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Journal of Controlled Release 123 (2007) 78 99



The utility of cyclodextrins for enhancing oral bioavailability

Rebecca L. Carrier a,, Lee A. Miller b,1 , Imran Ahmed c,2

Department of Chemical Engineering, Northeastern University, 457 Snell Engineering Center, Boston, Massachusetts 02115, United States
Pfizer, Inc., 2800 Plymouth Road, Ann Arbor, Michigan 48105, United States
Pfizer, Inc., Eastern Point Road, Groton, Connecticut 06340, United States
Received 18 April 2007; accepted 30 July 2007
Available online 16 August 2007

Cyclodextrins (CD) have been utilized extensively in pharmaceutical formulations to enhance oral bioavailability. A critical review of the
literature in which cyclodextrins were utilized for this purpose was conducted. The goal of this review was to determine if quantitative guidelines
for drug and cyclodextrin properties necessary for bioavailability enhancement using cyclodextrins could be extracted. Twenty-eight studies were
examined in which the focus was on the use of cyclodextrins as solubilizers to enhance bioavailability. Commonly observed factors included:
utilization of pre-formed complex rather than physical mixtures, drug hydrophobicity (logP N 2.5), low drug solubility (typicallyb 1 mg/ml),
moderate binding constant (b 5000 M 1), low dose (b 100 mg), and low CD:drug ratio (b 2:1). These general guidelines, however, did not apply
to all studies. Quantitative guidelines useful to a formulation scientist considering the use of cyclodextrins were difficult to develop due to missing
information and the complicated manner in which drug and cyclodextrin properties interact to influence key drug delivery processes (e.g.,
dissolution, absorption). The mechanisms by which cyclodextrins influence these processes, again emphasizing solubilization capabilities, are
discussed to provide further insight into why cyclodextrins will increase bioavailability in certain cases but not influence or possibly decrease
bioavailability in others.
2007 Elsevier B.V. All rights reserved.
Keywords: Cyclodextrins; Solubilization; Bioavailability; Modeling; Formulation


Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Characteristics of studies utilizing cyclodextrins to enhance oral bioavailability . . . . .
2.1. Reported influence of cyclodextrins . . . . . . . . . . . . . . . . . . . . . . .
2.2. Properties of compounds whose bioavailability is enhanced using cyclodextrins.
2.3. Use of complex vs. physical mixture of drug and cyclodextrin . . . . . . . . .
2.4. Complex formation methodology . . . . . . . . . . . . . . . . . . . . . . . . .
2.5. Immediate vs. controlled release . . . . . . . . . . . . . . . . . . . . . . . . .
2.6. Ionized vs. neutral drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7. Dose and molar CD:drug ratio . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8. Type of CD used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.9. Binding constant magnitude . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.10. Interaction with polymers and other formulation components . . . . . . . . . .












Corresponding author. Tel.: +617 373 7126; fax: +617 373 2209.
E-mail addresses: r.carrier@neu.edu (R.L. Carrier), lee.a.miller@pfizer.com (L.A. Miller), imran.ahmed@pfizer.com (I. Ahmed).
Tel.: +734 622 3628; fax: +860 686 6209.
Tel.: +860 441 4281; fax: +860 715 9575.
0168-3659/$ - see front matter 2007 Elsevier B.V. All rights reserved.













R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899


Explanations for ability of cyclodextrins to enhance bioavailability . . . . . .

3.1. Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Enhancement in dissolution kinetics . . . . . . . . . . . . . . . . . .
3.3. Increase in solubility . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4. Decrease in degradation kinetics . . . . . . . . . . . . . . . . . . . .
3.5. Change in intestinal membrane properties . . . . . . . . . . . . . . .
3.6. Shuttling and enhancement of drug concentration at the intestinal wall
4. When cyclodextrins do not enhance bioavailability . . . . . . . . . . . . . .
4.1. Binding constant magnitude and amount of dosed cyclodextrin . . . .
4.2. Degradation of cyclodextrins in the intestinal environment . . . . . . .
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
Cyclodextrins have been used extensively in pharmaceutical
research and development, and there are currently over 30
marketed cyclodextrin-containing pharmaceutical products
worldwide [1,2]. Cyclodextrins possess a special ability to
complex with drugs enabling them to increase solubility, reduce
bitterness, enhance stability, and decrease tissue irritation upon
dosing [3]. One of the most common applications of
cyclodextrins cited in the pharmaceutical literature is the
enhancement of bioavailability. When can cyclodextrins be
used to enhance oral bioavailability of a given compound? One
approach to addressing this question, taken in the present
review, is to seek guidance by examining the vast body of
literature in which cyclodextrins have been utilized to enhance
bioavailability. There are numerous excellent reviews on the use
of cyclodextrins in oral dosage forms, and many which
specifically address the effect of cyclodextrins on oral
absorption and/or bioavailability [111]. One recent review
by Loftsson et al. examines over 80 publications on the effect of
cyclodextrins on oral bioavailability of 50 different drugs using
17 different cyclodextrins in the context of the Biopharmaceutical Classification System [1]. The importance of drug
solubility and permeability is emphasized. Here, multiple
aspects of studies in which cyclodextrins were utilized to
enhance bioavailability were analyzed to gain further insight
into which physical and chemical properties of drug, cyclodextrin, dosage form, and delivery environment are suitable to
allow enhancement of bioavailability. The specific values of
drug and cyclodextrin properties as well as experimental
parameters (e.g., drug to cyclodextrin ratio, animal species
used) were studied for apparent trends.
As indicated by the large number of reviews on this topic, the
literature affords an abundance of references demonstrating the
use of cyclodextrins to enhance oral bioavailability of active
compounds. These studies have utilized a range of natural
cyclodextrins and cyclodextrin derivatives, numerous animal
species (including human), and various dosing vehicles, dose
levels, and cyclodextrin-to-drug ratios. The vast majority of
these studies demonstrate a positive affect of inclusion of
cyclodextrin in a dosed formulation. Most of the studies































attribute the influence on bioavailability to the solubilizing

capabilities of cyclodextrins, although some also discuss other
cyclodextrin effects, such as effects on physical or chemical
stability [1215]. Typically, the complex or physical mixture of
drug and cyclodextrin is dosed, and the resulting pharmacokinetic parameters are compared to those resulting when the drug
alone or in a commercial formulation is dosed. Given the wide
range of experimental parameters utilized in these studies and
the fact that most of them report positive results, the question
arises: Is it possible to gain insight into the important parameters
that determine the success or failure of bioavailability
enhancement with cyclodextrins from reviewing a finite number
of studies?
In this critical review, a survey of the literature reporting use
of cyclodextrins to enhance oral bioavailability is conducted.
Some of the important attributes of these studies are discussed
to give insight into key physical and chemical properties of the
drug, cyclodextrin, and dosage form that allow bioavailability
enhancement to occur. Physical mechanisms of bioavailability
enhancement using cyclodextrins are then discussed to provide
further understanding of why these parameter values are
important and how successful bioavailability enhancement
using cyclodextrins can be achieved. It should be noted that
while recent applications of cyclodextrins have included their
use for stabilizing protein, peptide, and nucleic acid therapeutics [2,8,11], the focus in this review is on the exploitation of
the solubilizing capacity of cyclodextrins for the delivery of
small molecular weight (typically b 500 Da) compounds.
However, much of the discussion of the influence of
cyclodextrins on the bioavailability of low molecular weight
compounds generally applies to biomolecules, with certain
additional mechanisms of action on biomolecules (e.g.,
prevention of protein aggregation or enhancement of endosomal membrane disruption in gene delivery) not emphasized in
this review [11]. In addition, cyclodextrins have been utilized
for a number of different drug delivery routes, and there has
been a large amount of recent investigation into cyclodextrin
polymers and cyclodextrins conjugated to other delivery
vehicles (e.g., nanoparticles, liposomes) [9]. However, the
current discussion is focused on oral drug delivery using
cyclodextrin monomers.


R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

2. Characteristics of studies utilizing cyclodextrins to

enhance oral bioavailability
2.1. Reported influence of cyclodextrins
Most of the literature on bioavailability enhancement using
cyclodextrins includes similar data [5]. Phase-solubility diagrams are often used to determine the stoichiometry of binding
and the equilibrium binding constant. NMR-spectra, X-ray
diffraction patterns, and DSC thermograms are typically used to
measure changes in the characteristic analytical features of a
drug molecule upon complexation as an indication that a
complex has been formed. Dissolution profiles for the drug,
physical mixture of drug and cyclodextrin, and/or complex of
drug and cyclodextrin are often presented to demonstrate the
influence of cyclodextrin on dissolution kinetics and the total
amount of drug in solution [16]. In addition, pharmacokinetic
parameters resulting from dosing a physical mixture of drug and
cyclodextrin or a pre-formed complex in comparison to drug
alone are often presented to demonstrate an overall improvement
in bioavailability upon dosing with cyclodextrin. These studies
often involve compounds with poor or variable bioavailability
and cite low solubility or slow dissolution kinetics as reasons for
bioavailability issues [1624]. The variability of pharmacokinetic and pharmacodynamic responses to drugs has been
reported to decrease with the inclusion of cyclodextrins in
dosage forms [25,26]. Pharmacokinetic responses to lowsolubility compounds are characteristically highly variable in
the absence of a solubilizing agent [17], and the ability of
cyclodextrins to solubilize drugs probably contributes to lower
response variability. Some studies also include information on
degradation rate of the studied compound and how it is
influenced by cyclodextrin. The reported increase in bioavailability is typically expressed as a change in an area under the
plasma concentration vs. time curve (AUC) value, a change in
the time to reach maximum plasma levels of the given compound
(Tmax), and/or the maximum plasma level achieved (Cmax)
[23,24,2628]. In some studies, the pharmacodynamics are
reported in addition to or in place of the pharmacokinetic
changes brought about by inclusion of cyclodextrin in a dosage
form, demonstrating that cyclodextrins can improve the efficacy
of a given dose of a therapeutic agent [25,29,30].
For the current review, twenty-eight randomly selected
articles from the literature in which cyclodextrins were utilized
to enhance bioavailability were examined in an effort to develop
a greater understanding of when cyclodextrins can be used for
bioavailability enhancement [12,17,18,20,2228,3046]. Specifically, the different properties of these studies were compared,
including the properties of the drug compounds utilized, the
properties of the cyclodextrins, the design of the dosage forms,
and the details of the experiment (e.g., animal species used,
manner in which material was dosed). The studies were selected
based on the information they provided and/or the ability to
obtain missing information from other literature sources so that
all studies could be compared [5,15,16,19,21,35,4762]. Table 1
compares some of the key aspects of studies conducted in which
cyclodextrins were used to enhance bioavailability, and Table 2

summarizes these same factors for experiments where it was

indicated that cyclodextrins were not successful in enhancing
bioavailability. The discussion below is focused on observations
resulting from the review of these articles, although many of the
comments apply to the cyclodextrin literature in general, and
several articles in addition to the twenty-eight studied in detail
are referenced. Again, it is emphasized that the articles examined
focused mainly on the solubilizing capabilities of cyclodextrins
for small molecular weight compounds. In other words, their
focus was not on other possible mechanisms of bioavailability
enhancement using cyclodextrins (discussed below) or the use of
cyclodextrins to influence delivery of peptides, proteins, or
nucleic acids, as has been the focus of much recent literature.
The studied articles contained a total of 58 comparisons made
between a dosed formulation containing cyclodextrins and one
that did not. Of these comparisons, 52 showed evidence of
bioavailability enhancement using cyclodextrins (as indicated
by a change in AUC or a similar parameter as noted in Table 1),
while 6 showed no change with inclusion of cyclodextrins. The
prominence of studies showing bioavailability enhancement
using cyclodextrins may be related to the tendency for positive
results to be reported more frequently than negative results. It is
also likely that drugs selected for studies with cyclodextrins tend
to possess qualities which make them candidates for solubilization (i.e. low solubility).
As can be seen in Table 1, about half of the increases in AUC
values were less than 100% increases. Of 47 studies where a
change in AUC (or a similar parameter as noted in Table 1) was
reported, 24 of those studies resulted in a ratio of AUC with
cyclodextrin to AUC without cyclodextrin between 1 and 2,
while 22 resulted in a ratio of 28 and one resulted in a ratio of
46. Increases in AUC brought about by utilizing cyclodextrins
with drug are accompanied by both increases and decreases in
Tmax and Cmax values [24,25,28]. This implies that when the
overall exposure to a compound is increased by inclusion of
cyclodextrin in a dosage form, the accompanying kinetics of
drug absorption in the intestine may increase or decrease. In
Table 1 there are 28 reported decreases in Tmax, 5 reported
increases, and 6 reports of no change. Most of the increases in
Tmax were of less than 3h. The fact that most studies reported a
decrease in Tmax with inclusion of cyclodextrin is logical in
light of the fact that cyclodextrin speeds up dissolution kinetics,
as described in more detail later in this review. An increase in
Tmax could be due to precipitation of a low solubility dosed
complex or decrease in free drug concentration in the intestinal
lumen because of binding to cyclodextrin. In Table 1 there are
38 reported increases in Cmax and one reported decrease. Most
increased Cmax values were less than double the control value,
and all except for two reported increases were less than ten
times the control value. There was no clear correlation between
magnitude of increase in Cmax or change in Tmax and magnitude
of increase in AUC (data not shown). The increase in Cmax is
logical as cyclodextrins speed up dissolution, and higher levels
of drug in solution in the intestine typically result in greater drug
absorption. It has been noted that when an increase in blood
plasma levels for a given compound is not desired, cyclodextrin
can be used to decrease the required dose [63].

