Pharmaceutical Applications of Cyclodextrins: Basic Science and Product Development
Pharmaceutical Applications of Cyclodextrins: Basic Science and Product Development
Pharmaceutical Applications of Cyclodextrins: Basic Science and Product Development
Abstract
Objectives Drug pipelines are becoming increasingly difficult to formulate. This is
punctuated by both retrospective and prospective analyses that show that while 40% of
currently marketed drugs are poorly soluble based on the definition of the biopharmaceu-
tical classification system (BCS), about 90% of drugs in development can be characterized
as poorly soluble. Although a number of techniques have been suggested for increasing
oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged
as a productive approach. This short review is intended to provide both some basic science
information as well as data on the ability to develop drugs in cyclodextrin-containing
formulations.
Key findings There are currently a number of marketed products that make use of these
functional solubilizing excipients and new product introduction continues to demonstrate
their high added value. The ability to predict whether cyclodextrins will be of benefit in
creating a dosage form for a particular drug candidate requires a good working knowledge
of the properties of cyclodextrins, their mechanism of solubilization and factors that con-
tribute to, or detract from, the biopharmaceutical characteristics of the formed complexes.
Summary We provide basic science information as well as data on the development of
drugs in cyclodextrin-containing formulations. Cyclodextrins have emerged as an important
tool in the formulator’s armamentarium to improve apparent solubility and dissolution rate
for poorly water-soluble drug candidates. The continued interest and productivity of these
materials bode well for future application and their currency as excipients in research,
development and drug product marketing.
Keywords biopharmaceutical characteristics; cyclodextrins; cyclodextrin-containing
formulations; pharmaceutical applications; solubilization
Introduction
In 1891 a French scientist, A. Villiers, published a short note on his isolation of a bacterial
digest which he named ‘cellobiosine’.[1] The compound was stable towards acid hydrolysis
and, like starch, did not display reducing properties. It is now thought that Villiers had
isolated a mixture of a- and b-cyclodextrin (aCD and bCD). Later an Austrian microbiolo-
gist, Franz Schardinger, described two compounds that he had isolated from bacterial digest
of potato starch,which he designated a-dextrin and b-dextrin.[2] It was not until the 1940s,
however, that the structure and physicochemical properties of cyclodextrins (CDs) were
described in detail.[3,4] The first CD-related patent was issued in Germany in 1953.[5] In this
patent, the basic properties of the natural aCD, bCD and g-cyclodextrin (gCD) are described
and how, through complex formation, these CDs can enhance aqueous solubility and chemi-
cal stability of biologically active compounds. Bacterial digests of starch consist of a crude
mixture of cyclic and linear dextrins as well as proteins and other impurities. It was difficult
to isolate pure CDs from the digests and, as a result, only very small amounts of pure natural
Correspondence: Professor aCD, bCD and gCD were available at that time. This hampered industrial exploitation of
Thorsteinn Loftsson, Faculty of CDs. Biotechnological advances that occurred in the early 1970s led to dramatic improve-
Pharmaceutical Sciences, ment in CD production and pharmaceutical-grade CDs can now be obtained at relatively low
University of Iceland,
Hofsvallagata 53, IS-107
prices. The first pharmaceutical product containing CD, prostaglandin E2/bCD sublingual
Reykjavik, Iceland. tablets (Prostarmon E, Ono), was marketed in Japan in 1976. Worldwide there are currently
E-mail: thorstlo@hi.is about 35 different CD containing drug products on various world markets (Table 1).
