Drug Delivery

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Exploring versatile applications of cyclodextrins:

an overview

Neha Sharma & Ashish Baldi

To cite this article: Neha Sharma & Ashish Baldi (2016) Exploring versatile applications of
cyclodextrins: an overview, Drug Delivery, 23:3, 729-747, DOI: 10.3109/10717544.2014.938839

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Drug Deliv, 2016; 23(3): 729–747

! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10717544.2014.938839

REVIEW ARTICLE

Exploring versatile applications of cyclodextrins: an overview

Neha Sharma and Ashish Baldi

Department of Quality Assurance, I.S.F. College of Pharmacy, Moga, Punjab, India

Abstract Keywords
Context: Ever since the discovery of cyclodextrins, a family of cyclic oligosaccharides based on a Bioavailability, drug delivery, inclusion
(1 ! 4) linkage among glucopyranose subunits, these versatile supramolecular hosts have complexes, pharmaceuticals, solubility
received tremendous attention for scientific explorations. Due to their property of forming
host–guest type inclusion complex, cyclodextrins and their synthetic derivatives exhibit History
wide range of utilities in different areas viz. pharmaceuticals, drug delivery systems, cosmetics,
food and nutrition, textile and chemical industry etc. Received 25 April 2014
Objective: The purpose of this review is to highlight properties, advantages, recent studies Revised 23 June 2014
and versatile benefits of cyclodextrins and to re-strengthen their prospective applications in Accepted 23 June 2014
novel directions for future research.
Methods: This article summarizes a variety of applications of cyclodextrins in various industrial
products, technologies, analytical and chemical processes and recent industrial advancements
by extensively literature search on various scientific databases, Google and websites of various
associated pharmaceutical industries and patenting authorities across the world.
Results and conclusion: Due to possibility of multidimensional changes in physical and chemical
properties of molecules upon inclusion complexation in cyclodextrins, these compounds are
of great commercial interest and may offer solution to many of the scientific problems of the
current world.

Introduction Production of parent CDs and some of their commercially

Cyclodextrins (CDs) are defined as the class of cyclic
oligosaccharides which contains glucopyranose units and
which are linked to each other by a-(1,4) bonds (Del Valle,
2004). Three naturally occurring cyclodextrins, also known
as first generation CDs or parent CDs (Singh et al., 2002),
are: a-cyclodextrin (a-CD), b-cyclodextrin (b-CD) and
g-cyclodextrin (g-CD), containing 6, 7 and 8 glucopyranose
units, respectively.
When starch is reacted with amylase, which is obtained
from Bacillus macerans, a crude mixture of a-CD (60%),
b-CD (20%) and g-CD (20%) together is formed with
some traces of CDs containing more than eight glucose units.
The purification of this mixture is very difficult because it
contains very less amounts of CDs and it also have other
linear and branched dextrins along with proteins and
other impurities (Chordiya & Senthilkumaran, 2012).
Various chronological in development of CDs are presented
in Table 1. Finally, in the 1970s, several biotechnological
advances led to major improvements in the production of pure
a-CD, b-CD and g-CD. Cyclodextrin glycosyl transferase
(CGTase) enzyme was used for the production of highly
pure a-CD, b-CD and g-CDs (Loftsson & Duchene, 2007).
Address for correspondence: Baldi Ashish, Professor and Principal, I.S.F.
College of Pharmacy, G.T. Road, NH 95, Moga, Punjab 142001, India.
Tel: +91-8968423848. E-mail: baldiashish@gmail.com
important derivatives are represented in Figure 1.
Structure and properties of CDs
CDs, white crystalline powder, chemically are a-(1,4)-linked
cyclic oligosaccharides containing glucopyranose units.
The glucopyranose units possess chair conformation, due to
which CDs are not cylindrical, and exhibit torus-like shape
(truncated cone), in which the primary hydroxyl groups are
present on narrow edge and secondary hydroxyl groups are on
the wider edge of the cone in the outer surface. In the interior
of the CD molecule, skeletal carbons with hydrogen atoms
and oxygen bridges are present leading to hydrophilic
outer surface and lipophilic central cavity of CD (Cal &
Centkowska, 2008; Figure 2). Some of the structural and
chemical properties of parent CDs are given in Table 2.
Cyclodextrin derivatives
Although, the natural CDs and their complexes are hydro-
philic, but their aqueous solubility is reported to be limited,
mainly in the case of b-CD. This is because CD molecules
binds relatively strongly in their crystal state (Loftsson &
Brewster, 2010). CDs contain glucopyranose units which
further consists of three free hydroxyl groups differing on the
basis of both functions as well as reactivity. The different
reaction conditions like pH, temperature and reagents affect
the relative reactivity of C-2 and C-3 secondary and the C-6
730 N. Sharma & A. Baldi Drug Deliv, 2016; 23(3): 729–747

Table 1. Chronological in development of cyclodextrins.

Year Scientists Advancements References

1891 A. Villers Crystalline substance isolated from bacterial digest of starch having Loftsson & Duchene (2007)
resistance for acid hydrolysis and deficient in reducing property.
Substance was found out to be dextrin and was termed as
‘‘cellulosine’’ by Villers.
1903 Franz Schardinger Fractionation of two more crystalline compounds, a-dextrin and Nitalikar et al. (2012)
b-dextrin, from bacterial digest of potato starch. Further, isolation
of considerably more amount of b-dextrin, and recognized as
Villers ‘‘cellulosine’’ was achieved. Later, these were better known
as a-CD and b-CD.
1935 Freudenberg and Jacobi g-CD was discovered. Nitalikar et al. (2012)
1935–1955 Freudenberg, Cramer and Identification of the chemical structure of CDs, their physiochemical Brewster & Loftsson (2007)
co-workers properties and their liability to form inclusion complexes.
1938 Freudenberg and Cramer CDs possess a ring structure containing glucose units, which are a Loftsson & Duchene (2007)
(1 ! 4)-linked and have a central cavity.
1976 Prostaglandin E2/b-CD (Prostarmon EÔ sublingual tablets), is the Loftsson & Brewster (2010)
world’s first testified CD based pharmaceutical product sold in
Japan.
1997 The first US approved product was announced named as Itraconazole/ Kumar Das et al. (2013)
2-hydroxypropyl-bCD oral solution (SporanoxÕ ).
1998 The first European CD containing product Piroxicam/b-CD (BrexinÕ Brewster & Loftsson (2007)
tablets) was introduced.

Figure 1. Parent and representative modified cyclodextrins of pharma-

ceutical interest [RAMEB: Randomly methylated b-cyclodextrin; HP-
b-CD: Hydroxy propyl b-cyclodextrin; HE-b-CD: Hydroxy ethyl
b-cyclodextrin; DIME-b-CD: Heptakis (2, 6-dimethyl)-b-cyclodextrin;
TRIME-b-CD: Heptakis (2, 3, 6-trimethyl)-b-cyclodextrin]. Figure 2. Torus-like shape of cyclodextrin.

