morphine Kondo, Irie, & Uekama,
drugs and due to their high molecular weights, they are hydrochloride 1996b
not absorbed through the skin. Cefmetazole Yanagi et al., 1991
β-CD Carmofur Kikuchi et al., 1987
γ-CD Diazepam Frijlink et al., 1992
Rectal drug delivery DM-β-CD Carmofur Masahikoa, Fumitoshia,
& Kaneto, 1987
Rectal drug delivery stands for a very important system
Insulin Watanabe et al., 1992
for a large number of patients, for example, children, Ethyl 4-biphenylyl Arima et al., 1992
infants, patients with nausea, swallowing, or vomiting. acetate
However, the main problems encountered in the admin- HP-β-CD Diazepam Frijlink et al., 1992
Journal of Drug Targeting Downloaded from informahealthcare.com by Dalhousie University on 04/13/13

istration of drugs by rectal route are generally considered Ethyl 4-biphenylyl Arima et al., 1992
to be the following ones: acetate
Tanshinone IIA Ling et al., 2007
(1) the majority of drugs are poorly absorbed through the β-CD Carmofur Kaji et al., 1985
rectal mucosa,
(2) restrictive absorbing surface area, physicochemical properties of the formed inclusion
(3) inefficient dissolution due to the small fluid present complexes.
in the rectum,
(4) drug metabolism into the rectal mucosa and
Novel nanoparticulate drug delivery systems
microorganisms.
Many efforts have been directed to use CD-based mate-
For personal use only.

In order to overcome these disadvantages, many studies
have been conducted consisting in the use of absorption
enhancers, mixed micelle and polymers, surfactants,
etc.
However, the most important factor in rectal absorp-
tion is the release and the stabilizing effects of drugs from
suppository bases, which inhibits the bioconversion of
drugs in the rectum. As such, many authors have shown
that CDs (parents and derivatives) inhibit bioconversion
of drugs in the rectum (Table 5).
However, the complexation of drugs with CDs (parents
and derivatives) makes the drugs insoluble in oleagi-
nous suppository base. For example, Kondo, Irie, and
Uekama (1996b) reported that the combination of α-CD
and xanthan gum (polysaccharide polymer) reduced the
bioconversion of morphine (first pass metabolism) in
the rectal mucosa. Hence, it appeared that xanthan gum
combined with α-CD exhibited a good stability of the
drug and facilitated the transport of morphine through
the rectal mucosa.
In comparison with parent CD (β-CD), DM-β-CD
significantly enhanced the rectal absorption of hydro-
phobic drugs like carmofur (1-hexylcarbamoyl-5-fluor-
ouracil, HCFU) in oleaginous suppository (Masahikoa,
Fumitoshia, & Kaneto, 1987). A higher stability of
DM-β-CD complexes compared with parent β-CD ones
was demonstrated.
In conclusion, a large number of reports have dem-
onstrated that the effects of CDs in rectal drug delivery
depends on the type of vehicle (hydrophilic or oleagi-
nous) on the presence of a tertiary element and on the
rials for the design of solid nanoparticles. In general,
nanoparticles present a higher stability than liposomes
in biological fluids, and a larger surface area than micro-
particles due to their smaller size. Moreover, their high
surface area can lead to intimate contact with biological
membranes, giving way to the increase in the bioavail-
ability of the entrapped drugs.
Nanoparticles are generally prepared using preformed
polymers by emulsification methods or nanoprecipita-
tion. Emulsion polymerization is another very frequently
employed method, for example, using alkyl cyanoacr-
ylates as monomers. Indeed, cyanoacrylates offer the
advantage of being biodegradable as well as easy to pre-
pare, since the polymerization process occurs in aque-
ous medium without any polymerization initiator except
water. Thus, CD-loaded nanoparticles were obtained
in acid conditions by anionic polymerization of alkyl
cyanoacrylates in the presence of parent or modified
CDs (Monza Da Silveira et al., 1999). Active compounds
such as taxol and doxorubicin were entrapped in these
CD-based nanoparticles with loadings ranging between
0.01 and 300 mg/g of nanoparticles (Monza Da Silveira
et al., 1999).
Studies carried out with amphiphilic “skirt-shaped”
CDs (obtained by the esterification of primary hydroxyl
groups with C6 to C14 alkyl chains) showed that these
derivatives were capable of forming spontaneous nano-
particles which could be loaded with a series of steroid
drugs (progesterone, testosterone, hydrocortisone)
(Duchene, Wouessidjewe, & Ponchel, 1999). In this type of
nanoparticles, the drugs were most probably molecularly

