R E V I E W S
`
`CYCLODEXTRIN-BASED
`PHARMACEUTICS: PAST, PRESENT
`AND FUTURE
`
`Mark E. Davis* and Marcus E. Brewster‡
`
`Abstract | Cyclodextrins are cyclic oligomers of glucose that can form water-soluble inclusion
`complexes with small molecules and portions of large compounds. These biocompatible, cyclic
`oligosaccharides do not elicit immune responses and have low toxicities in animals and humans.
`Cyclodextrins are used in pharmaceutical applications for numerous purposes, including
`improving the bioavailability of drugs. Current cyclodextrin-based therapeutics are described and
`possible future applications discussed. Cyclodextrin-containing polymers are reviewed and their
`use in drug delivery presented. Of specific interest is the use of cyclodextrin-containing polymers
`to provide unique capabilities for the delivery of nucleic acids.
`
`Cyclodextrins (CDs) comprise a family of cyclic
`oligosaccharides, and several members of this family
`are used industrially in pharmaceutical and allied
`applications. CDs are manufactured from starch, one
`of the two glucose-containing polymers produced by
`photosynthesis (the other is cellulose). Starch consists
`of D-glucopyranoside building blocks that have both
`α-1,4- AND α-1,6-GLYCOSIDIC LINKAGES. The degradation of
`starch (which is primarily derived from corn, but also
`from potatoes and other sources) by the enzyme gluco-
`syltransferase generates, by chain splitting and
`intramolecular rearrangement, primary products that
`are cyclic oligomers of α-1,4-D-glucopyranoside, or
`CDs. FIGURE 1 shows several schematic representations
`of β-CD. CDs derive their system of nomenclature
`from the number of glucose residues in their structure,
`such that the glucose hexamer is referred to as α-CD,
`the heptamer as β-CD and the octomer as γ-CD (FIG. 2).
`There are literally thousands of variations of CDs that
`have variable ring size and random or site-specific
`chemical functionalization. A comprehensive overview
`of all aspects of CDs is available1.
`The earliest reference to a substance that was later
`recognized as a CD was published in 1891 (REF. 2). By
`1953, Freudenberg et al.3 had received the first patent on
`the use of CDs in drug formulations. This patent covered
`
`most of the important concepts that are used even today,
`including the improvement of drug properties such as
`increased aqueous solubility and increased stability
`towards drug oxidation. Currently, CDs have found uses
`in many applications, such as in agrochemicals, pharma-
`ceuticals, fragrances, foods and so on. This review will
`concentrate on the pharmaceutical uses of CDs.
`
`The basis of CDs as pharmaceutical excipients
`The three-dimensional structure of CDs endows them
`with properties that are useful for pharmaceutical appli-
`cations. Because of the large number of hydroxyl
`groups on CDs, they are water-soluble. The water solu-
`bilities of α-, β- and γ-CD at ambient conditions are
`approximately 13%, 2% and 26% (weight by weight
`(w/w)), respectively (for β-CD this is approximately
`18.8 g per l or 16.6 mM)1. The lower solubility of β-CD
`compared with α-CD, even though the former contains
`a higher number of hydroxyl groups than the latter, is
`due to the formation of an internal hydrogen-bond
`network between the secondary hydroxyl groups. The
`disruption of hydrogen bonding via molecular
`manipulation gives rise to an increase in water solu-
`bility. For example, hydroxypropyl-β-CD (HPβCD)
`has an aqueous solubility of 60% (w/w) or more4.
`Although the entire CD molecule is water soluble, the
`
`α-1,4- AND α-1,6- GLYCOSIDIC
`LINKAGES
`The D-glucopyranoside unit
`contains six carbons and two
`of these units can be chemically
`linked from the 1-carbon of a
`unit to either the 4-carbon or
`the 6-carbon of the second unit.
`
`*Chemical Engineering,
`California Institute of
`Technology, Pasadena,
`California 91125, USA.
`‡Johnson & Johnson
`Pharmaceutical Research
`and Development,
`Turnhousteweg 30,
`2340 Beerse, Belgium.
`Correspondence to M.E.D.