primary hydroxyls of the CD molecule. With the substitution

of hydrogen and hydroxyl group with large number of
substituting groups, such as alkyl, hydroxyl alkyl, carboxy
alkyl, amino, thio, tosyl, glucosyl, maltosyl etc., and
thousands of ethers, esters, anhydro, deoxy, acidic and
basic etc., 21 hydroxyl groups of b-CD can be modified
to obtain different CD derivatives by chemical and enzymatic
reactions.
Such derivatizations are done to accomplish the following
objectives:
to enhance the solubility of different CD derivatives and their
complexes;
to improve the fitting and/or the association between the CD
and its guest, with concomitant stabilization of the guest,
reducing its reactivity and mobility;
to achieve insoluble, immobilized CD-containing struc-
tures and polymers, e.g. for chromatographic purposes
(Szejtli, 2004).
CD derivatives are mainly categorized as: (a) chemically
modified CD derivatives and (b) natural enzymatically
modified CD derivatives.
Enzymatically modified CD derivatives are formed with
the help of pullulanase enzyme and are known as branched
CDs. When the hydroxyls of b-CD are made to react with a
chemical reagent, the substitution occurs and a heterogeneous
product is generated (Szente & Szejtli, 1999). The extent to
which substitution occurs can be defined and expressed in
different ways as follows:
Degree of substitution: It is defined as the number of
the hydroxyl groups in a glucose moiety of CD molecule
that has been substituted. Therefore, it can be ranged
from 1 to 3. The average degree of substitution (DS) is the
average number of hydroxyl groups being substituted in
a glucose unit of CD. Its value can vary from 0 to 3
(Challa et al., 2005).
DOI: 10.3109/10717544.2014.938839
Table 2. Structural and chemical properties of parent cyclodextrins.
Features a-CD
Glucopyranose units 6 7
Molecular weight (g/mol) 972
Height (nm) 0.78
Cavity diameter (nm) 0.50
Outer diameter of cavity (nm) 1.46
Cavity volume (Å3) 174
Aqueous solubility at 25  C (mg/ml) 129.5 ± 0.7
Aqueous solubility at 25  C (%w/v) 14.5
Molar degree of substitution: It is the critical parameter,
which is mainly defined as the average number of substitu-
ent’s that completely reacts with one glucopyranose repeat
unit. If the molar degree of substitution (MS) value is equal
to 0, then no substitution or up to 3, when two or more
substituents react and form oligomeric or polymeric side
chains (Loftsson & Brewster, 1996).
CD derivatives like hydroxypropyl derivatives of b
and g-CD (HP-b-CD and HP-g-CD), randomly methylated
b-CD (RM-b-CD), sulfobutylether b-CD sodium salt
(SBE-b-CD) and the branched CDs, such as maltosyl-b-CD
(M-b-CD) are of great pharmaceutical interest (Ogawa
et al., 2012).
Formation of inclusion complexes
One of the most remarkable features of CDs is their tendency
to form solid inclusion complexes with a wide variety of solid,
liquid and gaseous compounds by the process of molecular
complexation. The complexes formed are called host–guest
type of complexes. Such type of complexes involves a guest
molecule (drug) which is properly fitted into the lipophilic
cavity of host (CD molecule; Del Valle, 2004). There is no
breakage or formation of covalent bond during the formation
of inclusion complex (Loftsson et al., 2005a,b). When the CD
is added to an aqueous solution, the polar water molecules get
fit into the lipophilic cavity of CD, but these are immediately
replaced by the more favored guest molecule, which is less
polar than replaced water molecules (Szejtli, 2004). The main
driving force behind this complex formation is the replace-
ment of high enthalpy water molecules with the guest moiety,
Vander Waals interaction, hydrogen bonding and charge
transfer interaction (Loftsson et al., 2005b). The ratio in
which host and guest bind together is generally 1:1 (Loftsson
et al., 2005a). The binding strength of the formed complex
depends on the ability of the guest molecule to bind well
with the host to form a stable complex. The formation of an
inclusion complex depends upon following factors:
 Size of the CD to the size of the guest molecule or some
main functional groups within the guest moiety. If the
guest is of inappropriate size, it will not fit properly into
the host cavity.
 Thermodynamic interactions between the various
components of the system (CD, guest, solvent; Del
Valle, 2004).
 Structure of added substituent to the CD derivative.
 Location of substituent within the CD molecule.
 Number of substituent per CD molecule.
Versatile applications of cyclodextrins 731
b-CD g-CD References
8 Szejtli (2004)
1135 1297 Singh et al. (2010)
0.78 0.78 Loftsson & Brewster (2010)
0.62 0.80 Loftsson & Brewster (2010)
1.54 1.75 Loftsson & Brewster (2010)
262 427 Cal & Centkowska (2008)
18.4 ± 0.2 249.2 ± 0.2 Loftsson & Brewster (2010)
1.85 23.2 Del Valle (2004)
Different techniques used for complex formation include
physical mixing, kneading method, spray drying, lyophiliza-
tion, co-precipitation, solvent evaporation method, neutral-
ization precipitation method, milling method and supercritical
anti-solvent technique (Patil et al., 2010).
Applications of cyclodextrins
Due to unique property of forming inclusion complexes
with diverse molecules, CDs offers versatile benefits in many
industries. Applications of CDs are summarized in Figure 3.
Modifications of existing drug molecules for
improved efficacy
A new formulating agent serving dual purpose, i.e. improving
the physical properties of new active pharmaceutical ingre-
dient and reformulation of existing drugs is the need of hour
in the pharmaceutical industries. CDs have been proven to be
better than the existing standard formulating agents. The
complexes formed between the active ingredients and CDs
show improved stability, solubility and bioavailability with
very few adverse effects. CDs are the agents which act as a
drug delivery system and also have potential drug delivery
profiles in many applications. These properties of CDs are
due to the fact that CDs have tendency to modify the physical,
chemical and biological properties of guest molecules by
formation of inclusion complexes. Due to bio-adaptability and
multi-functional property of CDs, there is improvement in the
unwanted properties of drug molecules in various routes of
administration, including oral, rectal, nasal, ocular, transder-
mal and dermal (Singh et al., 2002). Hence, CDs play a very
significant role in the field of pharmaceuticals. The process
of inclusion complex formation between the drug and CD and
subsequent absorption of drug are depicted in Figure 4.
Stability enhancement
CDs play an important role in the chemical stability of drugs.
The following properties are concluded after studying the
interaction between CDs and labile compounds: (a) CDs
retard degradation, (b) CDs have no effect on reactivity
or (c) CDs can accelerate drug degradation (Loftsson &
Brewster, 1996).
CDs are widely known to speed up or slow down the
different types of reactions such as hydrolysis, oxidation,
photolysis, dehydration and isomerization, based on the
characterization of the inclusion complex in aqueous and
buffer solutions. This can be well understood by the given
examples – in Vaseline and o/w emulsion, the stability of
732 N. Sharma & A. Baldi Drug Deliv, 2016; 23(3): 729–747

Figure 3. Versatile applications of cyclodextrins.

Figure 4. Schematic representation of cyclodextrins–drug complexation, subsequent release and absorption of drug.
DOI: 10.3109/10717544.2014.938839
Figure 5. Process of inclusion complex formation of drug and cyclodextrin.
tixoxortol 17-butyrate 21-propionate – a dermocorticoid, was
preserved by forming its inclusion complex with b-CD after
storing it for 30 days at 40  C (Matsuda & Arima, 1999).
In addition, CD derivatives have been proven to better than
the parent CDs in showing the stabilizing effects. Derivative
of b-CD, O-carboxymethyl-O-ethyl-beta-CD (CME-b-CD)
considerably maintained the stability of prostaglandin E
(PGE) in an ointment containing fatty alcohol/propylene
glycol (FAPG) and in aqueous solution, while the parent
b-CD promoted its degradation in neutral and alkaline
solutions (Matsuda & Arima, 1999).
Solubility and bioavailability improvement
CDs can enhance apparent water solubility by forming
dynamic, non-covalent, water-soluble inclusion complexes
(Davis & Brewster, 2004) as shown in Figure 5. Enhancement
of solubility of the drug further helps in the better bioavail-
ability and hence more therapeutic efficacy of the dosage
form. Table 3 shows various reports on solubility enhance-
ment of therapeutically important pharmaceutics by CD
complexation.
Safety and efficacy betterment
CDs are widely used to alleviate the irritation caused by
drugs. The enhanced solubility of drug–CD inclusion com-
plex results in better drug efficacy and potency, which further
reduces the drug toxicity since the drug becomes effective at
minimum doses. The soluble CD–drug inclusion complex
also helps in lowering down the toxicities caused due to
the crystallization of poorly water-soluble drugs in case of
parenteral formulations. Moreover, drug entrapment in CD
cavity at the molecular level protects the biological mem-
branes from direct contact of the drug, which reduces the side
effects associated with the drug as well as the local irritation
without affecting the therapeutic efficacy of the drug
(Rasheed et al., 2008).
Drug delivery through biological membranes
The CD permeability through the biological membranes is
affected by various factors like its molecular weight, chemical
Versatile applications of cyclodextrins 733
structure and very low octanol/water partition coefficient (log
P values) resulting in its inability to cross the biological
membranes quickly. The free form of drug, which is not
bound to the complex and is in equilibrium with the drug–CD
complexes, has the tendency of penetrating the lipophilic
membranes. CDs have no role in enhancing the permeability
of hydrophilic water-soluble drugs through lipophilic bio-
logical membranes. Whether CD increases or decreases the
drug delivery across the biological membrane will depend
upon the factors like the physicochemical properties of the
drug such as its aqueous solubility, the composition of the
drug formulation, i.e. aqueous or non-aqueous and physio-
logical composition of the membrane barrier like the presence
of an aqueous diffusion layer (Rasheed et al., 2008). The drug
delivery through aqueous diffusion-controlled barriers can be
increased by the use of CDs, but it restricts the drug delivery
through lipophilic membrane-controlled barriers. Still, there
is an exception to it, i.e. hydrophobic CDs (e.g. methylated
b-CDs) can easily pass through mucosa and helps to improve
the drug delivery through biological membranes, like the
nasal mucosa, by decreasing the barrier property of the
membranes (Loftsson et al., 2005b).
CD-based drug delivery approaches
Drug delivery through oral route
Among a number of routes available for the drug delivery,
oral route has always been the most preferred route for
developing a drug delivery system. The release of the drug in
oral drug delivery system can be either dissolution controlled,
diffusion controlled, osmotically controlled, density con-
trolled or pH controlled. The role of CDs in oral delivery
system is as an excipient to carry the drugs across an aqueous
phase to the lipophilic absorption surface in the gastrointes-
tinal tract, i.e. forming the inclusion complexes with CDs
helps in enhancing the dissolution rate of drugs with low
aqueous solubility. Hydrophilic CDs are mostly used for this
purpose. In the case of sublingual and buccal routes, the
drug–CD complexes with fast dissolution profiles are
prepared. A quick rise of drug concentration in the systemic
circulation is achieved in sublingual and buccal administra-
tion since the issue of hepatic first pass metabolism is
 734

Table 3. Various reports on solubility enhancement of therapeutically important pharmaceuticals by CD complexation.