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899


2.2. Properties of compounds whose bioavailability is

enhanced using cyclodextrins

constant, cyclodextrin:drug ratio, dose, possible influence of

cyclodextrin on intestinal permeability or efflux, etc.).

An obvious requirement for cyclodextrins to be a suitable

technology for bioavailability enhancement is the formation of a
complex between drug and cyclodextrin. Specific exceptions
include cases where cyclodextrins such as dimethyl betacyclodextrin (DM--CD) inhibit efflux by P-glycoprotein (Pgp) or metabolism by multi-resistant protein 2 (MRP2) or
proteolytic enzymes [64], or cases where drug is covalently bound
to cyclodextrin for site-specific delivery [65,66], but these
specific effects were not discussed in any of the studies presented
in Table 1. General guidelines on what molecules will complex
with cyclodextrin based on molecular properties are given in the
literature [67]. Drug-cyclodextrin complexation usually involves
interaction of hydrophobic moieties on drugs and the pocket of the
cyclic cyclodextrin molecule. Consideration of the calculated
octanolwater partitioning coefficient (clogP) values of the
compounds in Table 1 and examination of their structures (Fig. 1)
demonstrates the predominance of hydrophobic compounds
employed in studies reporting enhanced oral bioavailability
using cyclodextrins. 18 of the 29 studies examined involved
compounds with logP values greater than 2.5. In addition to
having a greater likelihood of complex formation, hydrophobic
compounds generally have low solubility and are more likely to
be dissolution rate-limited (as opposed to absorption rate-limited)
in overall absorption kinetics. The formulator should keep in mind
that if a factor other than dissolution kinetics is resulting in poor
bioavailability (e.g., low permeability of the intestinal membrane
to the compound being studied), it is unlikely that formulation
with cyclodextrins will result in bioavailability enhancement.
Most of the compounds listed in Tables 1 and 2, although
they are not salt forms, will be ionized during at least a portion
of gastrointestinal (GI) transit, as indicated by their pKa values.
This is important as the charge on the drug molecule can
influence its binding with cyclodextrin. Thus, the cyclodextrin
may influence the dissolution and solubility of the compound to
different extents in different areas of the GI tract. This fact
increases the complexity of comparing studies as listed in
Tables 1 and 2. If two compounds were used in the exact same
study and all properties of the compounds were identical except
for pKa values, they may achieve different bioavailability due to
variable binding with cyclodextrin during GI transit. The pKa
value will also influence the solubility of the compound at a
given pH, influencing the total amount of drug that can be in
solution in both free and complexed forms. Thus, both
unbuffered water solubilities and solubilities at specific pH
values, when available, are listed for the compounds in Tables 1
and 2. Most of the compounds have water solubilities of less
than 0.1 mg of drug/ml, indicating that dissolution may be a
limiting factor in drug absorption, but greater than 1 g/ml. The
critical solubility for drugs to exhibit dissolution limited drug
absorption from the GI tract has been reported as 0.1 mg/ml
[68]. The fact that some of the drugs listed in Table 1 have
solubilities greater than 0.1 mg/ml emphasizes the importance
of considering the complex interaction of multiple factors that
could determine the influence of cyclodextrins (e.g., binding

2.3. Use of complex vs. physical mixture of drug and cyclodextrin

As can be seen in Table 1, the vast majority of studies in
which cyclodextrins are utilized to enhance oral bioavailability
have employed the complex rather than the physical mixture of
the given drug with cyclodextrin. When the physical mixture
was used, it typically resulted in a significantly lower level or
complete lack of bioavailability enhancement. Of the six studies
reviewed in which physical mixtures of drug and cyclodextrin
were dosed, two did not show bioavailability enhancement
[26,46], and bioavailability enhancement was moderate (1.1 to
1.5 increase in AUC) for the other studies [18,20,36,41]. AUC
increases were approximately doubled for complexes vs.
physical mixtures of single compounds, and this is often
accompanied by greater decreases in Tmax and greater increases
in Cmax. This is likely related to decreased enhancement in
dissolution kinetics observed when the physical mixture rather
than the complex is utilized (see Explanations for the ability of
cyclodextrins to enhance bioavailability below). Several
studies have shown that a physical mixture of cyclodextrin
and drug exhibits dissolution kinetics either similar to or only
slightly greater than those of drug alone, and almost always
slower than those of the complex [23,6971]. It has been
documented that physical mixing of drug and cyclodextrin,
especially with addition of energy (e.g. from grinding) can
result in some complex formation [72,73]. However, it is clear
upon analysis (e.g., via DSC) that the majority of the mixed
material is still pure parent substances (rather than complex)
[20,24,36]. Thus, there is still likely to be a difference between
physical mixtures and pre-formed complex formations.
The much more common use of complexes rather than
physical mixtures indicates that it is generally expected that
formulations of physical mixtures will not enhance oral
bioavailability to the same extent as formulations of complexes.
An exception comes in the patent literature, where Stella et al.
claim that sulfoalkyl ether cyclodextrins formulated as both
physical mixtures with drug and complexes can be used to
equivalently enhance dissolution, solubility, and/or bioavailability [74,75]. These patents as well as published papers [76
80] give several examples of controlled-release tablet formulations containing physical mixtures with dissolution kinetics
similar to those containing complexes. However, they do not
present actual in vivo bioavailability data to support the
equivalence of physical mixtures and complexes in vivo. In
addition, it is stated in these papers and patents that an
appropriate dosage form will allow hydration of the drugcyclodextrin physical mixture within the dosage form to ensure
adequate formation of the complex. It is possible that the high
solubilities of sulfoalkyl ether cyclodextrins allow substantial
amounts of cyclodextrin to be in solution in the hydrated oral
controlled-release drug delivery device (e.g., matrix or osmotic
tablet). If the hydrated cyclodextrin and drug are present at
sufficiently high concentrations, there could be appreciable
complex formation prior to release from the drug delivery


Table 1
Summary of drug, cyclodextrin, and dosage form parameters for studies in which cyclodextrins were successfully utilized to enhance bioavailability

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

(continued on next page)


Table 1 (continued )

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

A = Acidic, B = basic, soln. = solution, clogP = calculated logP value, calculated using Advanced Chemistry Development (ACD/Labs) Software Solaris V4.67 (data from SciFinder). * = Calculated using Advanced
Chemistry Development (ACD/Labs) Software Solaris V4.67 (data from SciFinder). ** = Apparent 1:1 binding constant. Unless otherwise noted, the comparison and test dosage forms were the same with the
complex or physical mixture replaced by drug. UCD CD:drug is based on water solubility, unless otherwise specified, and on 1:1 complex formation and apparent 1:1 binding constants. Lines separating rows separate
studies. Shaded rows correspond to reports that explicitly mentioned the influence of CD on the stability of the compound.

Table 2
Summary of drug, cyclodextrin, and dosage form parameters for studies in which cyclodextrins were not successfully utilized to enhance bioavailability
Drug (species) pKa

6.18e 3 (pH 7.4);

2.3 4 (pH 3.0)

Glibenclainide 5.3 (A) 3.93

[26] (dog)

[38] (rabbit)

4.2(A) 3.11

Naproxen [19] 44 (A) 3.0


Rutin [12]

[46] (rabbit)

6.8(A) 2.23



Complex Dose Dosed

formation (mg) CD:




CD type, Binding Other
dosage form
CD:Drug constant formation
(M 1)

AUC increase Tmax
change change
(x AUC


No change


b3.578 (pH 1,4); N3.578, Complex Freezedrying

b35.78 (pH 7,8),
N35.78,b357.8 (pH 10)



(K = 5300), 1:1
(K = 523)

(pH 4)

b2.30 (pH 1,4); N23.03,

b230.3 (pH 7,8); N230.3
(pH 10)




.045 [59] b6.11 (pH 1,4,7,8);

N61.05,b610.5 (pH 10)


b2.70 (pH 1,4); N2,70,

b27.04 (pH 7); N27.04,
b270.4 (pH 8); N270.4
(pH 10)

Complex Freezedrying

Complex Slurry


100/ 1:1


(pH 7.4) capsule,
dosed with

Drug (in
with water)

Dosed with Freeze[51],
dried drug
523 [57]
(with water)

No change

(pH = 1,
25 C)


No change




2:1 [45]

196 [45]


Drug (in
gelatin capsule)
drug (in gelatin

No change

No change
replaced by drug)


No change



R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

clogP Water
Buffered solubility
MW solubility (mg/mL)

Notations are the same as those described for Table 1.



R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

Fig. 1. Structures of compounds used in studies, summarized in Tables 1 and 2, where cyclodextrins were employed to enhance bioavailability.

device, and it would thus be likely that devices formulated with

physical mixtures of these highly soluble cyclodextrins would
perform in vivo in a similar fashion to devices formulated with
complexes. It should be noted that formulation with a physical
mixture rather than a complex is desirable from a processing
viewpoint, since the steps involved in making the complex
could be skipped in the manufacturing process.

2.4. Complex formation methodology

While most studies utilizing cyclodextrins to enhance
bioavailability employ a drug-cyclodextrin complex, the
method of preparation of the complex varies, as can be seen
in Table 1. Investigators have used freeze-drying, spray-drying,
and co-precipitation of a cyclodextrin/drug solution, as well as

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

simple grinding with a mortar and pestle of a slurry of drug and

cyclodextrin [81]. The method of preparation of the complex
can greatly influence the dissolution kinetics, and, presumably,
the bioavailability enhancement obtained with a complex
[23,39,40,71]. This is logical in light of the fact that certain
methods of preparation can result in more or less complex
formation, a factor that is rarely quantified, as well as changes in
the particle size and degree of amorphous nature of the resulting
material, although the cyclodextrin-drug complex is often
amorphous. Material with a smaller particle size (greater surface
area per unit volume of material) and amorphous material will
generally have faster dissolution kinetics. These differences in
complex formation methodology, therefore, make it somewhat
difficult to make clear comparisons between studies. In some
studies, the particulate matter resulting from complex formation
has been sieved so that only a specific particle size was used in
the study [12,3840]. Care has been taken in some studies to
subject the comparator formulation (e.g., drug alone) to the
same processing as the complex, minimizing effects of
processing on any observed increases in dissolution kinetics
or bioavailability [38].
2.5. Immediate vs. controlled release
All studies referenced in Tables 1 and 2 and most studies
employing CD to enhance bioavailability in general have
involved immediate release dosage forms. There are several
examples of the use of cyclodextrins in controlled-release
dosage forms in the literature, but unfortunately very little
information on their affect on bioavailability. Cyclodextrins
have been shown to both increase and decrease the rate of drug
release from controlled-release devices. Increases in release rate
could be due to increase in solubility of the complex relative to
the drug alone and associated increase in drug in solution in the
releasing device. Decreases have been attributed to the
decreased diffusivity of the bulky complex relative to the
drug alone. Giunchedi et al. used complexation of the insoluble
drug naftazone with beta-cyclodextrin (-CD) and hydroxypropyl beta-cyclodextrin (HP--CD) to enhance dissolution
kinetics from hypromellose matrix tablets [82]. The influence of
cyclodextrin on prednisolone and carbamazepine release from
hydroxypropylmethylcellulose (HPMC) matrix tablets has been
investigated [21,79], and it was found that cyclodextrin
increased drug dissolution rate, with the increase being greater
when the drug and cyclodextrin were formulated as a complex
rather than a physical mixture. Quaglia et al. [83] reported that
inclusion of cyclodextrin in a formulation of nicardipine in
crosslinked polyethylenglycol (PEG) hydrogels decreased
release rate. The authors attributed this result to the decrease
in the diffusivity of drug when it is complexed to cyclodextrin
(due to increase in effective molecular size), and quantitative
treatment of this phenomenon was presented. Similarly,
Sangalli et al. [84] found that inclusion of -CD hindered
release of poorly soluble drugs from hydrophilic matrices
(HPMC) relative to matrices containing drug and lactose, while
it increased release rate from inert matrices (acrylic resins). This
result was attributed to the complex having difficulty diffusing