`e-mail:
`mdavis@cheme.caltech.edu
`doi:10.1038/nrd1576
`
`NATURE REVIEWS | DRUG DISCOVERY
`
`VOLUME 3 | DECEMBER 2004 | 1 0 2 3
`
`Hopewell EX1068
`Hopewell v. Merck
`IPR2023-00480
`
`1
`
`

`

`OH
`
`OH
`
`O
`
`OH
`
`O
`
`O H
`O
`
`O H
`
`O
`
`HO
`
`O
`
`H
`O
`
`H O
`
`H
`O
`
`O
`
`OO
`H
`
`H
`
`OH
`
`O O
`
`R E V I E W S
`
`HO
`
`O H
`
`O
`
`H O
`
`O H
`
`O
`
`HO
`
`O
`
`HO
`O
`
`OH
`
`HO
`
`O
`
`OH
`
`O
`OH
`
`OH
`Figure 1 | Schematic representations of β-cyclodextrin. The open and closed arrows point to primary and secondary
`hydroxyl groups, respectively. The cyclodextrin (CD) architecture is a cup that is 0.79 ± 0.01 nm from top to bottom (primary OH
`face to secondary OH face), and is slightly larger on the face containing secondary hydroxyl groups. The cavity (0.47–0.53,
`0.60–0.65 and 0.75–0.83 nm for α-, β- and γ-CD, respectively) and exterior diameters of the CDs (1.46 ± 0.04, 1.54 ± 0.04 and
`1.75 ± 0.04 nm for α-, β- and γ-CD, respectively, for the faces containing secondary hydroxyl groups) expand as the number of
`glucopyranoside units increase1.
`
`interior of the cup is relatively apolar and creates a
`HYDROPHOBIC micro-environment. CDs therefore have
`HYDROPHILIC cavity exteriors and hydrophobic cavity
`interiors. These properties are responsible for their
`aqueous solubility and ability to encapsulate hydro-
`phobic moieties within their cavities, and the incorpo-
`ration of ‘guest’ molecules in CD inclusion complexes
`in aqueous media has been the basis for most pharma-
`ceutical applications. A dynamic equilibrium between
`free CDs, free drug molecules and their formed inclu-
`sion complexes is established if drug molecules are of
`
`HYDROPHOBIC
`An affinity for, and propensity
`to dissolve in, non-polar solvents
`such as hydrocarbons.
`
`HYDROPHILIC
`An affinity for, and propensity
`to dissolve in, water and other
`polar solvents.
`
`a
`
`OH
`
`O
`
`O
`OH
`
`OH
`
`O
`
`OH
`O
`
`OH
`
`OH
`
`O
`
`HO
`
`OH
`
`O
`
`HO
`
`O
`
`b
`
`O
`OH
`
`OH
`
`HO
`
`O
`
`O
`OH
`
`OH
`O
`
`O
`
`HO
`OH
`
`HO
`
`OH
`O
`
`HO
`
`O
`
`sufficient size and have appropriate properties for the
`formation of inclusion complexes. FIGURE 3 schematically
`illustrates this dynamic equilibrium for 1:1 and 1:2
`drug–CD complexes. The formation of inclusion
`complexes is possible with the entire drug molecule or
`only a portion of it. FIGURE 3C presents models of how
`α-, β- and γ-CD can form inclusion complexes with
`prostaglandin E2. Because of cavity size, α-CD com-
`plexes well with aliphatic chains and molecules such as
`polyethylene glycol (PEG), whereas β-CD is appropriate
`for aromatic rings, such as that in paclitaxel.
`For CDs to be pharmaceutically useful, they must be
`biocompatible. CDs show resistance to degradation by
`human enzymes; CDs injected intravenously into
`humans are therefore essentially excreted intact via the
`kidney. However, bacterial and fungal enzymes (amy-
`lases) can degrade CDs. Ingested CDs can therefore be
`metabolized in the colon prior to excretion. The toxicities
`of CDs are dependent on their route of administration.