1607
1608 Journal of Pharmacy and Pharmacology 2010; 62: 1607–1621
a-Cyclodextrin (aCD)
Alprostadil Caverject Dual Intravenous solution Pfizer (Europe)
Cefotiam-hexetil HCl Pansporin T Tablet Takeda (Japan)
Limaprost Opalmon Tablet Ono (Japan)
PGE1 Prostavastin Parenteral solution Ono (Japan); Schwarz (Europe)
b-Cyclodextrin (bCD)
Benexate HCl Ulgut, Lonmiel Capsule Teikoku (Japan); Shionogi (Japan)
Cephalosporin Meiact Tablet Meiji Seika (Japan)
Cetirzine Cetrizin Chewable tablet Losan Pharma (Germany)
Chlordiazepoxide Transillium Tablet Gador (Argentina)
Dexamethasone Glymesason Ointment, tablet Fujinaga (Japan)
Dextromethorphan Rynathisol Synthelabo (Europe)
Diphenhydramine and chlortheophylline Stada-Travel Chewable tablet Stada (Europe)
Ethinylestradiol and drospirenone Yaz Tablet Bayer (Europe, USA)
Iodine Mena-Gargle Solution Kyushin (Japan)
Meloxicam Mobitil Tablet and suppository Medical Union (Egypt)
Nicotine Nicorette Sublingual tablet Pfizer (Europe)
Nimesulide Nimedex Tablets Novartis (Europe)
Nitroglycerin Nitropen Sublingual tablet Nihon Kayaku (Japan)
Omeprazole Omebeta Tablet Betafarm (Europe)
PGE2 Prostarmon E Sublingual tablet Ono (Japan)
Piroxicam Brexin, Flogene, Cicladon Tablet, suppository Chiesi (Europe); Aché (Brazil)
Tiaprofenic acid Surgamyl Tablet Roussel-Maestrelli (Europe)
2-Hydroxypropyl-b-cyclodextrin (HPbCD)
Cisapride Propulsid Suppository Janssen (Europe)
Indometacin Indocid Eye drop solution Chauvin (Europe)
Itraconazole Sporanox Oral and intravenous solution Janssen (Europe, USA)
Mitomycin MitoExtra, Mitozytrex Intravenous infusion Novartis (Europe)
Sulfobutylether b-cyclodextrin sodium salt (SBEbCD)
Aripiprazole Abilify Intramuscular solution Bristol-Myers Squibb (USA);
Otsuka Pharm. (USA)
Maropitant Cerenia Parenteral solution Pfizer Animal Health (USA)
Voriconazole Vfend Intravenous solution Pfizer (USA, Europe, Japan)
Ziprasidone mesylate Geodon, Zeldox Intramuscular solution Pfizer (USA, Europe)
Randomly methylated b-cyclodextrin (RMbCD)
17b-Estradiol Aerodiol Nasal spray Servier (Europe)
Chloramphenicol Clorocil Eye drop solution Oftalder (Europe)
g-Cyclodextrin (gCD)
Tc-99 Teboroximea CardioTec Intravenous solution Squibb Diagnostics (USA)
2-Hydroxypropyl-g-cyclodextrin (HPgCD)
Diclofenac sodium salt Voltaren Ophtha Eye drop solution Novartis (Europe)
Tc-99 Teboroximea CardioTec Intravenous solution Bracco (USA)
a
An older product contained gCD but has been replaced by HPgCD in the current product.