Water Enhancement Complexation Binding

Drugs pKa Log P solubility in solubility method C:D CD type constant (M1) References
N. Sharma & A. Baldi

Aceclofenac 4.7 2.17 0.058 mg/ml – KN 1:1 HPbCD 221.11 Kasliwal & Negi (2011)
Acyclovir 2.27 1.56 1.62 mg/ml – KN 1:1, 2:1, 3:1, 4:1 HPbCD, bCD – Sachan et al. (2010)
Amisulpride 9.37 1.10 16.89 mg/ml 3.74 times KN 1:1 gCD 1166.65 Negi & Singh (2013)
Artemether 4.8 3.02 – 1.8 times FD 1:1 HPbCD 220 Yang et al. (2009)
Albendazole 10.26 2.7 1.37 mg/ml 53.4 times PM 1:1 bCD 1266 Moriwaki et al. (2008)
Atorvastatin 11.82 5.7 20.4 mg/ml – FD, PM, KN, CE 1:1 bCD – Palem et al. (2009)
Amiodarone 8.47 7.57 0.2–0.5 mg/ml – FD, SD, CE, PM 1:1 bCD 1957 Riekes et al. (2010)
Cefdinir 3.2 0.2 0.46 mg/ml 101% bCD, KN 1:1 HPbCD, bCD – Aleem et al. (2008)
23.4% HPbCD
Darifenacin 9.2 4.5 2.98 mg/ml 8.24–20.57 mg/ml CE 1:1 HPbCD 465.30 Jagdale et al. (2012)
Daidzein 7.39 2.51 0.15 mg/ml 5.7-fold (bCD), FD 1:1 HPbCD, bCD, MbCD – Borghetti et al. (2011)
7.2-fold (MbCD),
9.4-fold (HPbCD)
Etodolac 4.65 2.5 16 mg/ml – FD, PM – HPbCD – Cappello et al. (2009)
Fexofenadin 13.2 5.6 3.6 mg/ml – – 1:1 bCD, HPbCD 1139, 406 Al Omari et al. (2007)
Gliclazide 5.98 2.6 55 mg/ml 20.31 times KN 2:1 bCD 691.45 Ozkan et al. (2000)
Isoquercitin 2.92 5.6 mg/ml 12.3 times – 1:1 DMbCD 783 Wang et al. (2009)
Itraconazole 3.7 5.66 1 ng/ml 12 times – 2:1 HPbCD – Miyake et al. (1999)
Josamycin 13.5 3.47 0.35 mg/ml 13.14 times CP 1:1 gCD 3060 El Harti et al. (2012)
Meloxicam 4.08 1.9 8 mg/ml – – 1:1 bCD – Awasthi et al. (2011)
Naringenin 9.46 2.47 4.38 mg/ml 1272.31 mg/ml – 1:16 HPbCD – Wen et al. (2010)
Omeprazole 4.77 2.23 82.3 mg/ml – FD, SD 1:1 MbCD 77.4 Figueiras et al. (2007)
Piroxicam 6.3 3 23 mg/ml – FD 2:1 bCD – Jug et al. (2005)
Repaglinide 4.01 3.97 34 mg/ml – – 1:1 HPbCD, bCD, RMbCD 377.4 Nicolescu et al. (2010)
Rapamycin 13.37 4.3 2.6 mg/ml 61 times FD 1:1 MbCD 579 Rouf et al. (2011)
Rofecoxib 19.7 3.2 – – KN 1:1 bCD 769 Rawat & Jain (2003)
Rifampicin 8.25 2.7 1.4 mg/ml 22 times – 1:1 RMbCD 73.4 Tewes et al. (2008)
Rutin 8.45 0.15 0.125 mg/ml – – 1:1 HPbCD 405.3 Miyake et al. (2000)
Raloxifene HCl 9.55 5.2 0.25 mg/ml – KN 1:1 HPbCD 4.59 Wempe et al. (2008)
Telmisartan 4.45 7.7 0.09 mg/ml – KN 2:1 bCD, HPbCD 644.56 Kane & Kuchekar (2010)
Vanillin 7.78 1.21 10 mg/ml – FD 1:1 bCD 5.3 Karathanos et al. (2007)
Valdecoxib 9.8 3.2 10 mg/ml – KN 2:1 HPbCD 1.63 Rajendrakumar et al. (2005)
Sulfamethoxazole 5.8 0.7 610 mg/ml – CP 1:1 bCD 122.3 Ozdemir & Erkin (2012)

KN, kneading; FD, freeze drying; PM, physical mixing; CE, co-evaporation; SD, spray drying; CP, co-precipitation.
Drug Deliv, 2016; 23(3): 729–747
DOI: 10.3109/10717544.2014.938839 Versatile applications of cyclodextrins 735
Table 4. Use of cyclodextrin in promoting oral drug delivery.

Cyclodextrin
Drugs used Work done Conclusion References
Furosemide (FS) b-CD b-CD complexes with the solid Suitability for development of drug Garnero et al. (2014)
forms of FS. delivery system.
Econazole nitrate (ECN) SBE-b-CD, Ternary complexes using b-CD Effective in better treatment of oral Jug et al. (2014)
HP-b-CD derivatives and compounds candidosis.
(l-AAs, CA, hydrophilic poly-
mers) for synergistic effect.
Tacrolimus (TL) b-CD Pluronic F127-modified liposome- Improved drug solubility and Zhu et al. (2013)
containing CD inclusion intestinal mucous membrane
complex. penetration.
Docetaxel (DTX) SBE-b-CD DTX–chitosan nanoparticles Better candidates for oral admin- Wu et al. (2013)
having CDs complexes. istration in comparison to
existing DTX formulations.
Dihydroartemisinin (DHA) HP-b-CD Inclusion complexes Improved pharmacokinetic param- Ansari et al. (2011)
eters along with better oral
delivery.
Praziquantel (PZQ) a-, b-, g-CD Inclusion complexes Enhanced solubility, bioavailabil- Becket et al. (1999)
ity through oral route.

resolved via this route (Tiwari et al., 2010). The bioavail-
ability of the drug is increased by CDs. This happens because
of improved water solubility and drug dissolution rate due
to drug–CD complexation. Moreover, they also play an
important role as conventional penetration enhancers.
However, there is a difference between administration of
CD containing formulation via sublingual and oral route.
For the drug to show its therapeutic action, it must be
released from the inclusion complex before it gets absorbed.
This is a bit difficult for sublingual application because a
very small amount of aqueous saliva is available for the drug
to get dissolve completely and also relatively short residence
time. The time for the drug to release from the complex
after administration is less since the dissolved drug is
removed from the buccal region within few minutes
(Rasheed et al., 2008).
CDs also help in achieving sustained or site-specific drug
release. This can be explained by taking an example of
hydrophobic (i.e. lipophilic) CDs like ethylated b-CD and
triacetyl-b-CD which are used to get sustained drug release.
In addition to this, CDs have also been used in osmotic pumps
for controlled drug delivery and in matrix tablets to control
solubility-dependent drug release (Okimoto et al., 1998).
Drug–CD conjugates have also been used to obtain colon-
specific drug delivery or sustained plasma levels (Loftsson
et al., 2004). Many researchers have carried out studies
recently to improve oral drug delivery of various drugs, which
has been summarized in Table 4.
Drug delivery through rectal route
One of the important applications of CDs is optimizing rectal
delivery of drugs meant for systemic use. The action of CD on
rectal drug delivery clearly depends upon following factors:
 Nature of vehicle used, i.e. hydrophilic or oleaginous.
 Physicochemical properties of inclusion complexes
formed.
 Existence of tertiary excipients like viscous polymer, etc.
In the case of rectal absorption of lipophilic drugs, the
improving effects of CDs are commonly dependent on the
improved release of vehicles used and the dissolution rates of
the drug in rectal fluids, while in the case of rectal delivery
of poorly absorbed drugs such as antibiotics, peptides and
proteins, the action of CD depends on its direct action on the
rectal epithelial cells. Furthermore, the continuous effects of
CDs on the levels of drug in blood is due to the sustained
release from the vehicles, slower rates of dissolution of drug
in the rectal fluid or the obstruction in the rectal absorption
of drugs due complex formation having very poor absorption
(Matsuda & Arima, 1999).
Normally, hydrophilic CDs help in improving the release
of drugs with very less water solubility from oleaginous
suppository bases because of the minimum interaction of the
resulting complexes with the vehicles. The lipophilic drugs
become insoluble in hydrophobic vehicles on complexation
with hydrophilic CDs, although the complex exists in the
form of well-dispersed fine particles in the vehicles. This step
serves the dual purpose as it improves the drug dissolution at
an interface between the molten bases and the surrounding
fluid as well as hinders the reverse diffusion of the drugs back
into the vehicles (Rasheed et al., 2008). Table 5 illustrates
representative work done in enhancing the rectal drug
delivery by using CDs.
Drug delivery through nasal route
Nasal drug delivery has become an appealing approach for the
purpose of systemic delivery of highly potent drugs, which
have the issue of low oral bioavailability because of the huge
amount of gastrointestinal breakdown and excessive hepatic
first-pass metabolism. CDs help in enhancing the nasal
absorption of the drugs like peptide and proteins, which have
less nasal bioavailability due to their large size and hydro-
philic nature, making their transport across the nasal mucosa
tough. CD enhances their water solubility by increasing
their nasal absorption (Merkus et al., 1999). The hydrophobic
CDs also have a role as penetration enhancers, particularly
in the nasal delivery of peptides. Very less local toxicity of
CDs after nasal administration has been reported (Rasheed
et al., 2008).
CD also serves as a pharmaceutical excipient and acts as a
solubilizer and absorption promoter in nasal drug delivery.
736 N. Sharma & A. Baldi Drug Deliv, 2016; 23(3): 729–747