through the matrix of hydrophilic polymer chains in the

hydrated HPMC tablet. In one study, the gel-forming properties
of HP--CD were utilized to design a controlled-release matrix
for metoprorol [85].
Cyclodextrins have also been used in osmotic systems to
enable delivery of low solubility compounds. In a patent of
Stella et al., examples of controlled-release formulations
containing cyclodextrins, including multilayer tablets and
osmotic formulations, are presented [75]. This same patent
provides examples from the literature of the use of cyclodextrins
in controlled-release formulations. In a separate reference,
Stella et al. discuss the relative importance of osmotic and
diffusional components of release kinetics in osmotic pump
tablets containing cyclodextrins [86]. It has been demonstrated
that certain cyclodextrins, especially sulfobutyl ether cyclodextrins, can have sufficient osmolality to act as osmotic agents in
an osmotic tablet, and the factors affecting release in
cyclodextrin-containing osmotic tablets have been studied
[7678,87,88]. Hydrophobic cyclodextrins have been utilized
in controlled-release formulations mainly as the controlledrelease agent, as they slow the release of soluble active
components [13,63,66]. Enteric type cyclodextrins have been
used to prevent drug release in the stomach [89]. Covalent
linkage with hydrophilic cyclodextrins (as opposed to noncovalent interactions typically involved in complex formation)
has been used to provide site-specific release in the cecum and
colon, where the covalent cyclodextrin-drug link is broken by
microflora enzymatic activity [66,90]. For example, covalent
bonding of -cyclodextrin has been utilized to target drug
release to the colon [90].
Special consideration of the use of cyclodextrins in oral
controlled-release dosage forms is warranted as they are
typically designed to release drug throughout a portion of GI
transit, and the variable GI environment can alter the influence
that cyclodextrin ultimately has on drug solubility. As a dosage
form travels through the GI tract, the changes in physiological
environment (e.g., pH, water content, bile salt concentration,
motility) can influence the dissolution kinetics and solubility of
drugs, cyclodextrins, and complexes, especially, as mentioned
above, if the drug and/or cyclodextrin is likely to change its
ionization state with the changes in physiological pH that occur
in the GI tract. The stability constant of the complex is also
dependent on pH, especially if the drug is ionizable [26,30,63].
A charge on a drug can offset the affinity of the hydrophobic
portion of the molecule for the cyclodextrin cavity. Thus, the
change in pH during GI transit can influence the strength of
drug interaction with cyclodextrin and ability of cyclodextrin to
solubilize the drug. It is therefore expected that a dosage form
that slowly delivers drug during GI transit may demonstrate
different pharmacokinetic changes with the inclusion of
cyclodextrin than a dosage form that delivers all drug
effectively at one time to the upper GI tract. Supporting
evidence for this statement is found in comparing bioavailability enhancement observed with dosing to different areas of the
GI tract. When carmofur complexed with DM--CD, trimethyl
beta-cyclodextrin (TM--CD), and -CD was dosed orally to
rabbits, increases in AUC of 7.5, 3, and 3 times, respectively,


R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

were seen over the AUC resulting from drug dosed alone.
However, when the same complexes were dosed rectally, only
the DM--CD showed a dramatic increase in AUC over drug
alone (3.3, 1.4, and 1.2 times the control for DM--CD, TM-CD, and -CD, respectively) [28]. The change in magnitude of
bioavailability enhancement could be related to the lower water
content or higher pH in the rectum compared to the upper
intestine altering the amount of complex formation. In a
different study, indomethacin labeled with 14C was dosed alone
or as a complex with -CD. When dosed to the small intestine,
56% of a dose of indomethacin alone was absorbed in the small
intestine, while 6% was absorbed when dosed to the large
intestine. However, in the case of complexed indomethacin,
absorption values were 68 and 66%, respectively, demonstrating a more pronounced influence of complexation on absorption
in the lower GI tract [91]. In a study aimed at improving oral
bioavailability of artemisinin through complexation with - and
-cyclodextrin, the statement was made that colonic absorption
was poor and negligible regardless of whether or not the
compound was complexed [27]. It was clear in the cited study
that the comparator for the dosed complexes, the commercial
formulation Artemisinin 250, stopped being absorbed approximately at the time it reached the colon, with percent absorption
leveling off at 60% of the dose. However, in the cases of the
complexes, nearly 100% of the dose was absorbed by the time
the dosage form reached the colon, making it difficult to draw
any conclusions regarding the influence of cyclodextrin on
absorption in the colon. Several other studies have demonstrated enhanced bioavailability using cyclodextrins of rectally
dosed compounds [5,63,92]. It is evident from the studies cited
above that there is not a clear understanding of the relative
ability of cyclodextrins to enhance bioavailability in the lower
GI compared to the upper GI. Such information, especially for
compounds that have very different solubilities at the pH of the
lower and upper GI, would be particularly useful to the
formulation scientist attempting to formulate controlled-release
dosage forms containing cyclodextrins.
2.6. Ionized vs. neutral drugs
As demonstrated in Table 1, most studies to date utilizing
cyclodextrin to enhance oral bioavailability did not utilize salt
forms of active compounds or consider the ionized state of the
compound upon dosing. This statement is based, however, on
lack of mentioning in the references of the use of a salt form, and
it is possible that specific information related to use of salt forms
may have been omitted from some references where they were
actually used. It is noted that all compounds listed in Table 2 will
be ionized in the small intestines (pH 5 to 7), while only a portion
of those listed in Table 1 will be. As described above, the ionized
state of the active compound and the presence of counterions are
likely to affect the drug's binding constant with cyclodextrin
[9395], and a decrease in binding constant with ionization of
drug is often observed. An opposite effect can be observed,
however, in cases where a charged cyclodextrin derivative (e.g.,
anionically charged sulfobutyl ether beta-cyclodextrin (SBE-CD)) interacts with a drug of opposite charge [95]. It has also

been demonstrated that a salt form of a compound can exhibit a

greater binding constant with cyclodextrin than the free base
drug, and it is believed this is due to the association of the
counterion with the charged drug in the complex [94]. In the case
of ziprasidone, the binding constant of the complex of the
ziprasidone mesylate ion pair with SBE--CD was 7892 M 1
compared to 957 M 1 for the complex with the dissociated ionic
compound. A lower binding constant due to charge does not
necessarily mean that cyclodextrins cannot be used to solubilize
a compound. In fact, a combination of pH adjustment (used to
deliver drug in an ionized and more soluble state) and
complexation with cyclodextrin has been used to successfully
solubilize compounds [96].
Quantitative consideration has been given to the influence of
the ionized state of the drug on binding constant and utility of
cyclodextrin to solubilize the drug [93,96]. Rao and Stella [93]
demonstrate theoretically that the decrease in binding constant
associated with charge on a compound relative to the binding
constant with the neutral compound (ranging in the studies
considered from 40-fold to no appreciable decrease [9599]) is
often outweighed by the accompanying increase in solubility of
the ionized compound. Another consideration of the synergism of
ionization and complexation is given by Li et al. [97]. The authors
derive the theoretical increase in total drug solubility with ionization and complexation and provide experimental validation.
2.7. Dose and molar CD:drug ratio
Examination of the typical drug and cyclodextrin properties
and doses used in studies where cyclodextrins were shown to
enhance bioavailability reveals that the majority of the doses
used were relatively low (b 100 mg in 25 out of 29 studies).
Many of the studies dosed drug as a suspension or a powder with
water, enabling a greater dose than would be possible in a
conventional oral dosage form such as a tablet or capsule. The
use of cyclodextrins in solid oral dosage forms, in particular, is
limited to low doses with relatively large stability constants due
to the relatively large size of cyclodextrin molecules and mass
and size limitations of oral dosing [5,6,67]. For example, in the
cases of -, -, and -cyclodextrins (MW = 972, 1132, and
1297 g/mol, respectively), 100 mg of 1:1 molar complex
contains only approximately 525 mg of a drug with a molecular
weight of 500. Most probably for similar reasons, the molar ratio
of cyclodextrin:drug utilized was low in most of the formulations studied, with more than half of the comparisons involving a
molar ratio of cyclodextrin to drug of 2:1 or less. The amount of
cyclodextrin necessary to create a desired increase in bioavailability for a given dose of drug is dependent on a number of
factors including the binding constant and the physicochemical
properties of the drug and cyclodextrin (e.g., solubility), all of
which influence the various processes occurring during delivery
of the drug in the GI environment (e.g., dissolution and
absorption), as described below (See Section 3 Explanations
for ability of cyclodextrins to enhance bioavailability).
Most of the literature concerning the use of cyclodextrins to
enhance bioavailability does not discuss the required amount of
cyclodextrin in quantitative terms. In the previously mentioned

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

patents of Stella et al. [74,75], it is stated for the particular types

of cyclodextrins and drug delivery devices discussed that the
molar ratio of CD:drug should be in the range of 1:1 to 20:1.
Rao and Stella presented a theoretical consideration of the
appropriateness of cyclodextrins as a solubilizing technology in
which the ability of a given amount of cyclodextrin to
adequately solubilize a given drug dose was determined by
whether or not a dimensionless parameter, cyclodextrin utility
number, (UCD) was greater than or less than one [93]. This
treatment is based on the fact that a UCD number greater than
one indicates that the cyclodextrin amount is sufficient to
solubilize the entire dose of drug. In order for this condition to
be met, the dose per unit available volume of solution must be
less than or equal to the total solubility of the drug in the
presence of the cyclodextrin. Here solubility refers to the
maximum amount of drug that can be in solution at equilibrium,
including both free and complexed drug. Therefore, the
solubility in the presence of cyclodextrin is the sum of the
free drug solubility and the maximum equilibrium concentration
of complex in solution. To determine an expression for this
solubility, first consider the definition of the binding constant
(K). The binding constant describes the equilibrium between
drug and cyclodextrin. For a 1:1 complex:

CDf drugf

The binding constant can also be expressed in terms of the

total molar amount of both bound and free cyclodextrin, CDtotal,
for a given volume V:

CDtotal =V  comdrugf

Rearranging and solving for [com],


K drugf

1 K drugf

The maximum complex concentration is present when the

drug concentration is equal to the free drug solubility, So.
Making this substitution, the maximum solubility of a drug in
the presence of a given molar quantity of cyclodextrin is:
drugtotal So

KSo CDtotal
1 KSo V

Thus, the requirement described by Rao and Stella for a

given molar dose of drug (Dtotal) is:
KSo CDtotal
V So
1 KSo V

This can be rearranged to:

So V
KSo CDtotal

Dtotal 1 KSo Dtotal

The first term is the inverse of the dose number, a

dimensionless number that has been used to assess the ability of


a given dose of drug to be delivered based on solubility. It can be

assumed to be much less than one in cases where cyclodextrins are
being used to enhance solubility and dissolution. The second term
is the UCD defined by Rao and Stella. Thus, the ability of a given
amount of cyclodextrin to solubilize a dose of drug is dependent
on the drug's solubility and the binding constant with cyclodextrin. A less obvious but still important factor is the solubility of
the cyclodextrin, which is assumed in the analysis not to be a
limiting factor.
It is interesting to compare the theoretical ratio of CD:drug
required according to the UCD with what has actually been used
in the literature. In Table 1, the molar ratio of CD:drug
necessary for a UCD of one has been calculated for studies in
which the necessary information was able to be obtained. The
water solubility, when available, was used to calculate the UCD.
If the water solubility was not available, the solubility at a
specific pH, as indicated in the table, was used. It is evident that
enhancement in bioavailability has been reported when a level
of cyclodextrin below the UCD-predicted amount has been
utilized. Of the studies in Table 1 about which enough
information was able to be obtained to compare a CD:drug
molar ratio necessary for a UCD of one and the dosed CD:drug
molar ratio, 20 utilized a CD:drug ratio less and 5 utilized a CD:
drug ratio greater than that predicted to be necessary by the
UCD. There appears to be no clear correlation of the difference
between the utilized and UCD-predicted CD:drug molar ratio
with the magnitude of the AUC increase. It should be noted that
considerable error can be introduced into the UCD CD:drug
molar ratio calculation by the variation that is seen in reported
solubility and binding constant values, making it possible that
the values calculated are not exactly those relevant to the study
at hand. For example, the binding constants reported for -CD
and piroxicam in two different studies were 101 and
28,000 M 1, leading to UCD-predicted necessary CD:drug
molar ratios of 1.9 and 103, respectively [23,41]. However, it
appears that it is not always necessary for the cyclodextrin
amount in a given formulation to be adequate to solubilize the
entire dose for enhancement of bioavailability. A very high CD:
drug molar ratio, in fact, can lead to a decrease in bioavailability
due to a decreased free drug concentration in the intestinal
lumen when a very large amount of drug is bound to
2.8. Type of CD used
Both natural cyclodextrins and cyclodextrin derivatives have
been used to enhance bioavailability, as can be seen in Table 1.
Cyclodextrin derivatives often have a higher solubility than
natural cyclodextrins, and they may have different binding
constants with a given compound, as well. This can result in
different levels of bioavailability enhancement using natural
cyclodextrins vs. derivatives [44,45]. For example, when the CD and HP--CD complexes of rutin were dosed, -CD had no
influence on bioavailability, while HP--CD resulted in a 2.9
times increase in the AUC [12]. Similarly, when salbutamol was
dosed as the perbutanoyl--CD (TB--CD) complex, the AUC
was increased 4.6 times in comparison to dosing of drug alone,