The following is intended to be a short introduction on natural CDs (i.e. aCD, bCD and gCD) is a three step process:
CDs and their pharmaceutical applications. For more compre- (1) bacterial fermentation and extraction of CD glycosyltrans-
hensive reviews of their chemistry, physicochemical proper- ferase; (2) enzymatic CD production from starch and precipi-
ties and applications the reader is referred to several books tation of CD through complexation; and (3) removal of the
and review articles that have been published in recent complexing agent and product purification. CDs with more
years.[4,6–21] than eight glucopyranose units (i.e. the large-ring CDs) are
usually produced through chromatographic separation of
the enzymatic product without precipitation. The large-ring
Chemistry CDs are more expensive, have generally less complexation
CDs are cyclic oligosaccharides containing six (aCD), seven capacity than aCD, bCD and gCD and are less relevant
(bCD), eight (gCD), or more (a-1,4-)-linked d-glucopyranose pharmaceutically, and therefore will not be covered in this
units (Table 2). Manufacturing of the three most common short compilation.[22,23] Due to the chair structure of the
Pharmaceutical applications of cyclodextrins Thorsteinn Loftsson and Marcus E. Brewster 1609
OD
ID Secondary
Hydrophobic cavity hydroxy groups
Primary hydroxy
groups
glucopyranose units, CD molecules are shaped like cones depend on the structure of the appended substituent but
with secondary hydroxy groups extending from the wider also on their location within the CD molecule and the
edge and the primary groups from the narrow edge (Table 2). number of substituents per CD molecule. The molar degree
This gives the CD molecule a hydrophilic outer surface of substitution (MS) is defined as the average number of
while the lipophilicity of their central cavity has been substituents that have reacted with one glucopyranose repeat
estimated to be comparable with an aqueous ethanolic unit (Table 3). In some cases, as in hydroxypropylation, the
solution.[24] Although the natural CDs and their complexes electrophile (propylene oxide) can react with hydroxyl
are hydrophilic, their aqueous solubility can be rather groups of the substituents forming a polymeric side chain
limited, especially in the case of bCD. This is thought to be (polypropylene glycol). Thus, the MS value can range from
due to relatively strong binding of the CD molecules in the 0 (no substitution) to over 3 when two or more substituents
crystal state (i.e. relatively high crystal lattice energy). react to form oligomeric or polymeric side chains. The
Random substitution of the hydroxy groups, even by hydro- number represents the average MS of a mixture of isomers.
phobic moieties like methoxy functions, will result in Hence, MS does not necessarily describe how many hydroxyl
dramatic improvements in their solubility. CD derivatives groups on each glucopyranose unit have been substituted.
of pharmaceutical interest include the hydroxypropyl In carbohydrate chemistry, the degree of substitution (DS)
derivatives of b- and gCD (HPbCD and HPgCD), randomly is defined as the number of hydroxyl groups per anhydro-
methylated bCD (RMbCD), sulfobutylether bCD sodium glucose unit that have been substituted. The values can
salt (SBEbCD) and the so-called branched cyclodextrins, range from 0 (no substitution) to 3 when all three hydroxyl
such as maltosyl-bCD (MbCD) (Table 3).[6,17,20] The physi- groups are substituted. By contrast, in CD chemistry, DS
cochemical properties of the CD derivatives, including their frequently represents the average number of substituents per
aqueous solubility and complexation capabilities, not only CD molecule.
1610 Journal of Pharmacy and Pharmacology 2010; 62: 1607–1621
Table 3 Characteristics of some common cyclodextrins that can be found in marketed pharmaceutical products or that are being investigated as
pharmaceutical excipients
OH
H2
O
CD O C C CH3 2-Hydroxypropyl-β-cyclodextrin
H
H2C C CH3
H
O CH3I Methyl-β-cyclodextrin
OH CD O CH3
OH
O
β-Cyclodextrin HO O
O OH
O
HO OH S
O O O O
S O2 Na*
CD O
O
Maltose-X