Table 5. Representative work done in enhancing the rectal drug delivery using cyclodextrins.

Cyclodextrin
Drugs used Work done Conclusion References
Diazepam and Flubiprofen TM-b-CD Inclusion complexes Better drug release and Lakshmi et al. (2012)
permeability.
Ethyl 4-biphenylylacetate b-CD, HP-b-CD, Inclusion complexes Better stability, release rate and Arima et al. (1992)
(EBA) DM-b-CD hence improved rectal
absorption.
Morphine a-CD Pharmacokinetic studies of mor- Improved rectal bioavailability Kondo et al. (1996)
phine and its glucuronides in of morphine.
rabbit plasma upon rectal
administration from hollow type
suppositories with xanthan
gum.

Table 6. Role of cyclodextrins in nasal drug delivery.

Cyclodextrin
Drugs used Work done Conclusion References
Dihydroergotamine RM-b-CD Development of nasal formulation Better stability with enhanced Rasheed et al. (2008)
(DHE) containing inclusion complex. concentration and improved
nasal drug delivery.
Estradiol (ES) DM-b-CD Inclusion complex formation. Better absorption hence enhanced Ali et al. (2012)
bioavailability.
Melatonin (MT) HP-b-CD, Inclusion complexes. HP-b-CD as well as RM-b-CD Babu et al. (2008)
RM-b-CD increased the nasal permeability
of MT.
Pirodavir HP-b-CD Formulation development for nasal Improved efficacy. Rasheed et al. (2008)
delivery

It is very effective even in a very low concentration and also
is inert from a pharmacological–toxicological point of view
(Chordiya & Senthilkumaran, 2012). Some representative
studies, in which CD has played a major role in the drug
delivery via nasal route, are given in Table 6.
to penetrate into the lipophilic barrier. As a result of this, drug
delivery through the cornea is decreased (Loftsson et al.,
2005b). Some of the recent studies conducted for improve-
ment in drug delivery through ophthalmic route by applying
CD–drug complexes are listed in Table 7.

Drug delivery through ophthalmic route
The basic remedy to treat the ocular diseases is mainly the
drug application topically in the form of aqueous eye drop
solutions. Recent reports have proved CDs as useful additives
in ophthalmic formulations as they increase the water
solubility, aqueous stability and bioavailability of ophthalmic
drugs, and helps in decreasing the drug irritation (Loftsson &
Jarvinen, 1999). The hydrophilic CDs, primarily 2-HP-b-CD
and SB-b-CD, have been reported to be nontoxic to the eye
and also are well tolerated in aqueous eye drop formulations
(Loftsson & Stefansson, 2002). Hydrophilic CDs do not have
access to the tight biological barriers such as the eye cornea,
but increase the ocular bioavailability of lipophilic drugs by
keeping the drugs in solution and increasing their availability
at the surface of the corneal barrier (Rasheed et al., 2008).
Very less amount (i.e. 55%) of the drug, which is delivered
topically is absorbed into the eye. By the means of CD,
solubilization increase in the dose-to-solubility ratio is
feasible thereby, facilitating the application of the drugs
topically, which were earlier delivered only by systemic
routes. CD solubilization of the drug results in the increase in
the amount of dissolved drug at the lipophilic membrane
surface, but at the same time, if excess of the CD is used, then
it will lead to the lowering of the ability of the drug molecules
Drug delivery through dermal route
There is a remarkable safety margin of CD in dermal and
transdermal application of drugs meant either for local or
systemic use. They have a significant role in improving the
solubility as well as stability of drugs in the topical
formulations, augmenting the transdermal absorption of
drugs, helps in the sustain release of the drug from the
vehicle and thus, circumventing the unwanted after effects
related with dermally applied drugs. Stratum corneum is the
outermost layer of the skin and is the principal hurdle for the
absorption of drugs given dermally (Rasheed et al., 2008).
To reduce its barrier properties, penetration enhancers such
as alcohols, fatty acids etc. are used. Due to hydrophobic
characteristics, CD-complexes are able to deliver the drug
through aqueous diffusion layer only. These complexes cannot
penetrate the drug through lipophilic barriers like stratum
corneum. Hence, an appropriate aqueous vehicle must be
selected for aqueous vehicle must be selected for maximizing
the utility of CDs as penetration enhancers. The rate of drug
permeability through skin by CD-complexes depend upon
two factors; release of drug from an aqueous vehicle; and
transport across aqueous diffusion layer on the outer surface
of skin. However, if drug permeation and subsequent
absorption depend on transport across lipophilic stratum
DOI: 10.3109/10717544.2014.938839 Versatile applications of cyclodextrins 737
Table 7. Application of cyclodextrins in ophthalmic drug delivery.

Cyclodextrin
Drugs used Work done Conclusion References
Dexamethasone CDs Inclusion complex. More patient compliance in com- Loftsson & Stefansson
parison to un-complexed drug- (2002)
based eye drops.
Econazole SBE-b-CD Chitosan nanoparticles containing Chitosan/SBE-b-CD nanoparticles Mahmoud et al. (2011)
complex CD were prepared and developed had the tendency to
monitored. act as a carrier for controlled
delivery of drug to eyes.
Methazolamide 2-HP-b-CD Effect on intra ocular pressure Better lowering of intraocular Gudmundsdottir et al.
estimated in a double-blind pressure due to CD (2000)
randomized trial in humans. complexation.
Zinc diethyldithiocarbamate HP-b-CD Formulation optimization and anti- Drug solubility and permeability Wang et al. (2004)
(Zn-DDC) cataract effects of aqueous eye were increased through the
drop having high concentration rabbit cornea.
of Zn-DDC.

Table 8. Applications of CDs for improving dermal and transdermal drug delivery.

Cyclodextrin
Drugs used Work done Conclusion References
Bupranolol (BPL) HPb-CD, PM b-CD Inclusion complexes. Improved solubility and Babu & Pandit (2004)
penetration.
Glipizide (GPZ) b-CD, DM-b-CD, Percutaneous formulations of the Effective means for transdermal Ammar et al. (2006)
HP-b-CD and drug complex in different bases delivery in management of type
HP-g-CD. (o/w emulsion, PEG, CMC and 2 diabetes.
Carbopol).
Gliquidone HP-b-CD Effect of pH and complexation on Higher transdermal delivery of Sridevi & Diwan (2002)
drug delivery. gliquidone was achieved due to
improved solubility and perme-
ability of the drug.
Isotretinoin HP-b-CD Elastic liposomes loaded with Possibility for skin targeting, Kaur et al. (2010)
complexes. extended drug release, less
photo degradation and least
possibility of skin irritation with
better topical delivery.