`For example, the dose that causes 50% death (LD50)
`values of α-, β- and γ-CD administered intravenously
`into mice are approximately 1.0 g per kg5, 0.79 g per kg5
`and more than 4.0 g per kg6, respectively. β-CD has an
`affinity for cholesterol and can extract it and other lipid
`membrane components from cells. At sufficiently high
`concentrations, β-CD can cause haemolysis of ery-
`throcytes. Additionally, parenteral administration of
`β-CD is not possible because of its poor solubility
`(which leads to microcrystalline precipitation in the
`kidney), as well as the fact that it forms complexes
`with cholesterol that accumulate in the kidney and
`produce renal tubule damage. Functionalized β-CDs
`can mitigate these problems.
`Chemically modified CDs result from etherification
`or the introduction of other functional groups at the 2-,
`3- and 6-hydroxyl groups of the glucose residues. These
`changes improve solubility through two mechanisms: by
`breaking the 2-OH–3-OH hydrogen bonds, and by pre-
`venting crystallization due to creation of a statistically
`substituted material that is made up of many isomeric
`components and gives rise to an amorphous product.
`
`O
`
`HO
`
`OH
`
`O
`
`OH
`
`OH
`
`OH
`
`HO
`
`HO
`O
`
`O
`
`OH
`
`O
`OH
`
`HO
`
`O
`
`O
`
`OH
`
`OH
`O
`
`HO
`OH
`
`O
`
`O
`OH
`
`OH
`
`O
`
`HO
`
`HO
`
`OH
`
`HO
`
`O
`
`O
`
`OH
`
`OH
`
`OH
`
`O
`
`OH
`
`O
`
`OH
`
`c
`
`HO
`
`O
`
`O
`
`HO
`
`O
`OH
`
`OH
`
`O
`
`OH
`
`OH
`
`OH
`O
`
`HO
`
`HO
`
`O
`
`HO
`
`HO
`O
`
`OH
`
`O
`
`OH
`
`O
`HO
`
`O
`
`OH
`
`OH
`
`HO
`O
`
`O
`HO
`Figure 2 | Schematic representations of cyclodextrins. α-CD (a), β-CD (b) and γ-CD (c)
`contain 6, 7 and 8 glucopyranoside units, respectively. The molecular masses of α-, β- and γ-CD
`are 972, 1,135 and 1,297 Da, respectively.
`
`O
`
`OH
`
`1024 | DECEMBER 2004 | VOLUME 3
`
`www.nature.com/reviews/drugdisc
`
`2
`
`

`

`R E V I E W S
`
`response in mammals. Because of these highly desirable
`properties, CDs have found numerous pharmaceutical
`applications; reviews on the use of CDs in drug delivery
`are available7–13.
`
`Pharmaceutical applications of CDs
`Current pharmaceutical research has a number of drivers,
`including the nature of the drugs being developed, the
`need for generating orally bioavailable dosage forms
`and the preparation of solubilized parenteral formula-
`tions. Drug discovery has evolved over the years to the
`point that high-throughput screening techniques have
`become routine. These approaches put significant evo-
`lutionary pressure on emerging drug candidates, and
`this has led to a systematic increase in molecular mass,
`lipophilicity and a decrease in water solubility for lead
`compounds over time14,15. This, in turn, has had a sig-
`nificant impact on what is required from drug delivery
`formulators, in that the number of formulation options
`has had to be increased to address the larger diversity of
`challenges presented.
`For a drug to be orally available, the compound
`must dissolve and be absorbed through the gastro-
`intestinal tract in such a way that it generates adequate
`drug levels at the pharmacologically active site to ensure
`that the desired action is obtained in a reproducible
`manner. Retrospective studies show that >40% of drug
`failures in development can be traced to poor biophar-
`maceutical properties, specifically poor dissolution or
`poor permeability16. In recognition of the importance of
`these factors, the FDA and other drug regulatory
`organizations have defined a Biopharmaceutical Classi-
`fication System in which drugs are divided into four
`types on the basis of their solubility and permeability
`characteristics (FIG. 4)17–19. High-throughput drug dis-
`covery methodologies are increasingly selecting difficult
`Type II compounds, and CDs can be an important
`enabling technology for these compounds in partic-
`ular20,21. By increasing the apparent water solubility of
`a drug candidate, formulations can be generated such
`that a Type II material behaves like a Type I compound,
`with a resulting increase in oral bioavailability20,22 (BOX 1).