Sulfobutylether-β-cyclodextrin sodium salt
CD O Maltose Maltosyl-β-cyclodextrin
Natural aCD, bCD and gCD are more resistant towards in a complex. After oral administration, gCD is almost
starch hydrolysing enzymes, and two to five times more resis- completely digested in the gastrointestinal tract while both
tant towards non-enzymatic hydrolysis than the linear oli- aCD and bCD are, to a large extent, digested by bacteria
gosaccharides.[24] In the solid state, CDs are at least as stable in the colon. aCD is, however, digested more slowly than
as sucrose or starch and can be stored for several years at room bCD. The CD derivatives are also susceptible to bacterial
temperature without detectable degradation.[25] The predomi- digestion in the gastrointestinal tract (Table 4).[8,14,21,29–33]
nating non-enzymatic degradation of CDs in aqueous solu-
tions is specific acid-catalysed hydrolysis of the a-acetal Pharmacokinetics and toxicology
linkages to form glucose, maltose and non-cyclic oligosac- Most CDs of current pharmaceutical interest (Table 1) are
charides.[26] The half-life (t1/2) for the ring-opening of bCD hydrophilic and, due to their bacterial digestion, high
was determined to be about 15 h at 70°C and pH 1.1.[26] The molecular weight (973–2163 Da), large number of hydrogen
CD derivatives are hydrolysed at about the same rate, ring- donors and acceptors, and high hydrophilicity (logKo/w
opening being the dominant degradation pathway. In aqueous between -8 and -12), their oral bioavailability is generally
media, CDs are chemically stable under neutral and basic below 4% (Table 4). The oral bioavailability of HPbCD in
conditions. CDs are resistant to b-amylases that hydrolyse humans is between 0.5 and 3.3% with 50–65% of the oral
starch from the non-reducing end, but are slowly hydrolysed dose excreted intact in the faeces and the remainder mainly
by a-amylases that hydrolyse starch from within the carbo- being metabolized by bacteria in the colon. CD absorbed
hydrate chain. a-Amylases are present in humans, mainly in intact is rapidly excreted in the urine. Toxicological studies
pancreatic juice and saliva. The hydrolytic rate depends on the have demonstrated that orally administered CDs of phar-
ring size and on the fraction of free CD. For example, aCD maceutical interest are practically nontoxic due to lack of
and bCD are essentially stable towards a-amylase in saliva absorption from the gastrointestinal tract.[8] However, there
while gCD is rapidly digested by salivary and pancreatic amy- is one exception, that being RMbCD. This methylated
lase.[27,28] aCD and bCD are not digested after oral adminis- bCD derivative (DS of 1.8) is somewhat more lipophilic
tration to germ-free rats while gCD is completely digested.[29] (LogKo/w = -2.4) and has fewer hydrogen-bond donors
In general, free CD is hydrolysed more rapidly than CD bound than the other CDs. Consequently its oral bioavailability
Pharmaceutical applications of cyclodextrins Thorsteinn Loftsson and Marcus E. Brewster 1611
Cyclodextrin Rats After intravenous injection After intravenous injection Max. dosage in marketed drug
to ratsb to humansc productsd
forala Vda t1/2a furine unch.a Vda t1/2a Oral Intravenous
(%) (l/kg) (h) (%) (l/kg) (h) (mg/day) (mg/day)
is slightly higher, or up to 12% in rats.[29] Presently, oral replaced by HPgCD in the current product (CardioTec;
administration of methylated bCDs is limited by their Bracco, USA).[38] Aqueous gCD solutions tend to turn opales-
potential toxicity. Oral administration of aCD is well toler- cent due to gCD aggregation while HPgCD solutions remain
ated and is not associated with any observable adverse clear. The parenteral dose of gCD and HPgCD in CardioTec
effects.[34,35] The same applies to bCD,[36] gCD,[28] HPbCD[37] appears to be about 50 mg. Due to their favourable toxico-
and SBEbCD.[21] The main side effects of oral administra- logical profile, CDs are frequently preferred to organic sol-
tion of high doses of these CDs are similar to those related vents during in-vitro/in-vivo evaluation of new chemical
to poorly digestible carbohydrates and include flatulence and entities.
