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Department of Chemical Engineering, Northeastern University, 457 Snell Engineering Center, Boston, Massachusetts 02115, United States
b
Pfizer, Inc., 2800 Plymouth Road, Ann Arbor, Michigan 48105, United States
c
Pfizer, Inc., Eastern Point Road, Groton, Connecticut 06340, United States
Received 18 April 2007; accepted 30 July 2007
Available online 16 August 2007
Abstract
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
Contents
1.
2.
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 . . . . . . . . . .
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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).
1
Tel.: +734 622 3628; fax: +860 686 6209.
2
Tel.: +860 441 4281; fax: +860 715 9575.
0168-3659/$ - see front matter 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jconrel.2007.07.018
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79
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3.
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
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91
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Table 1
Summary of drug, cyclodextrin, and dosage form parameters for studies in which cyclodextrins were successfully utilized to enhance bioavailability
83
(continued on next page)
84
Table 1 (continued )
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
Indomethacin
[38] (rabbit)
4.2(A) 3.11
358
Rutin [12]
(dog)
Tolbutamide
[46] (rabbit)
6.8(A) 2.23
611
2.34
270
Dosage
form
Physical
mixture
29:1
UCD CD:
Drug
(molar)
Comparison
CD type, Binding Other
dosage form
CD:Drug constant formation
components
(M 1)
Cmax
AUC increase Tmax
change change
(x AUC
(hr)
(g/ml)
control)
-CD
1:1
No change
0069
[49]
50
1:1
10.8
-CD
(K = 5300), 1:1
100.1
[56]
(K = 523)
0.04
(pH 4)
200
1:1
5.2
0.1053
[49]
Complex Freezedrying
Complex Slurry
200
(tablet)
(ethanol
water)/
kneading/
drying
Physical
mixture
1:1
100/ 1:1
kg
52.0
827
Gelatin
(pH 7.4) capsule,
dosed with
water
Drug (in
capsule,
with water)
5300
Dosed with Freeze[51],
water
dried drug
523 [57]
(with water)
No change
1378
(pH = 1,
25 C)
Gelatin
capsule
No change
-CD
1:1
266
Starch
-CD
2:1 [45]
196 [45]
-CD
1:1
Drug (in
gelatin capsule)
Freeze-dried
drug (in gelatin
capsule)
No change
Tablet
No change
(complex
replaced by drug)
Drug
No change
(serum
glucose
variation
coefficient)
4.5
3.5
0.084
0.12
clogP Water
Buffered solubility
MW solubility (mg/mL)
(mg/mL)
85
86
Fig. 1. Structures of compounds used in studies, summarized in Tables 1 and 2, where cyclodextrins were employed to enhance bioavailability.
87
88
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
com
CDf drugf
com
CDtotal =V comdrugf
K drugf
CDtotal
V
1 K drugf
KSo CDtotal
1 KSo V
z1
Dtotal 1 KSo Dtotal
89
90
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).
91
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.
92
ADdrug
lbl
KSo CDtotal
1 KSo V
10
93
ddrugabs
ka drugf Vlumen
dt
11
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
94
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
cyclodextrin
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
95
96
97
98
99
[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.