`The reasons for the inclusion of CDs in a particular
`formulation can vary widely (BOX 2)23, and are specific
`to the circumstance — that is, the specific physico-
`chemical issues that have to be overcome and the
`administration route24–26.
`
`Initial applications of α- and β-CDs: prostaglandin
`and nonsteroidal anti-inflammatory agents. CDs first
`came to the fore in marketed products as drug delivery
`technologies that enabled the development of various
`prostaglandins27,28. One of first of these compounds,
`PGE2, a substance with potent oxytocin-like effects,
`was of interest as a possible agent for the induction of
`labour in childbirth29,30. As with other members of the
`E-type prostoglandins, these compounds are highly
`unstable, and this feature complicated their formula-
`tion and development. β-CD complexes of PGE2
`resulted in a significant increase in their solid-state
`stability, and a product designed along these lines
`
`Drug
`
`1:1 drug–CD complex
`
`CD
`
`+
`
`+
`
`CD
`
`Drug
`
`1:2 drug–CD complex
`
`CO2H
`
`b
`
`O
`
`HO
`
`OH
`
`CO2H
`
`c
`
`O
`
`HO
`
`OH
`
`CO2H
`
`OH
`
`A
`
`B
`
`Ca
`
`O
`
`HO
`
`Figure 3 | Schematic illustration of the association of free cyclodextrin (CD) and drug to
`form drug–CD complexes. A | 1:1 drug–CD complex. B | 1:2 drug–CD complex. C | Proposed
`models of inclusion complexes between prostaglandin E2 and (a) α-CD, (b) β-CD and (c) γ-CD.
`Adapted from REF. 1.
`
`The complexity of these mixtures can be appreciated
`by considering β-CD. For this compound, there are 21
`hydroxyl functional groups and therefore 221 –1 possible
`combinations for substitutions (that is, more than 2
`million). If an optically active centre is introduced, as in
`the case of 2-hydroxypropylation, the number of geo-
`metrical and optical isomers is truly astronomical, given
`that the β-CD nucleus contains 28 chiral centres. It is
`conceivable that the pharmaceutical performance of
`these isomeric mixtures can change with the extent and
`degree of substitution, and so these factors have to be
`assessed and specified in the excipient. In practice, this
`is done by analogy with other chemically modified
`pharmaceutical starches and celluloses, such as hydroxy-
`propyl cellulose and hydroxylpropylmethyl cellulose.
`Both the European Pharmacopeial monograph and the
`proposed United States Pharmocopeial monograph on
`HPβCD, for example, specify that the material should
`have a molar substitution (expressed as the number of
`hydroxypropyl groups per anhydroglucose unit)
`between 0.4 and 1.5; this means 2.8–10.5 hydroxypropyl
`functional groups per cyclodextrin molecule. They also
`specify that less than 1.5% unmodified β-CD should be
`present. The molar substitution can be determined
`using nuclear magnetic resonance and infra-red
`methods. Two functionalized CDs, hydroxypropyl β-CD
`(HPβCD) and sulphobutyl ether β-CD (SBEβCD), are
`available in FDA-approved products for human use (see
`below). In addition, CDs do not produce an immune
`
`NATURE REVIEWS | DRUG DISCOVERY
`
`VOLUME 3 | DECEMBER 2004 | 1 0 2 5
`
`3
`
`

`

`On the basis of this administration route, the stabilizing
`effect of α-CD on PGE1 and the suitability of this CD
`for parenteral use (unlike β-CD), formulations of
`PGE1/α-CD complexes were developed. In 1979,
`alprostadil alphadex (Prostavasin) was approved for
`the treatment of peripheral vascular complications,
`including Buerger’s disease29,30. The compound also
`showed activity against chronic arterial occlusions and
`arteriosclerosis.