soft stools. aCD, bCD and HPbCD can all be found in HPbCD has a small volume of distribution (VD ª 0.2 l/kg)
various oral drug products and all three parent cyclodextrins and a short half-life (t1/2 ª 1.7 h), and is mainly excreted
(i.e. aCD, bCD and gCD) are being used in dietary pro- unchanged in the urine after parenteral administration to
ducts. The maximum CD dose that can be found in oral humans (Table 4; Figure 1).[21,33] In humans there is a linear
drug products is shown in Table 4. However, the CD dose relationship between the parenterally administered HPbCD
found in approved dietary products can be much higher. For dose and the area under the plasma concentration–time
example, the daily dose of aCD in FBCX tablets (ArtJen, curve (AUC). No side effects were observed after parenteral
Canada) is 6000 mg while the daily dose in registered drug administration of up to 24 g of HPbCD daily (12 g twice
products is only about 1 mg. daily) for 15 days. The pharmacokinetics of SBEbCD is very
Parenteral administration of CDs can be somewhat similar to that of HPbCD (Stella & He 2008).[21] The total
more limited. The haemolytic effect of CDs on human eryth- plasma clearance of both HPbCD and SBEbCD is similar to
rocytes in phosphate-buffered saline are in the order meth- the glomerular filtration rate and since CDs are predo-
ylated bCDs > bCD > HPbCD > aCD > gCD > HPgCD > minately eliminated unchanged in urine (see Table 4), their
SBEbCD.[8,9,16] There appears to be a correlation between the elimination half-life (t1/2) will increase with impaired or
haemolytic activity and the ability of the CDs to bind or reduced kidney function. However, in individuals with
extract cholesterol from the membranes.[8] This in-vitro cellu- normal kidney function, about 90% of parenterally adminis-
lar lysis study, as well as other comparable in-vitro studies tered CD will be excreted within 6 h of the administration
using intestinal cells, Escherichia coli, human skin fibroblasts and about 99% within 12 h. Thus, administration of CD
and liposomes, do not indicate in-vivo toxicity but rather
provide a method to classify CDs according to their potential Simulated curve Measured concentrations
to destabilize or disrupt cellular membranes.[9] Furthermore, 1000
bCD cannot be given parenterally due to its low aqueous
HPβCD (μg/ml)
Cyclodextrin complexes AP
Table 5 Intrinsic solubility (S0), stability constant (K1:1), complexation efficiency (CE), the drug : CD molar ratio in a drug saturated aqueous CD
solution, the oral dose and the formulation bulk (i.e. the minimum weight of a drug–CD complex containing a given oral drug dose)
Druga Cyclodextrina S0 (mg/ml)b K1:1 (M(1)c CEd Molar ratioe Dose (mg)f Formulation bulkg (mg)
Partly based on data from Loftsson et al.[54,122] a2-Hydroxypropyl-b-cyclodextrin (HPbCD); randomly methylated b-cyclodextrin (RMbCD); sulfobu-
tylether b-cyclodextrin sodium salt (SBEbCD). See Table 3. bDrug solubility in the complexation medium when no cyclodextrin is present. cCalculated
from the experimental determined solubility and Equation 4. dThe complexation efficiency calculated from the slope of a phase solubility diagram
according to Equation 7. eThe drug : CD molar ratio based on the calculated CE according to Equation 8. fSingle oral dosage, estimated values or
literature values. gThe formulation bulk of a solid dose containing the drug–cyclodextrin complex equivalent to the oral drug dose (see Equation 9).