corneum as rate determining factor, then cyclodextrins are not
capable to improve the drug delivery (Rasheed et al., 2008).
Applications of CDs for improving dermal and transdermal
drug delivery are shown in Table 8.
CDs are also known to enhance the release of drugs from
the vehicles by the complexation with the drug. CDs help in
easing the skin irritation instigated by drugs by decreasing the
extent of free drug occurring due to the inclusion equilibrium
(Chordiya & Senthilkumaran, 2012). CD discharges certain
constituents like proteins, cholesterol and phospholipids with
regard to the cutaneous irritation of CDs themselves to skin,
from the stratum corneum of skin. As the result of this, a
change may occur in the barrier function of skin and
permeability of drugs and other xenobiotics. Therefore,
special attention should be paid to the possible irritation
effects of skin (Matsuda & Arima, 1999).
CDs in cosmetics, toiletries and personal care
Recent use of CDs has been discovered in the field of the
cosmetic preparations, mainly in vaporization suppression
of perfumes, room fresheners and detergents by obtaining
the controlled release of fragrances from inclusion com-
plex compounds. The crucial advantages of CDs in this
regard are maintenance of stability, odor control and process
improvement by converting a liquid ingredient to a solid
form (Del Valle, 2004).
Following are the major roles of CD in the field of
cosmetic preparations.
Shielding from light and oxidation
Presence of CD safeguards cosmetic products from the
degredative effects of light and oxidation. In the absence of
light and oxygen, pure tea tree oil remains unchanged for a
month. Else the skin irritant, p-cymene, is formed because
of the reaction between the terpenes present in the oil with
light and oxygen. Due to the CD complexation, oil remains
stable against light and oxygen. Hence, the possibility of
the production of unwanted compounds is circumvented.
In addition, there is no change in the antimicrobial and anti-
inflammatory properties of tea tree oil after the complex
formation (Buschmann & Schollmeyer, 2002).
Preventing the loss by evaporation
The phenomenon of complexation by CD aids in the stability
of volatile compounds by decreasing their evaporation.
The complexes can be added in either powders or liquid
formulations. Now a days, even the solid form perfume
complexes are used in perfumes. The application of these
738 N. Sharma & A. Baldi
Table 9. Recent reports of cyclodextrins in cosmetics.
Cyclodextrin
Drugs used
Õ Õ
Eusolex 4360 (Avobenzone), Eusolex b-CD Effects of b-CD complexation
9020 (Oxybenzone) and EusolexÕ on transdermal penetration
232 (Ensulizole) of sun blocking agents.
Lemongrass volatile oil b-CD and Microparticles formed.
HP-b-CD
Octyl p-methoxycinnamate (OMC) b-CD Sunscreen preparations.
Phenylenediamine isomers (PDI) b-CD Detection of PDI in hair dyes.
suspensions on the skin satisfies the demand of a long-lasting
effect by slow release of the perfumes (Buschmann &
Schollmeyer, 2002).
Removal of unpleasant odors
The dry form of CD powders even with the size less than
12 mm are used for odor control in products like diapers,
menstrual products and paper towels etc. and are also widely
used in hair care preparations for limiting the volatility of
odorous mercaptans. Dishwashing and laundry detergents
also contain CDs as important constituent, which helps in
masking the odors in washed items (Del Valle, 2004).
CD complexation eliminates the undesirable odor of dihy-
droxyacetone which otherwise is very tough to be masked by
perfumes. It is used as a tanning agent. Moreover, this CD
complexation also causes the slow release of di-hydroxyace-
tone from the complex due to which there is more uniform
tanning of the skin. The product containing this CD complex
is marketed as Ultrasun Selftanß (Ultrasun) and in Self-
Action Super Tan For Faceß (Estee Lauder). CD is also used
in deodorants to control the unpleasant smell caused by
microbial degradation of sweat (Buschmann & Schollmeyer,
2002). Recent reports of cyclodextrins in cosmetics have been
given in Table 9.
CDs in nutrition industry
The food/nutrition industry also demands use of CDs as food
additives, for stabilization of flavors, for removal of offensive
tastes and other undesirable compounds for instance choles-
terol and to get rid of microbiological contaminations and
browning reactions (Astray et al., 2009). The stability
of colorants, flavors, unsaturated fats and vitamins can be
elevated by the process of molecular encapsulation of
lipophilic food ingredients with CD both in physical and
chemical aspect causing prolonged product shelf life (Singh
et al., 2002). Various experiments were conducted to monitor
the effect of CD on the shelf life of the product and it was
observed that almost all the natural and synthetic flavors and
flavor substances show exceptionally increased shelf life
throughout the long-term storage. Along with this, 12 various
complexes of natural and synthetic flavor/b-CD have been
kept in storage under normal conditions for the time span
of 14 years and their actual flavor loads were examined from
time to time by GC. Finally, the scientists concluded that the
Drug Deliv, 2016; 23(3): 729–747
Work done Conclusion References
Reduction of systemic absorp- Shokri et al. (2013)
tion of UV filters followed
by toxicity and allergic
reactions.
Efficacy improvement. Weisheimer et al.
(2010)
The lipo/OMC system proved Monteiro et al.
as most beneficial release (2011)
system.
Suitable method was Wu et al. (2011)
developed.
preserving power of the b-CD complexation relies on the
structure, polarity and geometry of the different flavor
substances. The strongest protection was seen with terpenoid,
phenyl-propane and alkylsulfide-type flavors, whereas the
flavors of phenolic structure were preserved comparatively
to a much lesser amount (Szente & Szejtli, 2004).
The use of CDs in food processing and as food additives
mainly focuses on the following goals:
 Preventing the lipophilic food components that may
undergo oxygen and light or heat induced degradation.
 To terminate the unpleasant odors or tastes.
 Stabilization of fragrances, flavors, vitamins, and essen-
tial oils against the undesirable changes.
 To obtain a controlled release of certain food
constituents.
 To promote the solubility of food colorants and vitamins
(Astray et al., 2009).
b-CD improves the quality and stability of food products
by acting as a cholesterol sesquestrant, i.e. it efficaciously
removes the cholesterol from animal products thereby,
enhancing their nutritional characteristics. In the case of
milk, the immobilized b-CD glass beads were prepared by the
process of silanization and b-CD immobilization reaction
led to cholesterol removal in milk up to 41% and a recycling
efficiency of almost 100% (Astray et al., 2009). Reduction
in cholesterol and decreased oxidation were observed in
phytosterol-supplemented mayonnaise with the help of cross-
linked b-CD without any change in its physicochemical
and sensory properties during storage (Jung et al., 2008).
When lard was treated under various conditions with 5%
crosslinked b-CD cholesterol removal was observed in the
range of 91.2–93.0% (Kwak et al., 2004).
One of the most important applications of interest of CD
is the CD-containing food-packaging materials. CD serves
a dual purpose in food-packaging materials. First, all the
residual organic volatile contaminants in packaging materials
are minimized by CD. Second, the barrier properties of the
packaging materials such as diffusion rate and transmission
rate are improved by the use of CD further boosting the
sensory properties by retaining the food quality and safety.
Now a days many CD complexes are employed in foods as
antiseptic or conserving agents. For instance, 0.1% iodine-
b-CD obstructs the decomposition for 2 months at 20 C
in fish paste or in frozen seafood products (Szente &
Szejtli, 2004).
DOI: 10.3109/10717544.2014.938839 Versatile applications of cyclodextrins 739
Table 10. Studies on use of cyclodextrins in food and flavors.

Food products Cyclodextrin used Work done Conclusion References

Cholesterol
Fat containing meal
Ginseng solution
Goat milk and its yogurt
Mandarin juices enriched
with pomegranate extract
and goji berries juice
b-CD Study of inclusion properties
and the factors affecting
encapsulation and stability.
a-CD Effect of a-CD on the acute
post-prandial responses in
healthy adults.
b-, g-CDs Studies on taste masking and
improvement of sensory
properties of ginseng.
a-, b-, g-CDs Effect of CDs on the flavor of
goat milk and its yogurt.
b-CD, HP-b-CD Antioxidant efficacy of tested
compounds was examined
upon addition of b-CD or
HP-b-CD.
Successful elimination of Dos Santos et al. (2011)
cholesterol in the new food
products.
Significant reduction of acute Jarosz et al. (2013)
post-prandial blood trigly-
ceride levels.
CDs in water and model energy Tamamoto et al. (2010)
drink base solutions con-
taining ginseng, help in the
formation of beverages suit-
able for consumers.
b-CD most effectively masked Young et al. (2012)
goaty flavor in yogurt with
retention of nutritional
benefits.
Juices containing HP-b-CD Navarro et al. (2011)
showed more intense color,
greater vitamin C content,
retinol equivalents and anti-
oxidant activity.