`Another vascular malady that can be treated
`with alprostadil alphadex is male erectile dysfunction,
`for which the complex is given by intracavernous
`injection31–34. The PGE1–α-CD complex was found to be
`effective in subjects who were not responsive to sildenafil
`citrate (Viagra; Pfizer), an oral inhibitor of phospho-
`diesterase-535. In a study of 67 patients that failed
`sildenafil citrate therapy at 50 and 100 mg, 85–90%
`reported improvements in erectile function when
`PGE1–α-CD was self-administered after ‘at-home’ treat-
`ment. Caverject Impluse is approved for use in the
`United States on the basis of these medical needs.
`The complexity of the administration route prompted
`the development of more convenient dosing options,
`including intravenous dosage forms. These drivers
`resulted in a modified formulation (Prostandin), which
`was approved in 1982 in Japan and subsequently in a
`number of other countries, including Germany29,30.
`A third example of a prostaglandin marketed as a CD
`complex is limaprost alphfadex (Opalmon/ Prorenal;
`Ono)29,30,36,37. This prostaglandin analogue was devel-
`oped for the treatment of vascular disease and was
`shown to have improved antiplatelet aggregation and
`vasodilation activity relative to PGE1. Importantly, the
`compound was orally available and showed a good sepa-
`ration between its therapeutic action and unwanted side
`effects (mainly oxytocin-like effects). The limoprost–α-
`CD complex was found to be safe and effective in the
`treatment of Buerger’s disease and was approved in 1988.
`Nonsteroidal anti-inflammatory drugs (NSAIDs) are
`a mainstay for the treatment of pain38. The major
`drawbacks of these otherwise useful compounds
`include upper gastrointestinal irritation and bleed-
`ing39. Piroxicam (Feldene; Pfizer) is an illustrative
`example. The drug is useful in the treatment of
`osteoarthritis and rheumatoid arthritis, as well as gout,
`acute musculoskeletal disorders and dysmenorrhea40–43.
`It has a relatively long pharmacokinetic half-life, meaning
`that it can be taken once a day, in contrast to many other
`NSAIDs. The parent drug is also poorly water soluble
`(~30 μg per ml), poorly WETTABLE (that is, with a contact
`angle of 70°) and highly crystalline (with a melting
`point of 202 °C and a ΔHmelt of 106 J per g)44–47. This
`imparts to the compound poor dissolution properties,
`as well as dissolution-limited oral pharmacokinetics.
`CDs were applied to this compound in an effort to
`improve several properties, including safety and drug
`dissolution rate. These improved characteristics reduced
`gastrointestinal irritation, and allowed more rapid drug
`absorption and a more rapid onset of the analgesic
`effect. Complexation studies indicated that a molar ratio
`of 2.5 per 1 was optimal for the drug–CD combination
`
`R E V I E W S
`
`Type III
`permeability
`Solubility,
`←
`←
`
`Type I
`←permeability
`Solubility,
`←
`
`Type IV
`Solubility, permeability
`←
`
`←
`
`Type II
`←permeability
`Solubility,
`
`←
`
`Solubility
`
`WETTABILITY
`The wettability of a liquid is
`defined as the contact angle
`between a droplet of the liquid
`in thermal equilibrium on a
`horizontal surface.
`
`Permeability
`
`Figure 4 | Biopharmaceutical Classification System
`(BCS) characterization of drugs based on solubility
`and permeability measures. Drug solubility is defined by
`the dose/solubility ratio, with a soluble drug defined as one
`in which the highest dose intended for human use will
`dissolve in 250 ml of water (the so-called FDA glass of
`water). Permeability can be defined by various in vivo or
`in vitro assays, but a permeable drug is one associated with
`≥90% oral bioavailability or ≥90% absorption as assessed
`by urinary excretion data.
`
`(dinoprostone betadex; Prostarmon E; Ono) was
`approved for the Japanese market in 1976 (TABLE 1).
`Prostarmon E is highly effective and represented a signif-
`icant medical advance, especially for the induction of
`labour in oxytocin-insensitive individuals, but also for
`its tendency to produce less bleeding after delivery.