Cyclodextrins and drug degradation where ff is the fraction of free drug and fc is the fraction
CD complexation can retard and sometimes accelerate chemi- of drug in complex. The concentration dependency of kobs
cal decomposition of drugs. Due to saturation kinetics, the can be used to determine K1:1[20,55] If we assume that only 1 : 1
observed first-order rate constants for a reaction (kobs) asymp- drug–CD complex is being formed the following equations
totically approaches a minimum value for stabilizing effect are obtained:
(inhibition) or a maximum value for destabilizing effect
d [ D] ⎛ k + k c K1:1 [ CD ] ⎞
(catalysis) with increasing CD concentration. The value of kobs − = k obs [ D ]T = ⎜ f [ D]T
⎝ 1 + K1:1 [ CD ] ⎟⎠
(11)
at a given CD concentration is the weighted average of the dt
first-order rate constants for degradation of the free (kf) and
the bound (kc) drug (Table 6): If the total CD concentration is much greater than the total
drug concentration ([CD]T ⱖ 10·[D]T) then it can be assumed
k obs = k f ff + k c fc (10) that [CD] ª [CD]T:
Table 6 The stabilizing effect of cyclodextrins on the hydrolytic degradation of methyl salicylate in dilute aqueous hydrochloric acid solutions
(pH 1.0; 65°C)
O H
O H
C OCH3 O H
K1:1 C OCH3 O H
+
O C CH3
O C CH3
O
+H O
+H
kf kc
O
C OCH3 O
C OCH3
OH + HO C CH3
O OH + HO C CH3
O
Table 7 Methods that have been used to enhance the complexation efficiency (CE) of cyclodextrins in aqueous solutions by increasing either the
apparent intrinsic solubility (S0) of the drug or increasing the apparent stability constant (K1:1) of the complex (see Equation 7)
Effect Consequences
Dug ionization Un-ionized drugs do usually form more stable complexes than their ionic counterparts. However,
ionization of a drug increases its apparent intrinsic solubility that can result in enhanced
complexation. S0↑[67–70]
Salt formation It is sometimes possible to enhance the apparent intrinsic solubility of a drug through salt formation
(i.e. forming a more water-soluble salt of the drug without significantly reducing its ability to form
CD complexes). S0↑[71–74]
Acid–base ternary complexes It has been shown that certain organic hydroxy acids (such as citric acid) and certain organic bases are
able to enhance the complexation efficiency by formation of ternary drug–CD–acid or base
complexes. S0↑ and/or K1:1↑[75–79]
Polymer complexes Water-soluble polymers form a ternary complex with drug–CD complexes increasing the observed
stability constant of the drug–CD complex. K1:1↑[80]
Metal complexes Many drugs are able to form somewhat water-soluble metal complexes without decreasing the drug’s
ability to form complexes with CDs. Thus, the complexation efficiency can be enhanced by
formation of drug–metal ion–CD complexes. S0↑[81]
Co-solvents Addition of co-solvents to the complexation media can increase the apparent intrinsic solubility of the
drug that can lead to enhanced CE. S0↑[82,83]
Ion pairing Ion pairing of positively charged compounds with negatively charged CDs enhances the complexation
efficiency. K1:1↑[84]
Combination of two or more methods Frequently the complexation efficiency can be enhanced even further by combining two or more of the
above mentioned methods. For example drug ionization and the polymer method, or solubilization
of the CD aggregates by adding both polymers and cations or anions to the aqueous complexation
medium. S0↑ and/or K1:1↑[73,81,80]
Drug delivery through biological membranes acids and surfactants, enhance drug delivery by decreasing
Most biological membranes consist of aqueous exterior and a the barrier properties of the lipophilic membrane (i.e. by
lipophilic membrane barrier and drugs are mainly transported increasing PM). In contrast, hydrophilic CDs, such as the
through the membranes via passive diffusion (Figure 3). Drug parent aCD, bCD and gCD, and CD derivatives, such as
permeation through such multi-layer barriers has been HPbCD and SBEbCD, increase drug delivery through
described as series of additive resistances analogous to elec-
tric circuits.[85–87] Assuming independent and additive resis- Donor UWL Membrane Receptor
tances of the individual layers, the total resistance (RT) of a (vehicle) RAq RM
simple bilayer membrane can be defined as (Figure 3):
J = PT C v = R T −1C V = ( R Aq + R M ) C V
−1
(17)
= (1 PAq + 1 PM ) C V
−1
CV
C1 K·C Aq
Drug concn
biological membranes by enhancing drug permeation through (FBCX tablets; ArtJen, Canada). Several studies in both
the UWL (i.e. by increasing PAq). In general, hydrophilic CDs animals and humans have indicated that drug–HPbCD and
can only enhance drug delivery through biological mem- drug–SBEbCD complexation has negligible effects on the
branes when PAq is relatively small compared with PM. Hydro- drug pharmacokinetics after parenteral administration.[94–101]
philic CDs do not in general enhance drug delivery through It has been shown that the binding constant of drug–CD com-
membranes if the lipophilic membrane barrier is the main plexes must be greater than about 105 m-1 to have any effect on
permeation barrier. When aqueous vehicles, such as hydrogels the drug pharmacokinetics after parenteral administration.[21]
and oil-in-water creams, are applied to membranes, the UWL Most commonly, drug–cyclodextrin binding constants
is extended into the vehicle and under such conditions have values between 10 and 2000 m-1 and binding constants
CDs can increase drug delivery from the vehicle through the much greater than 5000 m-1 are very rarely observed. Two
membrane. exceptions are, however, known. Sugammadex (Bridion; N.V.