R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

while it was only increased 1.7 times when dosed as the -CD
complex [13].
2.9. Binding constant magnitude
A range of binding constant values of 0 to approximately
100,000 M 1 have been reported for cyclodextrin complexes in
the literature, with 0 corresponding to absence of binding [6].
Very weak binding is roughly characterized by a binding
constant less than 500 M 1, while weak, moderate, strong, and
very strong binding are characterized by binding constants in
the ranges of 5001000 M 1 , 10005000 M 1 , 5000
20,000 M 1, and greater than 20,000 M 1, respectively. The
mean binding constant values of pharmaceutical compounds
and , , and -CD were determined to be 129, 490, and
355 M 1 when a large number of complexes were statistically
analyzed [93,100,101]. Of the 46 comparison for which binding
constant magnitudes were able to be found (Table 1), 23 had
very weak binding constants, while 5, 5, 10, and 3 had weak,
moderate, strong, and very strong binding constants, respectively. It has been suggested in the literature that error may exist
in reported binding constants, for example if they are measured
assuming 1:1 binding when a different stoichiometry actually
exists in the complex [101103].
The AUC increase is plotted vs. the binding constant in
Fig. 2. It is clear that there is no correlation between binding
constant and increase in AUC for the studies examined. The
majority of the studies surveyed involved lower binding constant
values. It also appears that as the binding constant increases,
there may be a decrease in the maximum AUC increase that can
be achieved. It has been reported in the literature that the
magnitude of binding constants is similar to molar ratios of CD:
drug in that if it is too big, a decrease in bioavailability over drug
dosed alone can actually result, while if it is too small, there may
not be any effect of cyclodextrin [7]. A theoretical model of a
cyclodextrin-drug system developed by Szejtli predicts that
dosing a complex of cyclodextrin and drug at a 1:1 molar ratio
should result in increased blood plasma levels of the drug over a
reasonable range of binding constants (50010,000 M 1). The
model also predicts, however, that it is possible with a high
binding constant (e.g., greater than approximately 10,000 M 1)

Fig. 2. Plot of AUC increase vs. binding constant. The y-axis represents the
factor by which the AUC was increased over the AUC when cyclodextrins were
not used (i.e., the ratio of these two AUC values).

and a large molar excess of cyclodextrin to obtain a lower

bioavailability in a system containing cyclodextrin than if drug
alone were dosed [5,104]. If a complex with a very high binding
constant is dosed, the complex may not dissociate appreciably,
and the complex itself is not absorbed [63]. Complexation with
agents other than cyclodextrin is known to be able to decrease
absorption if the complexed species is not able to be absorbed
One strategy for displacing drug that is tightly bound to
cyclodextrin is to co-dose a competitive binding agent. For example, complexation of cinnarizine with -CD resulted in AUC
values 8.0 and 1.4 times that of drug when dosed with and without
phenylalanine, respectively [34,107]. Interestingly, dosing of
uncomplexed drug with phenylalanine resulted in a decrease in
AUC and Cmax and an increase in Tmax relative to dosing drug
alone. It has been demonstrated that drug can also be displaced
from a complex by lipids in the rectum, mucus, and bile [63].
2.10. Interaction with polymers and other formulation components
While most of the studies surveyed in Table 1 involved dosing
a complex of drug and cyclodextrin as a powder alone or in a
gelatin capsule with water, some also included other excipients.
As the presence of other excipients, including polymers, is
known to possibly influence the interaction between drug and
cyclodextrins, it is important to take these factors into
consideration when reviewing the literature in search of guidelines for using cyclodextrins to enhance bioavailability. The
ability of water-soluble polymers to enhance the solubilizing
effect of cyclodextrins and thus possibly reduce the amount of
cyclodextrin necessary in a given dosage form has been
demonstrated [14,26,108110]. Formulations containing a
water-soluble polymer (e.g., HPMC or polyvinylpyrrolidone,
PVP) have been able to achieve bioavailability enhancement
equivalent to formulations containing up to 80% less cyclodextrin [26]. Such results are generally attributed to a synergistic
solubilizing effect of polymer and cyclodextrin believed to be
due to formation of ternary complexes or co-complexes between
drug, cyclodextrin, and polymer [110]. Polymers such as watersoluble cellulose derivatives can form complexes with cyclodextrin that have different physicochemical properties than those
of the cyclodextrin alone. For example, the solubility of the
cyclodextrin and/or the apparent binding constant between drug
and cyclodextrin can be changed in this manner [108].
It should be noted that formulations of drugs alone with these
polymers also often lead to enhancement in bioavailability, and
these polymers are known to interact with and solubilize drugs.
For example, when tacrolimus was dosed to rats in a
commercial PROGRAF tablet containing HPMC and compared
to drug alone, it resulted in an AUC012 increase of 3.6 times, an
increase in Cmax from 1.6 to 11.2 ng/ml, and a decrease in Tmax
from 0.5 to 1.3h, effects comparable to those observed when
tacrolimus was dosed with a 50:1 molar ratio of DM--CD [44].
Formulation of cyclodextrins with hydroxy acids or salts of
basic drugs can also enhance their solubilizing effects [14,111].
There is often a synergistic effect observed in dosing an acid
with a cyclodextrin, such that the total solubility enhancement

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

observed via dosing with both acid and cyclodextrin is greater

than the predicted combined effect from dosing with each alone.
There are several examples in the literature of using cyclodextrins together with acids to enhance solubility, dissolution
kinetics, and bioavailability, and several theories of possible
interactions between drug, acid, and cyclodextrin have been
proposed [111]. Other formulation components, including salts,
surfactants, preservatives, and organic solvents are known to
influence and often reduce the efficiency of binding between
drug and cyclodextrin. For example, the inclusion of non-ionic
surfactants has been shown to decrease binding of cyclodextrin
to diazepam due to competitive binding of the surfactant to the
cyclodextrin [112]. Formulation component effects can be
related to change in charge on the drug or cyclodextrin, as
described above, as well.
3. Explanations for ability of cyclodextrins to enhance
3.1. Significance
What are the properties of drug, cyclodextrin, delivery
device, and/or physiological environment necessary for cyclodextrins to enhance oral bioavailability? Answers to this
question in the form of general guidelines are found in
reviewing the literature, as described above and demonstrated
in Table 1 for cases where the solubilization properties of
cyclodextrins were specifically utilized. For example, it is
evident that most studies in which cyclodextrins have been used
to enhance oral bioavailability involve hydrophobic (logP N
2.5), low solubility (1 g/ml1 mg/ml) compounds with a dose
of less than 100 mg and a CD:drug ratio of 2:1 or less. Similar
general guidelines were outlined above for binding constant
magnitude and dosing of a physical mixture vs. a complex.
However, these are rough guidelines true of most studies, but it
is evident from the discussion above that there are many
exceptions to these general rules. In the limited range of studies
reviewed, there was no clear correlation between properties of
drug (e.g., solubility, binding constant with cyclodextrin) or
experimental parameters (e.g., type of cyclodextrin used, dose)
that could give definitive, quantitative guidance regarding when
and how cyclodextrins can be used for bioavailability
enhancement. This is likely related to the lack of information
regarding failed attempts to use cyclodextrin to enhance oral
bioavailability and the wide range of variables associated with
each study performed (method of preparation of complex, type
of cyclodextrin used, type of dosage form, animal species, etc.)
that make it difficult to assign boundaries to key parameters
based on available data. In addition, the drug and cyclodextrin
properties and experimental parameters interact to simultaneously influence processes in the intestinal drug delivery
environment, so that looking at one parameter of this system in
isolation provides limited information.
Further insight can be found in consideration of what
phenomena in the drug delivery environment are affected by the
presence of cyclodextrin and how, ultimately, overall drug
absorption is influenced by these changes. These phenomena


are described below. The text is organized according to common

explanations for bioavailability enhancement provided in the
literature followed by theoretical consideration of these
explanations. This theoretical consideration could provide the
basis for quantitative analysis of the simultaneous influence of
the properties of the cyclodextrin-drug-dosage form system on
key processes in the drug delivery environment that determine
bioavailability enhancement.
3.2. Enhancement in dissolution kinetics
The main cited reasons for enhancement in bioavailability
with inclusion of cyclodextrins in a dosage form are increase in
dissolution kinetics and increase in solubility, and it is often
stated that cyclodextrins will increase bioavailability when the
rate-limiting step in drug absorption is dissolution rather than
permeation through the intestinal membrane [7,20,66]. Most of
the compounds listed in Table 1 have low solubility, and, as
discussed above, most of the studies cited specifically refer to
the low solubility and slow dissolution of the compound as
motivating factors for studying the influence of cyclodextrin on
bioavailability. Many of the compounds listed in Table 1 are
reported to have both low and variable absorption, characteristics associated with low solubility and slow dissolution
kinetics [18,22,26,37]. In many of the studies cited, the
influence of cyclodextrin on the dissolution kinetics of the
compound is measured in vitro.
As depicted in Fig. 3, once solid drug is delivered to the
gastrointestinal tract as either free drug, physical mixture with
cyclodextrin, or complex with cyclodextrin, dissolution and
permeation across the intestinal membrane must occur in order
for the drug to be absorbed. If the dissolution kinetics are
limiting in the overall absorption process, enhancement of

Fig. 3. Diagram of the processes in the intestinal drug delivery system when a
drug is dosed either as a physical mixture or a complex with cyclodextrin.
Processes occurring that are influenced by the presence of cyclodextrin include
dissolution of drug and/or complex, precipitation of drug (if free drug
concentrations exceed equilibrium solubility), complexation of drug and
cyclodextrin, and absorption of drug. These processes interact to determine
the change with time in amount of solid (drug or complex); drug, cyclodextrin,
and complex in solution; and absorbed drug. The properties of the drug,
cyclodextrin, and intestinal environment determine the kinetics of these
processes and their effects on overall component absorption.


R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

dissolution kinetics via dosing a physical mixture with

cyclodextrin or dosing a complex will likely increase
bioavailability. The enhancement in dissolution kinetics
brought about by dosing a physical mixture of drug and
cyclodextrin is related to the fact that the dissolution of drug will
involve the flux of both free drug and complexed drug away
from the drug particle surface if cyclodextrin is present in the
immediate environment [63]. In the classical NoyesWhitney
dissolution expression for a drug particle in the absence of
cyclodextrin, dissolution rate is proportional to the concentration gradient across the unstirred boundary layer surrounding a
dissolving particle in a well-mixed compartment. For a neutral

 kdis So  drugf


The concentration of drug at the drug particle surface is taken

as its solubility (So), and the concentration at the edge of the
boundary layer is taken as the concentration of drug in the wellstirred intestinal lumen ([drug]f). The rate constant is equal to
the ratio of the product of the diffusivity of the drug (Ddrug) and
the surface area (A) to the length of the unstirred boundary layer
(lbl). When cyclodextrin is present in the environment of the
dissolving drug particle, the rate of dissolution is now
proportional to an additional driving force: the difference in
complex concentration at the particle surface and in the bulk
intestinal fluid [113]:

Ddrug So  drugf Dcom comsurface  com


Dissolution kinetics of complex are usually enhanced over

those of both the drug alone and the physical mixture [70,71].
For some drugs, the dissolution of drug alone or as a physical
mixture with -CD is indistinguishable, while the complex of
drug and -CD demonstrate much faster dissolution kinetics
(e.g., 90% vs. 25% dissolved in water in 10 min) [29,35,114].
This is related to the physical properties of the complex. The
complex of a low solubility drug typically is more hydrophilic
and has a higher solubility than the free drug itself. In addition,
in the case of the derivatized cyclodextrins, the complex is
usually amorphous. Water molecules break up amorphous
material with relative ease in comparison to crystalline drug
[25]. Replacement of the first term in Eq. (7), So, with the
enhanced solubility of the complex results in a much greater
driving force for dissolution. It is possible that the method of
formation of the complex will also result in an increased surface
area in relation to the surface area of dissolving drug alone or
physical mixture, increasing the dissolution rate constant in Eq.
(7). As a result of these various factors, the complex will
dissolve faster than the drug alone or the physical mixture [63].
There are reports of low solubility inclusion complexes that will

tend to precipitate, however, especially if formed from one of

the parent cyclodextrins [14,24]. This type of behavior gives
rise to what Higuchi defined as a B-type phase-solubility
diagram [115].
Enhancement in dissolution kinetics is not always accompanied by enhancement in bioavailability. For example, in a
study in which the -CD and HP--CD complexes of rutin were
studied, both cyclodextrins had comparable affects on dissolution kinetics and stability, but only HP--CD increased
bioavailability [12]. When indomethacin was processed as a
freeze-dried complex with -CD, it showed increased dissolution kinetics over freeze-dried drug alone. However, when the
complex and drug were dosed to rabbits, there was no increase
in percent drug recovered in urine with dosing of the complex
[38]. These results highlight the importance of gaining
understanding of all the interconnecting factors influencing
absorption when a cyclodextrin-drug system is dosed. It is
important to determine what the rate-limiting step is in
absorption of the compound when cyclodextrin is not present
and then assess the ability of cyclodextrin to influence this ratelimiting step.
3.3. Increase in solubility
Along with an increase in dissolution kinetics, increase in
solubility is often cited as being responsible for enhanced
bioavailability when dosing drug with cyclodextrins [24].
Solubility can be a key factor in kinetics of dissolution (Eq.
(7)) and can also influence permeation through the intestinal
membrane by influencing the concentration of drug in solution
in the intestinal lumen. Thus, low solubility is often blamed for
low bioavailability. It is useful to clarify what is meant by the
increase in solubility brought about by cyclodextrins,
however, in order to evaluate their ability to enhance
bioavailability. In the presence of cyclodextrin, the total amount
of drug in solution is equal to the sum of free drug and complex
in solution. As described above in Dose and molar CD:drug
ratio in the discussion of the cyclodextrin utility number [93],
the maximum value that this total amount of drug in solution
can have is the sum of the solubility of the drug itself and the
amount of complex formed when the free drug concentration in
solution is the drug solubility. Thus, for a neutral compound:
drugtotal drugf comf V So