`The second prostaglandin marketed as a CD com-
`plex was PGE1 (alprostadil alphadex; Prostavasin/
`Edex/Caverject/Prostandin; Schwarz Pharma). PGE1
`relaxes smooth muscle and increases blood flow, and
`was initially developed as a therapeutic to treat periph-
`eral circulatory disorders. Given its limited metabolic
`stability, initial therapies with PGE1 required intra-
`arterial administration to obtain useful clinical results.
`
`Box 1 | Solubilization with cyclodextrins
`
`+
`
`Drug
`
`Kc
`
`Cyclodextrin
`
`Kc = K1:1 =
`
`[D–CD]
`[D] [CD]
`
`Concentration of CD [M]
`
`Concentration of drug [M]
`
`Cyclodextrins (CDs) can enhance
`apparent water solubility by forming
`dynamic, non-covalent, water-soluble
`inclusion complexes as depicted in the
`figure. This interaction is an equilibrium
`governed by an equilibrium constant, Kc.
`The nature of the complex, as well as the
`numerical value of the equilibrium
`constant, can be derived from from
`measuring a particular property of the
`complex as a function of drug and CD
`concentrations. In phase-solubility
`analysis, the increased solubility is
`assessed as a function of CD
`concentration.As illustrated, a number of
`solubility profiles are possible, each giving
`insight into the type of complex formed,
`as well as its stoichiometry. An A-type
`profile (red line) represents the formation
`of soluble CD complexes, whereas B-type
`systems (blue line) indicate the formation
`of complexes of limited solubility.
`
`1026 | DECEMBER 2004 | VOLUME 3
`
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`
`4
`
`

`

`and, given the low piroxicam dose (20 mg), this did not
`add excessive bulk to the formulation48. The apparent
`solubility of piroxicam in the β-CD formulation was
`increased fivefold relative to the uncomplexed drug sub-
`stance. This enhanced solubility was associated with an
`increased dissolution rate and higher plasma levels at
`early time in humans, which, in turn, directly correlated
`with an increased absorption rate48,49. There was no
`change in terminal half-life or total area under the curve
`when piroxicam or the piroxicam–β-CD complex were
`compared. With regard to efficacy, piroxicam–β-CD has
`been demonstrated to have a faster onset of action in a
`number of clinical trials48,50,51.
`Although differences in the tolerability of piroxicam
`and its β-CD complex require the analysis of epidemio-
`logical data, acute studies might provide some useful
`insight. Several studies that have assessed the endo-
`scopic appearance of the stomach of volunteers taking
`either piroxicam or the piroxicam–β-CD complex
`have revealed significantly better outcomes in the case
`the complexed drug48,52,53.
`of administration of
`Similarly, radio-adhesive substrates demonstrated fewer
`gastric lesions with the piroxicam–β-CD complex relative
`to piroxicam48,54. Several branded piroxicam–β-CD
`products are available, including Brexin (Chiesi) and
`Cicladol (Chiesi).
`
`Applications of randomly methylated β-CD. Randomly
`methylated β-CD (RMβCD) (FIG. 5) provides good bio-
`compatibility and useful complexing efficiencies, and is
`beginning to be used in marketed products throughout
`the world. An eye drop preparation of the antibiotic
`chloramphenicol has been developed by Oftalder and
`marketed as Clorocil in Portugal55. The recently intro-
`duced nasal product Aerodil, which contains RMβCD, is a
`complex between the indicated CD and β-oestradiol56–60.
`A number of potential advantages are apparent for
`such an oestradiol delivery system. Although the safety
`of hormone-replacement therapy has been the subject of
`recent debate61,62, its efficacy in reducing menopausal
`symptomatology is well established. Traditional dosing
`strategies include oral administration of conjugated
`equine oestrogens, oestradiol esters or micronized
`oestradiol, as well as the use of transdermal patches to
`deliver this sex hormone63–65. Although both routes have
`a number of limitations, both provide relatively con-
`stant blood levels of drug, in contrast to endogenous
`oestrogen release, which tends be more pulsatile.
`The RMβCD-based nasal product avoids a number
`of issues related to oral or transdermal administration56.