Analysis of literature reports on the effects of CDs on oral Organon, Netherlands) is a gCD derivative that was designed
bioavailability of drugs illustrate this basic relationship to specifically bind rocuronium, a neuromuscular blocking
between PAq, PM and the effects of CDs on drug absorption.[88] agent. The binding constant of the rocuronium–sugammadex
According to the Biopharmaceutics Classification System complex has been determined to be 1.8 ¥ 107 m-1 and sugam-
(BCS) oral drugs are classified according to their aqueous madex is therefore able to reverse rocuronium-induced neu-
solubility characteristics and their ability to permeate the romuscular blockade after intravenous administration.[102,103]
intestinal mucosa.[91] Class I comprises relatively water- Another example is complexation of SBEbCD with certain
soluble drugs that are well absorbed from the gastrointestinal ozonide antimalarial drug candidates possessing binding
tract and, in general, possess the preferred physicochemical constants of about 106 m-1.[104] The pharmacokinetics of
properties for optimum oral bioavailability, which is over 90% these ozonide drug candidates in rats have been shown to be
according to the definition of BCS Class I. Class II consists of affected by the SBEbCD complexation.[105]
relatively water-insoluble drugs (i.e. generally aqueous solu-
bility ⱕ0.1 mg/ml) that, when dissolved, are well absorbed Product development
from the gastrointestinal tract. Class III consists of water-
A search of the literature (SciFinder Scholar, American
soluble drugs that do not readily permeate mucous mem-
Chemical Society, USA) shows that CDs are widely used
branes and, thus, have low oral bioavailability. Finally, Class
during pharmaceutical product development. In 2008 alone,
IV consists of water-insoluble drugs that do not easily perme-
there were about 600 published patents and patent applica-
ate mucous membranes. Data suggest that CDs have little
tions on drugs and drug formulations in which CDs were
effect or even decrease oral bioavailability of BCS Class I
mentioned and over 500 scientific articles included CD in
drugs. They enhance the oral bioavailability of Class II drugs
their studies. Although the main theme of many of these
and Class IV drugs, frequently providing up to a 4- to 6-fold
publications is not CD per se, the sheer number of patents
increase in the oral bioavailability. On the other hand, CDs do
and published research articles shows the extent of this field
not enhance bioavailability of the water-soluble Class III
within the pharmaceutical sciences. The applications of
drugs. The negligible effect of CDs on the bioavailability of
CDs in various drug formulations have been previously
BCS Class III drugs and the large effects they have on Class
reviewed.[15,17,106–110] We provide a few examples in the context
II and Class IV drugs support the notion that hydrophilic CDs
of this review to give a flavour of their drug enablement.