CD also helps in altering the taste and removal of
undesirable bitter tastes and odors of food products. Certain
food products have a very bad smell but, on addition of CDs
during their manufacturing, inclusion complexes are formed
between CD and food components thereby improving the
smell of the resultant product. Using the same phenomenon
the peculiar odors of food products like fish, soybean milk
and soy protein was improved (Astray et al., 2009).
The unique property of CD of forming the inclusion
complexes helps in the color modification of foods, since they
too form complexes with the polyphenol-oxidase enzyme
which is the accountable of catalyzing the browning reactions
(Astray et al., 2009). Table 10 shows use of cyclodextrin in
different food and flavors.
Environmental uses of CDs
CDs also have a crucial role to play in the field of
environmental science with respect to the enhancement and
elimination of organic pollutants and heavy metals from soil,
water and atmosphere and solubility of organic contaminants
(Gao & Wang, 1998). CDs are also put into application in
water treatment for enhancing the stabilization aspect,
encapsulation and adsorption of contaminants. One can get
rid of extremely poisonous and lethal substances from
industrial effluent by forming the inclusion complexes
utilizing CD (Szejtli, 1989). All the aromatic toxic hydrocar-
bons like phenol, p-chlorophenol and benzene, which are
present in wastewaters, are reduced to much lesser extent
than its initial amounts after the treatment of wastewaters
with b-CD (Singh et al., 2002). CDs are also employed in
washing away the gaseous effluent from organic chemical
industries (Szejtli, 1989). Different solubility enhancement
techniques of CDs are used in the testing of soil improvement.
The deterioration of various classes of hydrocarbons affecting
the growth kinetics is promoted by b-CD, resulting in
higher biomass yield and superior use of hydrocarbons as a
carbon and energy source. b-CD has become the powerful
tool for bioremediation process due to its properties such as
the low cost, biocompatible and effective degradation
(Singh et al., 2002).
CDs play a major role in environmental protection, which
is its usage in insecticide formulation. CDs are incorporated
in the preparation of an insecticide from neem seed extract
by forming water-soluble inclusion complex of neem seed
kernel extract enclosing azadirachtin-A in a CD carrier
molecule. In addition to all its above uses, CDs also helps in
the photodegradation process of organophosphorous pesti-
cides in humid water by catalyzing the reaction of pesticides
with reactive radicals, which are produced by the
humid photosensitizer and inclusion complexed CD (Singh
et al., 2002).
CDs in textile and packing industry
Since CD has potential to form inclusion complexes with a
variety of organic molecules. This property is responsible for
its use in different textile applications. CDs can be taken
into account as a new category of auxiliary substances for
use in the textile industry. Since CD has natural origin and is
environmentally safe, so it is considered for textile industry
(Voncina, 2011).
CD performs the function as retarding reagent in much
textile fiber dyeing such as cotton, polyester, polyamide,
polypropylene, polyacrylonitrile by complexing with dye
molecule, which are released slowly to the fiber thereby,
slowing down the dye migration because of the competition
for sites on the fiber between CD and dyes irrespective of its
mechanism of action. Normally, when CD is used as a
leveling agent or a retardant in the dyeing process, superior
quality of dyeing together with the improved bath exhaustion
is achieved and bath exhaustion in comparison to other
already existing marketed auxiliaries; stimulating the better
color levelness and some development in color depth when
textile fibers are dyed in the presence of CDs. Besides its use
in enhancing the quality of dyeing in textile industry, CD
also aids in lowering down the environmental damage of
exhausted baths. This mainly happens when covalently
740 N. Sharma & A. Baldi
Table 11. Cyclodextrins applicability in textile industry.
Cyclodextrins Work done
HP-g-CDs Use of CDs as a finishing agent of polyamide
fibers in order to obtain inguinal meshes
with enhanced antibiotic delivery properties.
Polymerization between citric acid and
CDs produced a cross-linked polymer
that physically adhered to the surface of
PA fibers.
MCT-bCD Making of reactive cotton/wool and viscose/wool
prints with outstanding UV-protection func-
tions through inclusion of definite UV-absor-
bers/blockers like as a reactive additive, in the
printing paste formulation with sodium
alginate as a thickening agent.
MCT-b-CD Alteration in wool fabric structure.
Monochlorotriazinyl-b-CD The cotton grafted with an inclusion compound
(MCT-b-CD) with natural anti-allergic active principles.
bonded CDs on textile support form inclusion complexes
with organic pollutants. With this, all the adsorbed pollu-
tants will change into water and carbon dioxide by the
process known as incineration (Voncina, 2011). Superior
quality fabrics with novel properties are generated with the
help of CDs. The bad smell gained by the fabrics due
to cigarette smoke and sweat is concealed by including CD
to fabrics.
One of the critical roles of CDs is in the area of packing
industry. The presence of CD inclusion complex in the oily
antimicrobial and volatile agents helps in its coating on a
water-absorbing sheet containing a natural resin binder, which
is further used for wrapping fresh products. The usefulness of
CD as food-packing material has been confirmed with the
manufacturing of food-packaging bag using CD with ethyl-
ene-tetracyclo-3-dodecane copolymer and hinokitol as it was
odorless and showed good antifungal properties when stored
for 1 week at room temperature (Singh et al., 2002). Some of
the uses of CD in textile industry have been listed in Table 11.
CDs in separation process
As the CDs efficiently differentiate between various pos-
itional isomers, functional groups, homologs and enantio-
mers, so it is broadly used in separation science. This
capability makes them one of the most effective candidates
worldwide for a variety of separations (Schneiderman &
Stalcup, 2000). Their tendency to form inclusion complexes
with smaller hydrophobic molecules also contributes to their
usage in separation. The factor like shape, size and selectivity
of CDs exert the major impact on the separation process
(Singh et al., 2002). CDs are considered to be the ideal
candidate by molecular recognition and further promote the
complex forming ability and selectivity in various separations.
One of the main uses of CDs is as chemically bonded or
sorbed ligands in stationary phase or immobile phase during
the separation process. Presently, CDs along with its deriva-
tives are widely used in case of chiral separations. In addition,
the hydrophilic CDs have been more commonly used as buffer
modifiers in capillary electrophoresis to accomplish the
Drug Deliv, 2016; 23(3): 729–747
Conclusion References
CDs as efficient drug delivery El Ghoul et al. (2008)
systems for multiple applica-
tions in the fields of biomater-
ials and medical textiles.
Outstanding UV-protection effi- Ibrahim et al. (2013b)
cacy even after 15 washing
cycles.
Superior post-printing, using dif- Ibrahim et al. (2013a)
ferent dyestuffs and outstanding
antibacterial activities.
Anti-allergic knitted fabric/thera- Radu et al. (2013)
peutic pajamas were obtained.
chiral separation of drugs and specialty chemicals (Zhang
et al., 2011).
Besides, CDs are also greatly used in high-performance
liquid chromatography (HPLC) as stationary phases con-
nected to solid support or even as mobile phase additives in
HPLC and in capillary electrophoresis to achieve the separ-
ation of chiral compounds. CDs also have a role in various
chromatographic techniques such as affinity chromatography,
capillary zone electrophoresis, ion-exchange, thin layer chro-
matography, electrokinetic chromatography, microdialysis,
isotachophoresis, gel electrophoresis, capillary gas chroma-
tography and separation through membrane. Furthermore,
CDs help in the stabilization of an analyte, prevention of non-
specific absorption and promoting analyte detection. Besides
all the above advantages, CD also aids in microscaling of
already used separation technologies; for instance, different
capillary techniques including capillary electrophoresis,
microbore liquid chromatography and microdialysis. CDs
are also employed in bulk scale preparations mainly extrac-
tions, dialysis, foam floatation, membrane separation and
electrophoresis (De Boer et al., 2000). Table 12 lists few
examples of the role of CDs in separation process of various
drugs.
CDs as anti-infective agents
Apart from utility of CDs for efficacy enhancement of
antibiotics through encapsulation, recently these compounds
are reported for direct use as anti-microbial. Anti-infective
properties of CDs are mainly attributed to their capability to
efficiently block pore forming bacterial toxins because of
same symmetry of these molecules as the target pores.
Applicability of CDs as anti-infectives and mechanistic
insights into inhibition of toxins has been reviewed and
reported CD based inhibitors of various bacterial toxins are
enlisted recently (Karginov, 2013). At least one CD derivative
can specifically inhibit various pore forming toxins and thus
allows possibilities to develop a novel range of CD derivatives
as broad-spectrum antibiotics against various pathogens
in near future. Table 13 shows some uses of CDs for
DOI: 10.3109/10717544.2014.938839 Versatile applications of cyclodextrins 741
Table 12. Role of cyclodextrins in separation process.

Drugs Cyclodextrin used Work done Conclusion References

Racemic trans-d-viniferin HP-b-CD Preparative chiral high-speed Effective separation of TVN Han et al. (2014)
(TVN) counter-current chromatog- enantiomers.
raphy method, based on which
induced circular dichroism
spectrum was developed.
Iodiconazole (IA) HP-g-CD Chiral separation of IA and 12 new Development of proper strategy for Li et al. (2012)
structurally related triadimenol chiral separation.
analogs using capillary electro-
phoresis by HP-g-CD.
Resibufogenin and g-CD RP-HPLC using CDs as mobile Effective separation. Xing et al. (2012)
cinobufagin phase additives.