pCD MD
dextran
β-CD
molecule alkyl side chain
of interest alkyle (C12)
loaded
Journal of Drug Targeting Downloaded from informahealthcare.com by Dalhousie University on 04/13/13
nanoparticles
Figure 3.  Schematic illustration of the interaction between poly-
β-CD and modified dextran (MD) in the nanoassemblies (Gref et al.,
2006).
dispersed in the alkyl chain hydrophobic domains and
were found to be released very rapidly.
Recently, a breakthrough CD-based nanotechnology
has been developed by the single mixing (at room tem-
perature) of two aqueous solutions of polymers consist-
ing of β-CD polymer (poly-β-CD) and a hydrophobically
For personal use only.
modified alkyl chain dextran (MD) (Gref et al., 2006). In
this system, nanoparticle production yields could reach
up to 95%. The authors further established that, in these
nanoassemblies, all alkyl chains were included within the
CD cavities. The ways to load drugs into those nanopar-
ticles were either to fashion an inclusion complex with
poly-β-CD before mixing with MD or by direct loading
into the preformed nanoassemblies. Noteworthy, the
incorporation of benzophenone or tamoxifen in such
nanocarriers did not hinder the sequestration of the
dextran alkyl moieties in β-CD cavities and thus did not
impede the formation of the corresponding associative
nanoassemblies (100–200 nm) (Figure 3).
Nanoparticles were prepared by ionic gelation using
CD and chitosan (CS) mixtures (Maestrellia et al., 2006b).
Briefly, aqueous solutions containing different concen-
trations of 2-HP-β-CD were incubated with CS for 24 h
under magnetic stirring and then filtered (cellulose fil-
ters). The cross-linking agent tripolyphosphate (TPP) was
added to this solution leading to the controlled gelation
of CS in the form of NPs. Finally, the NPs were isolated by
centrifugation and resuspended in water.
The higher solubilization as well as the protection of
the sensitive drugs triclosan and furosemide facilitated
the oral absorption of these molecules. The drug content
in these chitosan/CD nanoparticles was increased, in the
presence of 2-HP-β-CD due to their high solubilizing
properties.
Another type of nanoparticle based on CS, tripolyphos-
phate and CM-β-CD were elaborated for the delivery of
macromolecular drugs (i.e., insulin or heparin) (Krauland
Cyclodextrins for drug delivery   653
& Alonso, 2007). The encapsulation yields were up to
58.8% for insulin and 44.6% for heparin. The release pro-
file of insulin was shown to be very fast (84–97% within
15 min), whereas heparin remained associated with the
nanoparticles for several hours.
Among these diverse assemblies, micelle-like core-
shell nanospheres mediated by host–guest interactions
are recognized as promising nanocarriers for drug and
gene delivery in a recent year (Zhang & Ma, 2009). In
this work, the author’s selected β-CD as a host unit for
the construction of a hydrophilic host block that is cova-
lently linked with another hydrophilic segment, while
hydrophobic substances, either small molecules or
macromolecules, are employed as guest components.
Core-shell nanoassemblies can form by host–guest inter-
action mediated spontaneous assembly in an aqueous
solution. For example, the core-shell aggregates could
be assembled by polyethylene glycol (PEG) block and
a polyaspartamide block carrying β-CD units on the
side chain b-PCD (PEG-b-PCD) (aqueous solution) in
the presence of hydrophobic compound, mediated by
host–guest interactions between CD and hydrophobic
compound.
Thus, CD-based nanoparticles offer an interesting
alternative to soluble CD (or poly-CD) for the encap-
sulation and the delivery of hydrophobic drugs which
are capable of forming molecular inclusion complexes
with CDs in aqueous media. The protection of unstable
compounds from degradation in biological media is an
additional advantage of this type of technology.
Conclusions
This review outlines the current applications of natural
and chemically modified CDs in the design of advanced
dosage forms. It clearly appears that the CDs have a wide
range of applications in different areas of drug delivery
and pharmaceutical industry, due to their complexa-
tion ability with a large number of drugs. In general, the
most common pharmaceutical applications of CDs are
to enhance the solubility, stability, safety, and bioavail-
ability of drug molecules.
CDs interact with poorly water-soluble drugs resulting
in an increase in their apparent water solubility, phenom-
enon based on the ability of CDs to form non-covalent
dynamic inclusion complexes in solution. Other solubi-
lizing attributes include the ability of CDs to form non-
inclusion–based complexes and to form and stabilize
supersaturated drug solutions. The increase in solubility
often also leads to an increase in the dissolution rates,
thus improving the oral bioavailability of many drugs.
Moreover, a number of CD-based products have reached
the market based on their ability to camouflage undesir-
able physicochemical properties of the drugs. Indeed,
 654   A.L. Laza-Knoerr, R. Gref, and P. Couvreur
the bioadaptability and multifunctional characteristics of
CDs make them capable of alleviating several undesirable
properties of the drug molecules through the formation
of inclusion complexes. The drug:CD complexes can be
further used in constructing new classes of drug delivery
systems such as nanoparticles, liposomes, or site-specific
prodrugs.
The CDs have extensively been used to formulate
insoluble, volatile, or irritating drug molecules. Because
of their continuing ability to find novel applications in
drug delivery, the CDs are expected to solve challenges
related to the delivery of novel drugs through different
routes of administration.
Journal of Drug Targeting Downloaded from informahealthcare.com by Dalhousie University on 04/13/13
Declaration of interest
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the
paper.
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