KSo CDtotal
1 KSo V


Similar expressions can be written for the total amount of

ionizable compound in solution in the presence of cyclodextrin
based on the binding constant with ionized drug [96]. This total
amount of free drug and complex is typically referred to as
enhanced solubility. For example, the solubility of prednisolone in water at room temperature is 0.25 mg/ml, while the
solubilities in the presence of 15 mg/ml -CD and DM--CD
are 3.4 mg/ml and 3.3 mg/ml, respectively [5]. This enhanced
solubility forms the basis for the theoretical treatment of amount
of cyclodextrin required in a formulation provided by Rao and
Stella [93]. It is important to note, however, that the value of the

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899


free drug concentration at equilibrium will not exceed the

solubility of the free drug. This is a key point as the rate of
permeation through the intestinal membrane is dependent on the
free drug concentration in the intestinal lumen:

dispersed drug is released rapidly from the nanospheres,

enhancing dissolution rate for low-solubility compounds.

ka drugf Vlumen

Stability of many compounds has been enhanced via

complexation with cyclodextrins, as has been extensively
reviewed in the literature. Stability can be enhanced either in
the dosage form itself, by inhibiting polymorphic transitions, for
example [121], or once the drug is actually dosed. Of the studies
presented in Table 1, reports in which explicit mention was
made of compound stability issues are highlighted. In these
highlighted studies, the bioavailability of the drug molecule is
generally known to be influenced by its degradation rate, and in
some studies bioavailability enhancement using cyclodextrins
was at least partially attributed to the stabilizing effect of
cyclodextrin on the drug molecule. As many of these studies
involve low-solubility compounds, it is difficult to determine if
the bioavailability enhancement is due to the effect of
cyclodextrins on dissolution, degradation, or both. Binding of
cyclodextrin can reduce the reactivity of a drug by shielding the
drug molecule from attack and/or changing the chemical and
physical stability of the molecule itself via conformation
changes, for example. Thus, if a compound is prone to
hydrolysis at intestinal pH or intestinal enzymatic degradation,
complexation with cyclodextrins can aid in maintaining
intestinal drug concentrations and thus absorption through the
intestinal membrane according to Eq. (11) [1215]. For
example, complexation of salbutamol with -CD and TB-CD was used to increase the bioavailability relative to dosing
drug alone 1.7 and 4.6 times, respectively [13]. This was
attributed to decreased biotransformation (mainly glucuronidation) in the intestine. In vitro tests demonstrated that
complexation led to decreased dissolution rate for this highly
soluble drug, especially in the case of complexation with the
hydrophobic cyclodextrin derivative TB--CD. Such protection
may be particularly useful in oral delivery of peptides that are
particularly susceptible to physicochemical and enzymatic
degradation in the intestine [122]. It is also possible, however,
that changes in physical or chemical drug properties brought
about by complexation with cyclodextrins enhance the
degradation of a given drug molecule [123].


Although there are studies in which transport of cyclodextrins across the intestinal membrane has been reported [116], it
is generally accepted that neither the complex nor free
cyclodextrin are absorbed to an appreciable extent [7,66,117].
Thus, based on the dependence of absorption on free drug
concentration (Eq. (11)), the equilibrium enhanced solubility
brought about by cyclodextrins described by Eq. (10), on its
own, will not enhance rate of permeation through the intestinal
membrane. In fact, it is possible that complexation with
cyclodextrin, especially in cases where the binding constant is
high, will reduce the absorption rate due to the fact that the
complex is not absorbed and the free drug concentration can be
reduced by binding [34].
In spite of the apparent inability of cyclodextrins to increase
the equilibrium free drug solubility, there are ways that
cyclodextrins can result in free drug concentration greater than
the solubility in the intestinal lumen for a transient period of
time. For example, if the complex is dosed, it will disassociate as
it goes into solution to an extent determined by the binding
constant and concentrations of drug, cyclodextrin, and complex
in the intestinal lumen. Association and disassociation are often
assumed to be instantaneous in comparison to the kinetics of
dissolution and permeation through the intestinal membrane,
and free drug molecules can be considered to be in pseudoequilibrium with molecules bound in the cyclodextrin cavity at
all times [14,118]. Free drug and cyclodextrin will precipitate if
their concentrations in solution, as dissolution and decomplexation are taking place, are higher than their equilibrium
solubilities [119]. However, if dissolution of the complex and
disassociation are rapid enough relative to precipitation, dosing
of a complex can result in free drug concentration higher than the
solubility of the drug for a period of time [5,7,63,104]. This can
lead to increased drug absorption through the intestinal
membrane. Water soluble polymers (e.g., hydroxypropyl
cellulose (HPC) or PVP) have been used to prolong the
supersaturated state brought about by complex dissolution [7].
A second way that cyclodextrins may enhance free drug
concentration is by slowing the precipitation of free drug [5].
Precipitation kinetics are proportional to the drug concentration
and thus are reduced when some of the drug is bound by
cyclodextrin. In addition to dosing a complex, dosing a salt form
of the drug can result in transient concentrations of free drug
higher than the equilibrium solubility.
Another cited method of using cyclodextrins to enhance
bioavailability related to dissolution kinetics and solubility is
through the formation of nanospheres. Amphiphilic CDs, such
as native CDs derivatized on secondary hydroxyl groups with
alkyl chains, are capable of self-assembling into nanospheres
that can be loaded with drug [66,120]. The molecularly

3.4. Decrease in degradation kinetics

3.5. Change in intestinal membrane properties

The interaction of cyclodextrins with biological membranes
and possible associated changes in permeability have been
investigated [8,9,11,124]. The nature and extent of interaction of
cyclodextrins with the intestinal membrane is not completely
understood, but appears to depend on the type of cyclodextrin
present. Free cyclodextrin may remove membrane components.
For example, in a rat intestinal model, -CD was shown to
preferentially release phospholipids, and -CD selectively released cholesterol. An influence of cyclodextrins on P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2)
has also been reported and investigated [11,64,125]. Certain
cyclodextrins (e.g., DM--CD) inhibited these efflux proteins in


R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

Caco-2 cell monolayers, while other cyclodextrins (e.g., HP-CD) had little effect. It was hypothesized that the P-gp inhibition
brought about by DM--CD is due to its solubilizing effect on
cholesterol, an abundant component of the caveolae where P-gp is
localized. It has been shown that methylated cyclodextrins can
extract lipids from the nasal mucosa, possibly enhancing
paracellular transport via this mechanism, and a similar mechanism may apply to the GI tract [11]. Interaction of cyclodextrins
with calcium ions has also been implicated in loosening of tight
junctions [9]. Peracylated -cyclodextrins have been shown to
have mucoadhesive properties [13,126]. Cyclodextrins can also
reduce local irritation of the GI tract that would occur if the drug
were dosed alone [39], and thus possibly influence absorption in
this manner. In general, the possible interaction between
solubilizing capabilities, degradation inhibition, and/or changes
in intestinal properties make it difficult to develop quantitative
guidelines on the use of cyclodextrins to enhance bioavailability
based on reports in the literature, such as those summarized in
Tables 1 and 2.
3.6. Shuttling and enhancement of drug concentration at the
intestinal wall
The intestine is often modeled as a well-mixed compartment
(i.e., uniform concentrations of all species) [127]. However, in
reality, there is an unstirred boundary layer near the intestinal
wall as well as other solid species present, and there are concentration gradients within these boundary layers. There may be a
decreasing concentration of drug in the boundary layer adjacent to
the intestinal membrane due to the fact that drug is being depleted
by absorption and may not be replenished quickly enough by
diffusion through the boundary layer. It is possible that complexing agents diminish this effect. As free drug is depleted in the
vicinity of the intestinal wall, disassociation of complex occurs to
re-establish equilibrium, potentially replenishing free drug
concentration faster than it can be replenished via diffusion.
This phenomenon could be aided by the use of amphiphilic
derivatives of natural cyclodextrins formed by grafting aliphatic
chains to the glucopyranose units. These hydrophobic moieties
may aid in intimate contact of cyclodextrins with biological
membranes [120,128]. It has also been hypothesized that
components of the intestinal wall (mucus, lipids) displace the
drug from the complex, leading to an elevated drug concentration
at the intestinal wall [63,92].
4. When cyclodextrins do not enhance bioavailability
4.1. Binding constant magnitude and amount of dosed
The majority of the literature deals with successful use of
cyclodextrins to enhance bioavailability, but there are reports of
no improvement or decreases in bioavailability with use of
cyclodextrins, as well. There are no clear differences between
parameters of studies in Table 2, where cyclodextrins were not
successful in increasing bioavailability, and those in Table 1. As
mentioned above, all of the compounds listed in Table 2 will be

ionized to a certain extent at the pH of the small intestines, which

can lead to a decreased binding constant. However, some of the
compounds listed in Table 1 will also be ionized at the pH of the
small intestines, yet still experienced enhanced bioavailability
using CD. In some studies, the lack of bioavailability enhancement has been attributed to the magnitude of the binding constant
with cyclodextrin. The reasoning is that a binding constant that is
too small does not lead to enough complexation for the
dissolution kinetics or solubility to be influenced significantly,
and a binding constant that is too big may lead to decreased free
drug concentration in the intestine, lowering overall absorption
(Eq. (11) and Fig. 2) [5,63]. For example, the low level of
bioavailability enhancement observed when cinnarizine was
dosed with -CD was attributed to a relatively high binding
constant (6200 M 1) [34,129]. However, similar increases in
bioavailability were seen when cinnarizine complexed with HP-CD and SBE--CD was dosed in spite of very different binding
constants with these two cyclodextrins (2242 and 4276 M 1,
respectively) [33,129]. A clear method does not currently exist for
determining the range of appropriate binding constant values for a
given compound due to the complexity of the interaction of
processes occurring in the intestinal drug delivery environment
and their dependence on the properties of the drug, drug delivery
device, and cyclodextrin. These results again highlight the
importance of understanding the interacting processes involved
in dosing a drug to the intestinal environment with a complexing
agent such as cyclodextrin as opposed to focusing on the
influence of a single parameter, such as binding constant. An
excess of cyclodextrin can have the same effect as a high binding
constant with regards to potentially decreasing bioavailability.
Both factors result in shifts in the equilibrium between drug,
cyclodextrin, and complex toward complexation.
4.2. Degradation of cyclodextrins in the intestinal environment
While not explicitly mentioned in the studies presented in
Table 2, one factor to consider when assessing the utility of
cyclodextrins to enhance bioavailability of orally delivered
compounds, especially in the case of controlled-release
formulations, is the stability of cyclodextrins in the intestinal
environment. Cyclodextrins are resistant to the enzymes that
hydrolyze starch. They are completely resistant to -amylase
attack, in fact. -amylases attack the inside of the cyclodextrin
molecule at a relatively slow rate [130]. -CD is metabolized by
enzymes in the saliva, while -CD and -CD are not [3]. -CD
and -CD are not believed to be hydrolyzed during transit
through the small intestine, but are degraded by colonic flora.
Cyclodextrin metabolism was investigated by Anderson et al. by
orally administering 14C-labeled -CD to rats [131]. The rats
exhaled approximately 55% of the radioactivity within 24 h,
with maximum radioactivity observed at 48 h. In a similar
study, Gerloczy et al. administered 14C-labeled cyclodextrin and
glucose to rats [132]. Radioactivity was apparent in the respired
air from rats administered glucose only 2 h after feeding, while it
appeared 48 h after feeding in rats administered cyclodextrin.
In both cases, approximately 60% of the administered
radioactivity was accounted for in respired air. These results