do not enhance drug bioavailability by reducing the barrier
properties of the lipophilic epithelium. Rather, the principal
mechanism appears to be an increase in drug solubility Piroxicam
and enhanced drug permeation through the aqueous mucus Piroxicam is a non-steroidal anti-inflammatory drug that is
upon formation of water-soluble drug–CD complexes. CD practically insoluble in water, based on the USP definitions
enhancement of oral bioavailability allows for a lower drug (Figure 4). It is a borderline BCS Class I drug, relatively potent,
dose to be administered and results in more consistent drug with a biological half-life (t1/2) of 30–60 h but it can cause some
plasma profiles. upper gastrointestinal side effects such as bleeding. The
oral dose is 20 mg piroxicam once a day. A piroxicam–bCD
Release of drugs from the complex complex can be prepared by dissolving piroxicam and bCD
The major driving force for drug release from the CD com- (molar ratio 1 : 2.5) in aqueous ammonium hydroxide solution,
plexes is simple dilution although other mechanisms, such as followed by lyophilization or spray drying to form white
drug–protein binding, direct drug partition from the complex
to tissue and competitive binding, do contribute to rapid
drug release from the complexes.[16,20,21,92] Thus, with only few O O
exceptions, administration of drugs in the form of drug–CD S CH3
N
complexes does not hamper their therapeutic effect. In the H
majority of cases CDs increase the oral absorption of drugs, N
but there are a couple of reports of reduced bioavailability.
For example, oral absorption of [3H]benzo[a]pyrene was OH O N
reduced upon simultaneous administration of the compound
and relatively large doses of bCD[93] and large oral dosages Figure 4 Piroxicam. Piroxicam is a weak acid: pKa 6.3, MW 331.3 Da,
of aCD are used to reduce oral absorption of dietary fat m.p. 198–300°C, logKoctanol/water 3.1. Data from Moffat et al.[118]
1618 Journal of Pharmacy and Pharmacology 2010; 62: 1607–1621
complex powder.[111] The aqueous solubility of un-ionized Table 8 The effect of salt formation on ziprasidone solubility in pure
piroxicamis about 0.02 mg/ml. Ionization of the drug increases water and in aqueous solutions containing either 40% (w/v) HPbCD
the apparent S0, which leads to an enhanced CE (Equation 7, (MW1309) or 40% (w/v) SBEbCD (MW 2163)
Table 7). Since ammonia has a low vapour pressure, it is almost Salt Solubility corresponding to weight of ziprasidone
completely removed during lyophilization or spray drying.[74] free base (mg/ml)
The product is a true piroxicam–bCD inclusion complex.[112]
Pure water 40% (w/v) 40% (w/v)
The stability constant (K1:1) of the piroxicam–bCD complex
HPbCD SBEbCD
is 90 m-1 and 191.3 mg of the complex powder is equivalent
to 20.0 mg of pure piroxicam. Formation of the complex Free base 0.0003 0.26 0.35
increases the aqueous solubility of the drug from about Hydrochloride 0.08 2.4 4.0
0.02 mg/ml to about 0.15 mg/ml (pH 5 and 37°C) as well as its Aspartate 0.17 1.3 9.3
wettability and thus the drug dissolution rate is enhanced.[113] Tartrate 0.18 12.4 26
The advantages of tablets containing the piroxicam– Esylate 0.36 13.7 15
Mesylate 1.0 17.3 44
bCD complex (Brexin tablets) over tablets containing
un-manipulated piroxicam, were more rapid absorption, more The solubility values represent mg free base dissolved in 1 ml. The pH
rapid onset of analgesia and apparently reduced gastrointesti- of the salt solutions was 2.3→2.8 pH units below the apparent pKa of
nal irritation, but the complexation did not affect the absolute the drug molecule. Modified from Kim et al.[115,116]
bioavailability of this BCS Class I drug.[113,114]
Figure 5 Ziprasidone. Ziprasidone is a weak base: pKa 6.5, MW Figure 6 Itraconazole. Itraconazole is a weak base: pKa 3.7, MW
412.9 Da (free base) or 467.4 Da (hydrochloride), oral bioavailability 705.6 Da, m.p. 166.2°C, logKoctanol/buffer pH 8.1 5.66. Data from Moffat
59%. Data from Moffat et al.[118] et al.[118]
Pharmaceutical applications of cyclodextrins Thorsteinn Loftsson and Marcus E. Brewster 1619
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