Table 13. Cyclodextrin as anti-infectives.

Drugs Cyclodextrin used Work done Conclusion References

Artemisinin (AN) b-CD Agglomerated powder dosage form Enhancement in drug Balducci et al. (2013)
for oral administration based on bioavailability.
primary microparticles contain-
ing AN/b-CD complex.
Norfloxacin b-CD The solid-state properties of com- Better understandings of the Chattah et al. (2013)
plexes of b-CD and norfloxacin molecular fragments.
at the molecular level.
Voriconazole (VA) HP-b-CD, The influence of CD complexation 2-O-methyl-b-CD was found as Miletic et al. (2013)
2-O-methyl-b-CD on VA solubility, dissolution more efficient solubilizer.
rate and chemical stability was
studied.
Zaltoprofen (ZP) 2-HP-b-CD Development of gel formulation No dermal irritation. Baek et al. (2013)
using carbomer complexed drug
and other excipients.

complexation and efficacy improvement of existing anti-
infective agents.
CDs in non-viral gene delivery
Gene delivery is the most promising area of biotechnological
research, and has already proved its capability in biomedical
applications. The parent CDs are inefficient in complexing
with plasmid DNA (pDNA), this drawback of CD limits their
transfection efficiency. To overcome this problem, CDs are
normally derivatized before using it in gene transfer. This
can be well exemplified by CD derivatives polycationic
amphiphilic CDs (paCDs; built by the change in the facial
anisotropy of the truncated-cone CD by the introducing
cationic and hydrophobic elements). By controlling the
various molecular parameters such as charge density, hydro-
philic–hydrophobic balance, nature of the functional groups
and spacer length, the complexing of DNA with CDs can
be improved finally, regulating the transfection efficiency of
paCDs (Lai, 2014).
CDs also have an important role in linking various
polymers through covalent linkage forming large molecular
structures similar to gene carriers, thereby behaving as a
linking agent. This can be well explained by the example of
polymers which were synthesized by linkage of low molecu-
lar weight poly(ethylenimine) (PEI), a cationic aziridine
polymer displaying a high proton buffering capacity over a
wide range of pH with b-CD using tosyl chloride, initially
generating an amine reactive tosyl deoxy-b-CD, which was
later reacted with PEI gives rise to the CD-PEI conjugate
(PEI-b-CD; Neu et al., 2005). Besides the parent CDs,
the derivatives of CDs have also been found to act as
linking agents. Their activity as linking agent was confirmed
when cross-linking of PEI was done by Huang et al. using
2-HP-b-CD and 2-HP-g-CD. The two resultant polymers
were better in properties as they showed lower cytotoxicity
than PEI 25 kDa, with transfection efficiency in SKOV-3
cells approximately 20 and two times greater than that
obtained by PEI 600Da and PEI 25 kDa, respectively
(Lai, 2014).
CDs are also known for its functioning as a structural
modulator since they were used to structurally modify already
prevailing gene carriers. In this, CD can fulfill the function
of both as a threading device as well as that of pendants.
The role of CD as threading agent can be better explained by
the experiments conducted by Li’s group, who have produced
large number of supramolecular polyrotaxanes, which com-
prise of cationic a-CD rings threaded and blocked on a
poly [(ethylene oxide)-ran-(propylene oxide)] [P (EO-r-PO)]
random copolymer. The function of CDs as pendants can be
explained by taking the example of vectors produced by this
method is the polyamidoamine (PAMAM) dendrimer conju-
gates with all the three parent CDs (Lai, 2014). Some of the
applications of CD in non-viral gene delivery are given in
Table 14.
CDs in bioconversion process
The proficiency of bioconversion process suffers from
certain constraints due to the inhibitory or toxic influences
742 N. Sharma & A. Baldi
Table 14. Use of cyclodextrins in non-viral gene delivery.
Cyclodextrin used Work done
Polycationic amphiphilic A novel targeted gene delivery system was
CDs (paCDs) developed and assessed.
a-CD Investigation of in vitro and in vivo gene
delivery efficiency of polyamidoamine
starburst dendrimer conjugates with a-CD.
b-CDs Nanoparticles coated with b-CD coupled to
amino acids with different surface charges
through direct ligand-exchange reactions
were synthesized and used to deliver
siRNA.
Table 15. Use of cyclodextrins in bioconversion process.
Cell culture Substrate Product
Saccharomyces cerevisiae Androstenedione Testosterone
Mucuna pruriens 17-b-estradiol 4-hydroxyestradiol
Lactobacillus bulgaricus Cholesterol Testosterone
from either the substrate or product on the biocatalyst.
Likewise, another hindrance to this process is that the
biocatalyst is most active in its natural environment,
mainly an aqueous medium, despite the fact that the majority
of organic substrates are lipophilic in nature and sparingly
soluble in water. As a result, very less amount of sub-
strate is available to the biocatalyst. Therefore, one of the
most suitable approach to overcome these inadequacies
involves the addition of CD in bioconversion. CDs have
tendency of enhancing the solubilization of organic com-
pounds, reducing the toxicity by complexation with toxins
and the biocompatibility. Representative studies on effi-
ciency enhancement of bioconversion processes using CDs
are given in Table 15.
CDs in plant cell technology
Precursor feeding has been an evident and widespread
approach to increase secondary metabolite production in
plant cell cultures. The concept is based upon the idea that
any compound, which is an intermediate in or at the
beginning of a secondary metabolite biosynthetic route,
stands a good chance of increasing the yield of the final
product (Rao & Ravishankar, 2002). The increase in product
content is probably due to enhanced availability of precursor
to the cells in a more dissolved state due to CD complexation
which resulted in more conversion to product. However, most
of these intermediates of biosynthetic pathway are poorly
soluble in aqueous media and therefore are less accessible for
bioconversion to the desired product due to their lipophilic
nature in plant cell cultures. This property confines their use
as precursors to enhance productivity. Many plant cell
cultures barely convert precursors in the presence of organic
phases, often as a result of dramatic decrease of cell viability
and reduced enzymatic activities in these systems. In order
to overcome these problems and enhance availability of water
Drug Deliv, 2016; 23(3): 729–747
Conclusion References
Suitability for cost effective production at Aranda et al. (2013)
large scale.
Establishment of Lac-a-CDE as a non-viral Arima et al. (2010)
vector for gene delivery toward
hepatocytes.
New insights into the mechanisms of amino Zhao et al. (2011)
acid mediated delivery and monitoring
of gene silencing studies.
Inference References
Bioconversion increased in the Singer et al. (1991)
presence of HP-b-CD from 27%
to 78%.
The solubility of steroid and bio- Woerdenbag et al. (1990)
conversion efficiency was
enhanced.
Increase in rate of bioconversion. Singh et al. (2002)
insoluble precursors, complexation with cyclodextrin has
been efficaciously used as a novel approach. This method
has advantages of both apolar systems (higher solubility
of substrate) and aqueous systems (maintenance of cell
viability). The culture characteristics, i.e. cell growth and
pH does not differ when only CDs are added in cultures
(Baldi, 2008). The CDs are also reported not to be
metabolized by plant cell enzymes or to serve as a carbon
source (Woerdenbag et al., 1990). Few of the studies
involving CDs for precursor availability enhancement in
plant cell cultures are given in Table 16.
CDs in catalysis
One of the most promising role of CDs is in the catalytic
reactions. They have the capability to function as enzyme
mimics. These are fabricated by changing the naturally
occurring CDs with the substitution on its primary or
secondary face with different functional groups or attaching
various reactive groups. The substituted groups attached to
the CD molecule are responsible for the molecular recogni-
tion which makes the modified CDs beneficial as enzyme
mimics (Szejtli, 1998). Morozumi et al. (1991) made use of
modified b-CD in the catalysis and further employed it for
the selective hydroxyl ethylation and hydroxyl methylation
of phenol. This chemical modification significantly enhanced
the catalytic activity with the resultant CD derivative acting
as a transamine mimic and acting as a catalyst for the reaction
in which the phenylpyruvic acid is converted to phenylalanine
(Singh et al., 2002).
The steric effects shown by CDs are held responsible for its
role in biocatalytic reactions. It acts by improving the enantio-
selectivity. The catalytic reaction can be completely stopped
or can be improved in a better way by the participation of
CD as it gets involved with the catalyst by forming inclusion
complexes (Singh et al., 2002).
DOI: 10.3109/10717544.2014.938839
Table 16. Cyclodextrins in plant cell technology.
Cell culture Precursor Product
Catharanthus roseus Methyl jasomate Ajmalicine
suspension culture
Artemisia annua sus- Methyl jasomate Artemisinin (AN)
pension culture
Vitis vinifera suspension Methyl jasomate Trans-Resveratrol
culture
Linum album suspen- Coniferyl alcohol Podophyllotoxin,
sion culture 6-methoxypodophyllotoxin
Toxicity considerations
It has been revealed from the various studies carried out
on CD and its derivatives that very limited number of
hydrophilic CDs and drug/CD complexes formed can pass