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

indicate that cyclodextrins are metabolized in the rat. It has been

suggested based on these and similar studies that absorption of
cyclodextrin does not occur in the small intestine, but rather in
the colon where cyclodextrin is metabolized by colonic bacteria.
In fact, as described above, the use of cyclodextrins as pro-drugs
for colon-targeted delivery of compounds has been investigated
[65,66,90]. The kinetics of degradation of - and -CDs by
human colon anaerobes was studied by Antenucci et al. [133]. It
was found that degradation is well under way in as little as 12 h,
and most of the Bacteroides strains studied were shown to
degrade the cyclodextrins. Extensive degradation was observed
within 18 h, suggesting that colonic transit time may be adequate
to cause extensive deterioration of dosed cyclodextrins. The
degradation observed is attributed mainly to cyclomaltodextrinase (CDase), an enzyme that hydrolyzes cyclic dextrins and
linear maltodextrins [134,135]. CDase is known to rapidly
hydrolyze cyclodextrins. Characterization of the influence of
such degradation on the performance of a controlled-release
dosage form is important for formulation development.
5. Conclusions
A survey of the literature related to use of cyclodextrins for
enhancing oral bioavailability was conducted in order to gain
understanding of when cyclodextrins can be used for this purpose.
The focus of the literature reviewed was on the solubilizing
capabilities of cyclodextrins and their contribution to bioavailability enhancement, as is the focus of most literature on the use of
cyclodextrins in oral pharmaceutical formulations. General
guidelines were evident from examining the studies, including
information related to typical affect on bioavailability. For
example, most studies report successful improvement in bioavailability. Of these studies, the majority report an increase in AUC
between 0 and 100% (1 to 2 times). Most studies (72% of those
examined) report a decrease in Tmax of less than 3 h, while the vast
majority (98%) report an increase in Cmax, most often to a value
less than double that when drug is dosed alone. Regarding the
properties of the compounds utilized in these studies, they were
generally hydrophobic (18 out of 29 studies involved compounds
with logP N 2.5) and poorly soluble (most with a solubility of 1 g/
ml1 mg/ml). This is expected, as cyclodextrins enhance overall
absorption by influencing dissolution kinetics. The complex of the
drug rather than a physical mixture is typically dosed, and in
comparing studies in which both complex and physical mixture
were used, the AUC approximately doubled with the complex
compared to the physical mixture. This phenomenon is related to
the high solubility of most cyclodextrin complexes. Most studies
involved low doses (b 100 mg in 25 out of 29 studies) and low CD:
drug ratios (more than half with 2:1 or less), with very weak to
moderate binding constants (b 5000 M 1 in 33 out of 46 studies
reporting the constant values). Low doses are required for
practical use of cyclodextrins in traditional oral dosage forms
(tablets, capsules). CD:drug ratios are also limited by practical
dosage form sizes. Low to moderate CD:drug ratios and binding
constants are also important as a negative affect of cyclodextrin on
bioavailability can be related to a high percentage of bound drug
limiting the free drug in solution available for absorption.


In spite of these general guidelines, many studies reported

parameters outside of these guidelines, and it was difficult to
distinguish between parameters of studies in which success or
lack thereof in bioavailability enhancement was reported. Therefore, it was not possible to develop clear quantitative guidelines
for what drug and cyclodextrin properties are key to enabling oral
bioavailability enhancement using cyclodextrins. This is likely
partially due to complicating factors (method of complex formation, charge of drug during GI transit) and variability in reported
parameters (e.g., binding constant). It is also partially due to the
other effects of cyclodextrins in certain dosage forms, such as
decreasing degradation kinetics or inhibiting compound efflux,
which were not taken into consideration in comparing studies.
However, even in cases where adequate information regarding
experimental parameters are supplied and other effects of
cyclodextrin in addition to solubilization are not believed to
play a role, it is difficult to correlate a single parameter to the
ability of cyclodextrins to enhance bioavailability. The mechanisms of bioavailability enhancement using cyclodextrins were
therefore discussed to provide further insight. The influence of
cyclodextrins on the dissolution of drug in the intestinal lumen as
well as the absorption of drug, a process proportional to the free
drug concentration in the intestinal lumen, were considered. It is
evident that the physical and chemical properties of a given drug,
cyclodextrin, and dosage form interact to influence kinetics of key
processes of oral drug delivery, including dissolution and
absorption. These interactions create difficulty in precisely
specifying one range of values for one parameter (e.g., binding
constant, solubility) that will result in successful bioavailability
enhancement using cyclodextrins. A more comprehensive
theoretical analysis of the influence of cyclodextrins on the
kinetics of simultaneous processes occurring in the drug delivery
environment may provide further guidance.
Surface area of dissolving particle, dm2
Total molar amount of free and bound cyclodextrin,
Complex diffusivity, dm2/s
Drug diffusivity, dm2/s
Molar dose of drug, moles
Cyclodextrin complexation constant, M 1, assuming
1:1 binding
Free drug solubility, M
Total volume, L
Volume of the intestinal lumen, L
Moles of drug absorbed, moles
Moles of free drug in solution, moles
Absorption rate constant, min 1
Dissolution rate constant, Ms 1
Precipitation rate constant, units depend on specific
Boundary layer thickness, dm
Molar concentration of free drug in solution, M
[drug]total Total molar concentration of free and bound drug in
solution, M
Molar concentration of complex in solution, M


R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

[com]surface Concentration of complex at dissolving drug

particle surface, M
Molar concentration of free cyclodextrin in solution,
[1] T. Loftsson, M.E. Brewster, M. Masson, Role of cyclodextrins in
improving oral drug delivery, Am. J. Drug Del. 2 (4) (2004) 175261.
[2] M.E. Davis, M.E. Brewster, Cyclodextrin-based pharmaceutics: past,
present and future, Nat. Rev. Drug Discovery 3 (2004) 10231035.
[3] G.L. Mosher, D.O. Thompson, in: J. Swarbrick (Ed.), Encyclopedia of
Pharmaceutical Technology, 2nd Edition, Marcel Dekker, 2002.
[4] J. Szejtli, Cyclodextrin Technology, Kluwer Academic Publishers,
Dordrecht, 1988.
[5] J. Szejtli, Medicinal applications of cyclodextrins, Med. Res. Rev. 14
(1994) 353386.
[6] R.A. Rajewski, V.J. Stella, Pharmaceutical applications of cyclodextrins. 2.
In vivo drug delivery, J. Pharm. Sci. 85 (1996) 11421169.
[7] K. Uekama, M. Otagiri, Cyclodextrins in drug carrier systems, Crit. Rev.
Ther. Drug Carr. Syst. 3 (1) (1987) 140.
[8] R. Challa, A. Ahuja, J. Ali, R.K. Khar, Cyclodextrins in drug delivery: an
updated review, AAPS PharmSciTech 6 (2) (2005) E329E357.
[9] H. Arima, F. Hirayama, C.T. Okamoto, K. Uekama, Recent aspects of
cyclodextrin-based pharmaceutical formulations, Recent Res. Devel.
Chem. Pharm. Sciences 2 (2002) 155193.
[10] D.O. Thompson, Cyclodextrins-enabling excipients: their present and future
use in pharmaceuticals, Crit. Rev. Ther. Drug Carr. Syst. 14 (1) (1997) 1104.
[11] K. Uekama, Design and evaluation of cyclodextrin-based drug
formulation, Chem. Pharm. Bull. (Tokyo). 52 (8) (2004) 900915.
[12] K. Miyake, H. Arima, F. Hirayama, M. Yamamoto, T. Horikawa, H.
Sumiyoshi, S. Noda, K. Uekama, Improvement of solubility and oral
bioavailability of rutin by complexation with 2-hydroxypropyl-cyclodextrin, Pharm. Dev. Technol. 5 (3) (2000) 399407.
[13] F. Hirayama, T. Horikawa, M. Yamanaka, K. Uekama, Enhanced
bioavailability and reduced metabolism of salbutamol by perbutanoylb-cyclodextrin after oral administration in dogs, Pharm. Sci. 1 (11) (1995)
[14] T. Loftsson, M.E. Brewster, Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization, J. Pharm. Sci. 85 (10)
(1996) 10171025.
[15] M. Usuda, T. Endo, H. Nagase, K. Tomono, H. Ueda, Interaction of
antimalarial agent artemisinin with cyclodextrins, Drug Dev. Ind. Pharm.
vol. 26 (2000) 613619.
[16] K. Uekama, T. Fujinaga, F. Hirayama, M. Otagiri, M. Yamasaki, H. Seo,
T. Hashimoto, M. Tsuruoka, Improvement of the oral bioavailability of
digitalis glycosides by cyclodextrin complexation, J. Pharm. Sci. 72 (11)
(1983) 1338134141.
[17] K. Uekama, T. Fujinaga, M. Otagiri, H. Seo, M. Tsuruoka, Enhanced
bioavailability of digoxin by -cyclodextrin complexation, J. Pharmacobio-dyn. 4 (1981) 735737.
[18] J.L. Vila-Jato, J. Blanco, A. Vilar, Spironolactone/-cyclodextrin complex:
oral bioavailability in humans, Pharm. Technol. 32 (2) (1986) 8285.
[19] F.J. Otero-Espinar, S. Anguiano-Igea, N. Garcia-Gonzalez, J.L. Vila-Jato,
J. Blanco-Mendez, Oral bioavailability of naproxen--cyclodextrin
inclusion compound, Int. J. Pharm. vol. 75 (1991) 3744.
[20] S. Choudhury, K.F. Nelson, Improvement of oral bioavailability of
carbamazepine by inclusion in 2-hydroxypropyl-b-cyclodextrin, Int. J.
Pharm. 85 (13) (1992) 175180.
[21] L.S. Koester, P. Mayorga, V.L. Bassani, Carbamazepine/CD/HPMC
solid dispersions. I. Influence of the spray-drying process and bCD/
HPMC on the drug dissolution profile, Drug Dev. Ind. Pharm. 29 (2)
(2003) 139144.
[22] M.D. Dhanaraju, K.S. Kumaran, T. Baskaran, M. Sree Rama Moorthy,
Enhancement of bioavailability of griseofulvin by its complexation with
-cyclodextrin, Drug Dev. Ind. Pharm. 24 (6) (1998) 583587.

[23] S.A. Elkheshen, S.M. Ahmed, B.T. Al-Quadeib, Inclusion complexes of

piroxicam with b-cyclodextrin derivatives in comparison with the natural
-cyclodextrin, Pharm. Ind. 64 (7) (2002) 708715.
[24] O.A.E. Soliman, K. Kimura, F. Hirayama, K. Uekama, H.M. ElSabbagh, A.E.-G.H. El-Gawad, F.M. Hashim, Amorphous spironolactone-hydroxypropylated cyclodextrin complexes with superior
dissolution and oral bioavailability, Int. J. Pharm. 149 (1997) 7383.
[25] J. Geczy, J. Bruhwyler, J. Scuvee-Moreau, V. Seutin, H. Masset, J.C. Van
Heugen, A. Dresse, C. Lejeune, E. Decamp, L. Szente, J. Szejtli, J.-F.
Liegeois, The inclusion of fluoxetine into -cyclodextrin increases its
bioavailability: behavioural, electrophysiological and pharmacokinetic
studies, Psychopharmacology (Berl). 151 (2000) 328334.
[26] J. Savolainen, K. Jarvinen, H. Taipale, P. Jarho, T. Loftsson, T. Jarvinen, Coadministration of a water-soluble polymer increases the usefulness of cyclodextrins in solid oral dosage forms, Pharm. Res. 15 (11) (1998) 16961701.
[27] J.W. Wong, K.H. Yuen, Improved oral bioavailability of artemisinin
through inclusion complexation with - and -cyclodextrin, Int. J. Pharm.
227 (2001) 177185.
[28] M. Kikuchi, F. Hirayama, K. Uekama, Improvement of oral and rectal
bioavailabilities of carmofur by methylated -cyclodextrin complexations, Int. J. Pharm. 38 (1987) 191198.
[29] J.L. Vila-Jato, J. Blanco, J.J. Torres, Biopharmaceutical aspects of
glibornuride-b-cyclodextrin inclusion compound, S.T.P. Pharma 3 (1)
(1987) 2832.
[30] H.-G. Choi, B.-J. Lee, J.-H. Han, M.-K. Lee, K.-M. Park, C.S. Yong, J.-D.
Rhee, Y.-B. Kim, C.-K. Kim, Terfenadine-b-cyclodextrin inclusion
complex with antihistaminic activity enhancement, Drug Dev. Ind.
Pharm. 27 (8) (2001) 857862.
[31] J. Luengo, T. Aranguiz, J. Sepulveda, L. Hernandez, C. Von Plessing,
Preliminary pharmacokinetic study of different preparations of acyclovir
with -cyclodextrin, J. Pharm. Sci. 91 (12) (2002) 25932598.
[32] B. Evrard, P. Chiap, P. DeTullio, F. Ghalmi, G. Piel, T. Van Hees, J.
Crommen, B. Losson, L. Delattre, Oral bioavailability in sheep of
albendazole from a suspension and from a solution containing hydroxypropyl--cyclodextrin, J. Control. Release 85 (13) (2002) 4550.
[33] T. Jarvinen, K. Jarvinen, N. Schwarting, V.J. Stella, -Cyclodextrin
derivatives, SBE4--CD and HP-b-CD, increase the oral bioavailability
of cinnarizine in beagle dogs, J. Pharm. Sci. 84 (3) (1995) 295299.
[34] T. Tokumura, M. Namba, Y. Tsushima, K. Tatsuishi, M. Kayano, Y.
Machida, T. Nagai, Enhancement of bioavailability of cinnarizine from its
-cyclodextrin complex on oral administration with DL-phenylalanine as
a competing agent, J. Pharm. Sci. 75 (1986) 391394.
[35] K. Uekama, S. Narisawa, F. Hirayama, M. Otagiri, Improvement of
dissolution and absorption characteristics of benzodiazepines by
cyclodextrin complexation, Int. J. Pharm. 16 (3) (1983) 327338.
[36] H.P.R. Bootsma, H.W. Frijlink, A. Eissens, J.H. Proost, H. Van Doorne,
C.F. Lerk, -Cyclodextrin as an excipient in solid oral dosage forms: in
vitro and in vivo evaluation of spray-dried diazepam--cyclodextrin
products, Int. J. Pharm. 51 (3) (1989) 213223.
[37] G.L. Stracciari, J. Malvisi, P. Anfossi, G.B. Fregnan, Pharmacokinetics of
dipyridamole--cyclodextrin complex in dogs, Arch. Int. Pharmacodyn.
Ther. 300 (1989) 713.
[38] N. Nambu, M. Shimoda, Y. Takahashi, H. Ueda, T. Nagai, Bioavailability
of powdered inclusion compounds of nonsteroidal anti-inflamatory drugs
with -cyclodextrin in rabbits and dogs, Chem. Pharm. Bull. (Tokyo). 26
(10) (1978) 29522956.
[39] G. Ramprakash, M.S. Nagarsenker, Cyclodextrin based oral delivery of
flurbiprofen: effect of method of preparation on drug release and studies
on in-vivo performance, 28th International Symposium on Controlled
Release of Bioactive Materials and 4th Consumer & Diversified Products
Conference, vol. 28, Controlled Release Society, Inc., San Diego, CA,
2001, pp. 772773.
[40] L.H. Emara, R.M. Badr, A.A. Elbary, Improving the dissolution and
bioavailability of nifedipine using solid dispersions and solubilizers,
Drug Dev. Ind. Pharm. 28 (7) (2002) 795807.
[41] D.N. Reddy, U.V. Singh, S. Pandey, N. Udupa, Evaluation of piroxicam
oral and transdermal preparations, Indian J. Pharm. Sci. 54 (4) (1992)

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

[42] K. Uekama, M. Otagiri, Y. Uemura, T. Fujinaga, K. Arimori, N. Matsuo,
K. Tasaki, A. Sugii, Improvement in oral bioavailability of prednisolone
by -cyclodextrin complexation in humans, J. Pharmacobio-dyn. 6
(1983) 124127.
[43] F. Hirayama, T. Horikawa, M. Yamanaka, K. Uekama, Enhanced
bioavailability and reduced metabolism of salbutamol by perbutanoyl-cyclodextrin after oral administration in dogs, Pharm. Sci. 1 (11)
(1995) 517520.
[44] H. Arima, K. Yunomae, K. Miyake, T. Irie, F. Hirayama, Comparative
studies of the enhancing effects of cyclodextrins on the solubility and oral
bioavailability of tacrolimus in rats, J. Pharm. Sci. 90 (2001) 690701.
[45] F. Veiga, C. Fernandes, F. Teixeira, Oral bioavailability and hypoglycemic
activity of tolbutamide/cyclodextrin inclusion complexes, Int. J. Pharm.
vol. 202 (2000) 165171.
[46] J.L. Vila-Jato, Biopharmaceutical aspects of the tolbutamide-betacyclodextrin inclusion compound, Il Farmaco 43 (1988) 3745.
[47] C. Von Plessing Rossel, J. Sepulveda Carreno, M. Rodriguez-Baeza, J.B.
Alderete, Inclusion complex of the antiviral drug acyclovir with
cyclodextrin in aqueous solution and in solid phase, Quim. Nova 23
(6) (2000) 749752.
[48] T. Tokumura, H. Ueda, Y. Tsushima, M. Kasai, M. Kayano, I. Amada, Y.
Machida, T. Nagai, Inclusion complex of cinnarizine with -cyclodextrin
in aqueous solution and in solid state, J. Incl. Phenom. vol. 2 (1984)
[49] H. Ueda, D. Ou, T. Endo, H. Nagase, K. Tomono, T. Nagai, Evaluation of
a sulfobutyl ether -cyclodextrin as a solubilizing/stabilizing agent for
several drugs, Drug Dev. Ind. Pharm. 24 (9) (1998) 863867.
[50] E.S. Kostewicz, U. Brauns, R. Becker, J.B. Dressman, Forecasting the
oral absorption behavior of poorly soluble weak bases using solubility
and dissolution studies in biorelevant media, Pharm. Res. 19 (3) (2002)
[51] Y. Hamada, N. Nambu, T. Nagai, Pharmaceutical interactions in dosage
forms and processing. III. Interactions of - and -cyclodextrin with
several nonsteroidal antiinflammatory drugs in aqueous solution, Chem.
Pharm. Bull. (Tokyo). 23 (6) (1975) 12051211.
[52] K. Ikeda, K. Uekama, M. Otagiri, Inclusion complexes of -cyclodextrin
with antiinflammatory drugs fenamates in aqueous solution, Chem.
Pharm. Bull. (Tokyo). 23 (1) (1975) 201208.
[53] M.D. Veiga, P.J. Diaz, F. Ahsan, Interactions of griseofulvin with
cyclodextrins in solid binary systems, J. Pharm. Sci. 87 (7) (1998)
[54] M. Platzer, M.A. Schwarz, R.H.H. Neubert, Determination of formation
constants of cyclodextrin inclusion complexes using affinity capillary
electrophoresis, J. Microcolumn Sep. 11 (3) (1999) 215222.
[55] K.P.R. Chowdary, R.G. Kamalakara, Controlled release of nifedipine
from mucoadhesive tablets of its inclusion complexes with -cyclodextrin, Pharmazie 58 (10) (2003) 721724.
[56] Y.L. Loukas, Multiple complex formation of unstable compounds with
cyclodextrins: efficient determination and evaluation of the binding
constant with improved kinetic studies, Analyst 122 (4) (1997) 377381.
[57] S. Lee, C. Kwon, Y. Choi, D.-H. Seo, B.-W. Kim, S. Jung, Inclusion
complexation of a family of cyclosophoraoses with indomethacin,
J. Microbiol. Biotechnol. 11 (3) (2001) 463468.
[58] X. Guo, Y. Yu, G. Zhao, G. Zhang, J. Chao, S. Shaomin, Study on
inclusion interaction of piroxicam with -cyclodextrin derivatives,
Spectrochim. Acta A. Mol. Biomol. Spectrosc. 59A (14) (2003)
[59] M.R. Lauro, M.L. Torre, L. Maggi, F. De Simone, U. Conte, R.P. Aquino,
Fast- and slow-release tablets for oral administration of flavonoids: rutin
and quercetin, Drug Dev. Ind. Pharm. 28 (4) (2002) 371379.
[60] V. Lemesle-Lamache, M. Taverna, D. Wouessidjewe, D. Duchene, D.
Ferrier, Determination of the binding constant of salbutamol to
unmodified and ethylated cyclodextrins by affinity capillary electrophoresis, J. Chromatogr. A 735 (1+2) (1996) 321331.
[61] H. Seo, M. Tsuruoka, T. Hashimoto, T. Fujinaga, M. Otagiri, K. Uekama,
Enhancement of oral bioavailability of spironolactone by - and cyclodextrin complexations, Chem. Pharm. Bull. (Tokyo). 31 (1) (1983)


[62] Y. Namiki, A. Fujiwara, N. Kihara, S. Koda, K. Hane, T. Yasuda, Factors

affecting tautomeric phenomenon of a novel potent immunosuppressant
(FK506) on the design for injectable formulation, Drug Dev. Ind. Pharm.
21 (7) (1995) 809822.
[63] O. Bekers, E.V. Uijtendaal, J.H. Beijnen, A. Buit, W.J.M. Underberg,
Cyclodextrins in the pharmaceutical field, Drug Dev. Ind. Pharm. 17
(1991) 15031549.
[64] K. Yunomae, H. Arima, F. Hirayama, K. Uekama, Involvement
of cholesterol in the inhibitory effect of dimethyl--cyclodextrin
on P-glycoprotein and MRP2 function in Caco-2 cells, FEBS Lett. 536
(2003) 225231.
[65] H. Yano, F. Hirayama, H. Arima, K. Uekama, Preparation of prednisoloneappended alpha-, beta- and gamma-cyclodextrins: substitution at secondary
hydroxyl groups and in vitro hydrolysis behavior, J. Pharm. Sci. 90 (4)
(2001) 493503.
[66] F. Hirayama, K. Uekama, Cyclodextrin-based controlled drug release
system, Adv. Drug Delivery Rev. 36 (1999) 125141.
[67] J. Szejtli, Cyclodextrins in drug formulations: part II, Pharm. Technol. Int.
3 (3) (1991) 1624.
[68] J.B. Dressman, J. Butler, J. Hempenstall, C. Reppas, The BCS: where do
we go from here? Pharm, Technol. N. Am. 25 (7) (2001) 6876.
[69] S.Y. Lin, Y.H. Kao, Studies on drug interaction in pharmaceutical
formulations. Part XII. Solid particulates of drug--cyclodextrin
inclusion complexes directly prepared by a spray-drying technique, Int.
J. Pharm. 56 (3) (1989) 249259.
[70] M.S. Islam, M.M. Narurkar, The effect of 2-hydroxypropyl--cyclodextrin
on the solubility, stability, and dissolution rate of famotidine, Drug Dev. Ind.
Pharm. 17 (9) (1991) 12291239.
[71] S.-Z. Lin, D. Wouessidjewe, M.-C. Poelman, D. Duchene, Indomethacin
and cyclodextrin complexes, Int. J. Pharm. 69 (1991) 211219.
[72] S. Baboota, M. Dhaliwal, K. Kohli, Physicochemical characterization, in
vitro dissolution behavior, and pharmacodynamic studies of rofecoxibcyclodextrin inclusion compounds. Preparation and properties of
rofecoxib hydroxypropyl -cyclodextrin inclusion complex: a technical
note, AAPS PharmSciTech. 6 (1) (2005) E83E90.
[73] J.M. Gins, M.J. Arias, C. Novk, P.J. Snchez-Soto, A. Ruiz-Conde, E.
Morillo, Thermal study of complex formation of triamterene with
-cyclodextrin by spray-drying and co-grinding, J. Therm. Anal. Calorim.
45 (4) (1995) 659666.
[74] V. Stella, R.A. Rajewski, J.W. McGinity, Sulfoalkyl ether cyclodextrin
based solid pharmaceutical formulations and their use, United States
Patent 5,874,418, February 23, 1999.
[75] V.J. Stella, R.A. Rajewski, V.M. Rao, J.W. McGinity, G.L. Mosher,
Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations, United States Patent 6,046,177, April 4, 2000.
[76] V.J. Stella, R.A. Rajewski, K. Okimoto, K. Uekama, T. Irie, S. Shiraishi,
E.A. Zannou, V. Rao, Oral controlled release of poorly water soluble
drugs utilizing Captisol as both a solubilizer and osmotic agent, Int.
Symp. Control. Release Bioact. Mater. (2000) 145146.
[77] K. Okimoto, M. Miyake, N. Ohnishi, R.A. Rajewski, V.J. Stella, T. Irie,
K. Uekama, Design and evaluation of an osmotic pump tablet (OPT) for
prednisolone, a poorly water soluble drug, using (SBE)7M--CD, Pharm.
Res. 15 (10) (1998) 15621568.
[78] K. Okimoto, A. Ohike, R. Ibuki, O. Aoki, N. Ohnishi, R.A. Rajewski, V.J.
Stella, T. Irie, K. Uekama, Factors affecting membrane-controlled drug
release for an osmotic pump tablet (OPT) utilizing (SBE)7M--CD as
both a solubilizer and osmotic agent, J. Control. Release 60 (23) (1999)
[79] V.M. Rao, J.L. Haslam, V.J. Stella, Controlled and complete release of a
model poorly water-soluble drug, prednisolone, from hydroxypropy
methylcellulose matrix tablets using (SBE)7M--cyclodextrin as a
solubilizing agent, J. Pharm. Sci. 90 (7) (2001) 807816.
[80] K. Okimoto, Y. Tokunaga, R. Ibuki, T. Irie, K. Uekama, R.A. Rajewski,
V.J. Stella, Abblicability of (SBE)7M-beta-CD in controlled-porosity
osmotic pump tablets (OPT)s, Int. J. Pharm. 286 (2004) 8188.
[81] L.A. Miller, R.L. Carrier, I. Ahmed, Practical considerations in
development of solid dosage forms that contain cyclodextrin, J. Pharm.
Sci. 96 (7) (2007) 16911707.