through the hydrophobic membranes like gastrointestinal
mucosa and skin. Due to this, they exhibit very less absorption
hence having no toxic effects inside the body. Therefore,
these are safe to administer orally. Unlike hydrophilic CDs,
the lipophilic methylated b-CDs can permeate easily through
the biological membranes thereby, show better absorption
approximately equivalent to 10% from the GIT. As a result of
this, oral formulations should contain less amount of hydro-
phobic CD derivatives to completely get rid of the possibility
of adverse effects, which may be caused because of these
lipophilic CDs. These CDs are incompatible for parenteral
formulations (Loftsson & Duchene, 2007). The toxicity
studies conducted on different CDs have disclosed that
a-CD and b-CD are unfit for incorporation in the parenteral
preparations so their utilization via this route should be
strictly restricted (Irie & Uekama, 1997).
Furthermore, during the animal studies, it was observed
that administration of g-CD intravenously did not show any
significant toxic effects. Large-scale toxicology studies were
compiled on two main extensively used CD derivatives, i.e.
2-HP-b-CD and SBE b-CD. There are many marketed
formulations available containing significant amount of
these two CD derivatives (Loftsson & Duchene, 2007). 2-
HP-b-CD is another better option other than a-, b- and g-CD,
which can be considered for the study as it possess improved
aqueous solubility combined with very less toxic effects.
Various animal studies done on HP-b-CD using animals such
as rats, dogs and mice reached at a conclusion that the oral
administration of HP-b-CD is well tolerated in these animals
tested with negligible toxic effects even at daily oral dosing
of 516 g for at least 14 days (Gould & Scott, 2005).
Market potential and future prospects of CDs
Besides the vast applications of CDs at the present time, CD
has ample scope in future also involving the evolution of new
CD derivatives as well as the demand of already existing
derivatives. Till date, there are more than 50 marketed
formulations, which contain CD complexes with drugs and
a range of excipients are available commercially (Szejtli,
2004; Loftsson & Brewster, 2010; Kumar Das et al., 2013).
Some representative examples are:
 The oral formulation of the drug limaprost com-
plexed with a-CD is marketed under the trade
Versatile applications of cyclodextrins 743
Inference References
Improvement in ajmali- Almagro et al. (2011)
cine production
300-fold enhancement Durante et al. (2011)
in AN content.
Increment in productiv- Belchi Navarro et al., (2012)
ity was achieved.
Increase in product Baldi (2008)
content due to CDs
by many folds.
names of Opalmon and Prorenal (Davis & Brewster,
2004).
 The sublingual preparation of nitroglycerin containing
b-CD is in the market under the trade name of Nitropen
in Japan (Zhang & Rees, 1999).
 The complex of piroxicam b-CD given via oral route is
sold in Europe under the trade name of Brexin (Brewster
& Loftsson, 2007).
 The intravenous formulation containing inclusion com-
plex of voriconazole and sulfobutylether b-CD is sold
in countries such as Europe, United States under trade
name of Vfend (Loftsson & Duchene, 2007).
 Sporanox is the marketed formulation of Europe and
United States taken orally as well as intravenously
containing complex of drug, itraconazole and
2-HP-b-CD (Kumar Das et al., 2013).
For future prospective, CDs might prove to be beneficial
to introduce some better changes with respect to formulation
or it may help in drug delivery of protein, peptide and
oligonucleotide dosage forms. The problem of agitation-
associated aggregation in a mixture of a number of proteins,
including human growth hormone, as well as lyophilization
related aggregation of interleukin-2 (IL-2) can be overcome
by the use of HP-b-CD together with other hydrophilic
and lipophilic CD derivatives (Davis & Brewster, 2004). The
physical and chemical deterioration of insulin formulation
can be prevented by the use of CDs (Brewster et al., 1989).
Therefore, it is responsible for the stabilization of insulin
formulations. This is mainly related to the fact that by the
interactions with readily available hydrophobic amino acid
residues CDs stabilizes the protein conformation. CDs are
also known to interact with aggregated/denaturated proteins
resulting in natural refolding, thus acting like an artificial
chaperones. One more future application of CD lies in its
role in enhancing the cellular delivery of oligonucleotides.
The uptake of phosphorothiolate oligodeoxynucleotides by
human T-cell leukemia cells (H9) is upgraded several folds
with the use of HP-b-CD. Moreover, ability of CD to complex
is helpful in decreasing the immunogenicity of oligonucleo-
tides as well other undesirable side effects of oligonucleotide
administration comprising of the effects of macromolecules
on platelet count. Besides its increasing demand as drug
carriers, CDs are helpful in extraction of various compounds.
Efforts have been made to merge CDs together with polymers
and small molecule drugs to limit the amount of CD used
along with the release rates of the drug. Biodegradable
polymers including complexes of CDs and antibiotics have
been formulated and these have showed promising results
744 N. Sharma & A. Baldi
in the production of bacteria-resistant films and fibers. More
advancement is occurring, most important being the discov-
ery of many new CD derivatives. Recently, CDs consisting
of quaternary amine groups have been found to act as
multifunctional agents in ophthalmic formulations. Earlier
also, CDs were included in eye drops as an important
ingredient, e.g. eye drops of 2-HP-b-CD complexed indo-
methacin and RAME-b-CD complexed chloramphenicol,
which contain as a complexing agent (Loftsson &
Stefansson, 2002; Halim Mohamed & Mahmoud, 2011).
Despite of advancements for more than 100 years and great
commercial success, CDs still holds many unexplored poten-
tial in diverse facets of science and technology, which should
be tapped in future by researcher across the globe.
Conclusion
CDs have been known worldwide and are very beneficial
additive used in the pharmaceutical and other industries.
All the advantages of the CD have been attributed to its
tendency of complexing with varied drug molecules resulting
in the formation of inclusion complexes. This interaction
between CD and drug is host–guest type, i.e. it acts like a
host and drug molecule (guest) gets partially or completely fit
into its lipophilic cavity to form a complex. This single
interaction is sufficient to change the physiochemical and
pharmaceutical properties of the drug molecule in the form
of enhanced water solubility of drugs further improving
the bioavailability of the drug, better stabilization of drugs
under the conditions such as light, heat and oxidizing
conditions, i.e. avoids the deterioration of drugs in these
sources and also reduction in the volatility of drugs.
Therefore, all these improvements brought about in the drug
characteristics depict the great potential of the CD as most
advanced drug delivery system. Despite the fact that CDs are
known and are used pharmaceutically since decades, in the
recent times many more applications of CD have emerged
apart from its usage in enhancing solubility and maintaining
the stability of various drugs. CDs have a function as
penetration enhancer. The hydrophobic CDs help in the
permeation of the drugs through the biological membranes.
One of the most important applications of CD known from the
different experiments carried out in humans and animals
as well is enhancing the drug delivery of majority of the
formulations. CDs help in the delivery of sustained release
preparations to be delivered via different possible routes.
Most of the research conducted has revealed that the
hydrophobic and ionizable CDs derivatives are mainly used
as drug carriers in the delivery of sustained-release or delayed
release formulations. The property of CDs to complex with
various drugs is the ultimate solution to the various issues
related to drug delivery. In addition to all these aspects, gene
therapy continues to develop the interest of researchers.
For the non-viral delivery of nucleic acids, CD containing
polycations are used. Even though these agents have
given promising results for gene delivery in animals, but no
conclusions have been made in case of humans. CDs are
also known for acting as molecular chelating agents with
huge demand in the area of food, pharmaceuticals and
chromatographic techniques established. CDs are also known
Drug Deliv, 2016; 23(3): 729–747
worldwide for its role as toxicity modifier. CDs have
improved biocatalysis reactions by increasing enantio-
selectivity. Seeing such vast applications of CDs in number
of bioprocesses, further survey and research on CDs should
be done at small as well as on large scale to investigate its
role in various other fields. Hence, it can be concluded that
because of its distinctive structural features, CDs are the most
demandable and important requirement of the researchers in
the drug development, in various separation procedures, as
enzyme mimics and most importantly as a complexing agent
in pharmaceutical, food, cosmetic and many other industries.
Acknowledgements
We are thankful to Praveen Garg, Chairman, ISFCP, Moga,
Punjab for providing necessary facilities.
Declaration of interest
The authors report no declarations/conflicts of interest.
Financial assistance provided by Punjab State Council for
Science and Technology, Chandigarh is gratefully
acknowledged.
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