R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

[82] P. Giunchedi, L. Maggi, A. LaManna, U. Conte, Modification of the

dissolution behavior of a water-insoluble drug, naftazone, for zero-order
release matrix preparation, J. Pharm. Pharmacol. 46 (6) (1994) 476480.
[83] F. Quaglia, G. Varricchio, A. Miro, M.I. La Rotonda, D. Larobina, G.
Mensitieri, Modulation of drug release from hydrogels by using
cyclodextrins: the case of nicardipine/-cyclodextrin system in crosslinked polyethylenglycol, J. Control. Release 71 (2001) 329337.
[84] M.E. Sangalli, L. Zema, A. Maroni, A. Foppoli, F. Giordano, A.
Gazzaniga, Influence of betacyclodextrin on the release of poorly soluble
drugs from inert hydrophilic heterogeneous polymeric matrices, Biomaterials 22 (2001) 26472651.
[85] Y. Ikeda, K. Kimura, F. Hirayama, H. Arima, K. Uekama, Controlled
release of a water-soluble drug, captopril, by a combination of
hydrophilic and hydrophobic cyclodextrin derivatives, J. Control.
Release 66 (2) (2000) 271280.
[86] V.J. Stella, V.M. Rao, E.A. Zannou, The pharmaceutical use of captisol:
some surprising observations, J Incl. Phenom. Macro. 44 (2002) 2933.
[87] E.A. Zannou, W.H. Streng, V.J. Stella, Osmotic properties of sulfobutylether
and hydroxypropyl cyclodextrins, Pharm. Res. 18 (8) (2001) 12261231.
[88] K. Okimoto, K. Miyake, O. Aoki, N. Ohnishi, T. Irie, Design and
evaluation of a porosity-controlled osmotic pump tablet for chlorpromazine using (SBE)7M--CD, in: J.J. Labandeira, J.L. Vila-Jato (Eds.), 9th
International Symposium on Cyclodextrins, Kluwer Academic Publishers, Santiago de Comostela, Spain, 1999, pp. 285288.
[89] T. Horikawa, R. Hirayama, K. Uekama, In-vivo and in-vitro correlation
for delayed-release behaviour of a molsidomine/O-carboxymethyl-Oethyl--cyclodextrin complex in gastric acidity-controlled dogs,
J. Pharm. Pharmacol. 47 (2) (1995) 124127.
[90] M. Kamada, F. Hirayama, K. Udo, H. Yano, H. Arima, K. Uekama,
Cyclodextrin conjugate-based controlled release system: repeated- and
prolonged-releases of ketoprofen after oral administration in rats,
J. Control. Release 82 (2002) 407416.
[91] J. Szejtli, L. Szente, Interaction between indomethacin and -cyclodextrin, Pharmazie 36 (10) (1981) 694698.
[92] H.W. Frijlink, A.J.M. Schoonen, C.F. Lerk, The effects of cyclodextrins on
drug absorption. I. In vitro observations, Int. J. Pharm. 49 (1989) 91102.
[93] V.M. Rao, V.J. Stella, When can cyclodextrins be considered for
solubilization purposes? J. Pharm. Sci. 92 (5) (2003) 927932.
[94] Y. Kim, D.E. Oksanen, W. Massefski, J.F. Blake, E.M. Duffy, B. Chrunyk,
Inclusion complexation of ziprasidone mesylate with -cyclodextrin
sulfobutyl ether, J. Pharm. Sci. 87 (12) (1998) 15601567.
[95] K. Okimoto, R.A. Rajewski, K. Uekama, J.A. Jona, V.J. Stella, The
interaction of charged and un-charged drugs with neutral (HP--CD) and
anionically charged (SBE7--CD) -cyclodextrins, Pharm. Res. 13
(1996) 254256.
[96] A.Y. Tinwalla, B.L. Hoesterey, T.X. Xiang, K. Lim, B.D. Anderson,
Solubilization of thiazolobenzimidazole using a combination of pH
adjustment and complexation with 2-hydroxypropyl--cyclodextrin,
Pharm. Res. 10 (1993) 11361143.
[97] P. Li, E. Tabibi, S.H. Yalkowsky, Combination effect of complexation and
pH on solubilization, J. Pharm. Sci. 87 (1998) 15351537.
[98] M.D. Johnson, B.L. Hoesterey, B.D. Anderson, Solubilization of a
tripeptide HIV protease inhibitor using a combination of ionization and
complexation with chemically modified cyclodextrins, J. Pharm. Sci. 83
(1994) 11421146.
[99] V. Zia, R.A. Rajewski, V.J. Stella, Effect of cyclodextrin charge on
complexation of neutral and charged substrates: comparison of (SBE)7M-CD to HP--CD, Pharm. Res. 18 (2001) 667673.
[100] K.A. Connors, Population characteristics of cyclodextrin complex
stabilities in aqueous solution, J. Pharm. Sci. 84 (7) (1995) 843848.
[101] K.A. Connors, The stability of cyclodextrin complexes in solution, Chem.
Rev. 97 (5) (1997) 13251357 (Washington, D. C.).
[102] R.R. Burnette, K.A. Connors, Statistical properties of thermodynamic
quantities for cyclodextrin complex formation, J. Pharm. Sci. 89 (11)
(2000) 13891394.
[103] Y.L. Loukas, Understanding molecular association and isomers recognition in isomer-cyclodextrin multiple complex formation by improved
liquid chromatographic studies, Anal. Chem. 70 (5) (1998) 966970.

[104] J. Szejtli, in: J.E.D. Davies (Ed.), Cyclodextrin Technology, Kluwer

Academic Publishers, Dordrecht, 1988, pp. 186306.
[105] G. Levy, E.J. Mroszczak, Effect of complex formation on drug absorption
VI, J. Pharm. Sci. 57 (2) (1968) 235239.
[106] R.E. Davis, C.W. Hartman, J.H. Fincher, Dialysis of ephedrine and
pentobarbital from whole human saliva and simulated saliva, J. Pharm.
Sci. 60 (3) (1971) 429432.
[107] T. Tokumura, Y. Tsushima, M. Kayano, Y. Machida, T. Nagai,
Enhancement of bioavailability of cinnarizine from its -cyclodextrin
complex on oral administration with DL-phenylalanine as a competing
agent, J. Pharm. Sci. 74 (4) (1985) 496497.
[108] T. Loftsson, H. Fridriksdottir, A.M. Sigurdadottir, H. Ueda, The effect of
water soluble polymers on drug-cyclodextrin complexation, Int. J. Pharm.
110 (1994) 169177.
[109] T. Loftsson, H. Fridriksdottir, T.K. Gudmundsdottir, The effect of watersoluble polymers on aqueous solubility of drugs, Int. J. Pharm. 127
(1996) 293296.
[110] M. Valero, B.I. Perez-Revuelta, L.J. Rodriguez, Effect of PVP K-25 on
the formation of the naproxen:-cyclodextrin complex, Int. J. Pharm. 253
(2003) 97110.
[111] E. Redenti, L. Szente, J. Szejtli, Drug/cyclodextrin/hydroxy acid
multicomponent systems. Properties and pharmaceutical applications,
J. Pharm. Sci. 89 (1) (2000) 18.
[112] C. Kraus, W. Mehnert, K.H. Froemming, Interactions of -cyclodextrin with Solutol HS 15 and their influence on diazepam solubilization, Pharmazeutische Zeitung-Wissenschaftsausgabe 4 (1) (1991)
[113] D.R. Olander, Simultaneous mass transfer and equilibrium chemical
reaction, AIChE J. 6 (1960) 233239.
[114] C.D. Yu, S.A. Sweetana, N.I. Chu, G.J.L. Lee, I.J. Massey, Enhancement
of solubility, dissolution rate, and oral bioavailability of RS-82856 by
complex formation with cyclodextrins, Drug Dev. Ind. Pharm. 15 (4)
(1989) 609620.
[115] T. Higuchi, K.A. Connors, in: C.N. Reilly (Ed.), Advances in Analytical
Chemistry and Instrumentation, vol. 4, Wiley-Interscience, New York,
1965, pp. 117212.
[116] T. Irie, Y. Tsunenari, K. Uekama, J. Pitha, Effect of bile on the intestinal
absorption of a-cyclodextrin in rats, Int. J. Pharm. 43 (1988) 4144.
[117] J. Szejtli, in: W.F. Smolen, L.A. Ball (Eds.), Controlled Drug
Bioavailability, vol. 3, Wiley, New York, 1985, p. 365.
[118] V.J. Stella, V.M. Rao, E.A. Zannou, V. Zia, Mechanisms of drug release
from cyclodextrin complexes, Adv. Drug Delivery Rev. 36 (1999)
[119] J. Szejtli, Cyclodextrins in drug formulations: part I, Pharm. Technol. Int.
3 (2) (1991) 1522.
[120] E. Memisoglu, A. Bochot, M. Oz alp, M. Sen, D. Duchene, A.A. Hincal,
Direct formation of nanospheres from amphiphilic -cyclodextrin
inclusion complexes, Pharm. Res. 20 (1) (2003) 117125.
[121] K. Kimura, F. Hirayhama, H. Arima, K. Uekama, Effects of aging on
crystallization, dissolution and absorption characteristics of amorphous
tolbutamide-2-hydroxypropyl-beta-cyclodextrin complex, Chem. Pharm.
Bull. (Tokyo). 48 (5) (2000) 646650.
[122] B. Haeberlin, T. Gengenbacher, A. Meinzer, G. Fricker, Cyclodextrins
useful excipients for oral peptide administration? Int. J Pharm. 137 (1996)
[123] K. Uekama, F. Hirayama, M. Daiguji, Effects of - and -cyclodextrins
on base-catalyzed isomerization of prostaglandin A1 and prostaglandin
A2, Chem. Lett. 4 (1978) 327330.
[124] K. Nakanishi, T. Nadai, M. Masada, K. Miyajima, Effect of cyclodextrins
on biological membrane. II. Mechanism of enhancement on the intestinal
absorption of non-absorbable drug by cyclodextrins, Chem. Pharm. Bull.
(Tokyo). 40 (1992) 12521256.
[125] K. Yunomae, H. Arima, F. Hirayama, K. Uekama, Contribution of Pglycoprotein to enhancing effects of dimethyl -cyclodextrin on oral
bioavailability of tacrolimus in rats, 28th International Symposium on
Controlled Release of Bioactive Materials and 4th Consumer &
Diversified Products Conference, Controlled Release Society, Minneapolis, MN, San Diego, CA, United States, vol. 1, 2001, pp. 712713.

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 7899

[126] K. Uekama, T. Horikawa, M. Yamanaka, F. Hirayama, Peracylated
-cyclodextrins as novel sustained-release carriers for a water-soluble
drug, molsidomine, J. Pharm. Pharmacol. 46 (1994) 714717.
[127] L.X. Yu, E. Lipka, J.R. Crison, G.L. Amidon, Transport approaches to
the biopharmaceutical design of oral drug delivery systems: prediction
of intestinal absorption, Adv. Drug Delivery Rev. 19 (3) (1996)
[128] D. Duchene, D. Wouessidjewe, G. Ponchel, Cyclodextrins and carrier
systems, J. Control. Release 62 (1999) 263268.
[129] H. Ueda, J.H. Perrin, T. Nagai, A microcalorimetric investigation of the
binding of cinnarizine to cyclodextrins, J. Pharm. Biomed. Anal. 7 (1989)
[130] J. Szejtli, The significance of cyclodextrins: biological effects, J. Drug
Dev. 4 (Suppl. 1) (1991) 311.


[131] G.H. Anderson, F.M. Robbins, F.I. Dominigues, C.L. Long, The
utilization of Schardinger dextrins by the rat, Toxicol. Appl. Pharmacol.
5 (1963) 257266.
[132] A. Gerloczy, A. Fonagy, J. Szejtli, Absorption and metabolism of
-cyclodextrin by rats, First International Symposium on Cyclodextrins,
Reidel Publishing, 1981, pp. 101108.
[133] R.N. Antenucci, J.K. Palmer, Enzymatic degradation of - and
-cyclodextrins by Bacteroides of the human colon, J. Agric. Food
Chem. 32 (1984) 13161321.
[134] B.C. Saha, J.G. Zeikus, Cyclodextrin degrading enzymes, Starch/Staerke
44 (1992) 312315.
[135] G. Schmid, in: J.L. Atwood, J.E.D. Davies, D.D. MacNicol, F. Vogtle, J.-M.
Lehn (Eds.), Comprehensive Supramolecular Chemistry, vol. 3, Pergamon,
2000, pp. 615626.