`Nasal administration results in direct systemic uptake,
`and so the first-pass effect is reduced or eliminated. In
`addition, the nasal route is convenient, non-invasive and
`provides for consistency of drug absorption. Drug
`uptake is rapid, and peak plasma concentrations are
`achieved within 10–30 min of drug dosing. Drug levels
`also dissipate rapidly and return close to baseline within
`2 hours56. This pattern is more akin to physiological
`oestrogen secretion than that associated with oral or
`transdermal approaches. Another feature of this route is
`that, unlike oral dosing of oestrogens that generate a
`
`R E V I E W S
`
`Box 2 | Pharmaceutical applications of CDs
`
`Cyclodextrins (CDs) can be used to achieve the
`following:
`• Enhance solubility
`• Enhance bioavailability
`• Enhance stability
`• Convert liquids and oils to free-flowing powders
`• Reduce evaporation and stabilize flavours
`• Reduce odours and tastes
`• Reduce haemolysis
`• Prevent admixture incompatibilities
`
`high oestrone/oestradiol ratio, nasal delivery gives rise
`to a more physiological ratio of the two hormones56–60.
`A number of clinical trials have confirmed these
`product design principles. Studd et al. studied 420 post-
`menopausal women and found that the nasal product
`based on oestradiol and RMβCD was effective in amelio-
`rating menopausal symptoms as early as four weeks
`after initiation of therapy in a dose-dependent manner,
`and continued to improve the post-menopausal symp-
`toms even after 12 weeks56. The minimum effective
`oestradiol dose was 200–400 μg per day. These doses
`were similar in efficacy to 2 mg of oestrogen adminis-
`tered orally, although the reduced systemic exposure
`results in a potentially improved safety profile. Inter- and
`intrasubject variability was less than that demonstrated
`in the oral oestrogen group.
`
`Applications of hydroxypropylated β-CD. Two hydroxy-
`propylated CDs (HPβCDs) have been approved in var-
`ious world markets (United States and Europe)25,27,66–69.
`HPβCD (FIG. 5) is available in registered oral, intra-
`venous, buccal, rectal and ophthalmic products, whereas
`HPγCD is available in an eye drop formulation that
`contains the anti-inflammatory agent diclofenac
`sodium70. Of the HPβCD products, the oral and intra-
`venous solutions of itraconazole (Sporanox; Janssen)
`have the most widespread use71.
`Itraconazole is a triazole-type drug that exerts its
`effect by inhibiting fungal cytochrome P450 and
`inhibiting the biosynthesis of ergosterol, an essential
`component of the fungal membrane. The compound is
`noteworthy in that it was the first approved orally
`bioavailable agent with significant clinical activity
`against both Candida spp. and Aspergillus spp., the
`two most common human fungal pathogens72–75.
`Formulation development for this drug was complicated
`by its challenging set of physico-chemical properties,
`which include a pKa of 4, a LOG P >5 and an aqueous
`solubility at neutral pH estimated at 1 ng per ml71,76. The
`production of solid oral dosage forms was eventually
`made possible by using solid solution technology in
`which the drug and a polymeric carrier (hydroxypropyl
`methylcellulose (HPMC)) were sprayed on inert sugar
`spheres to form a thin film. As the film dissolves in the
`stomach, the molecularly dissolved drug is released at
`supersaturated levels. The co-dissolving HPMC inhibits
`
`LOG P
`The logarithm of the partition
`coefficient of a substance in
`octanol–water.
`
`NATURE REVIEWS | DRUG DISCOVERY
`
`VOLUME 3 | DECEMBER 2004 | 1 0 2 7
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`

`R E V I E W S
`
`Intravenous
`Oral
`Oral
`
`Prostavastin, Caverject, Edex
`Pansporin T
`Opalmon, Prorenal
`
`Europe, Japan, United States
`Japan
`
`Table 1 | Approved and marketed drug–cyclodextrin* complexes in various world markets
`Drug
`Administration route
`Trade name
`Market
`α-Cyclodextrin
`Alprostadil (PGE1)
`Cefotiam hexetil HCl
`Limaprost
`β-Cyclodextrin
`Oral
`Benexate
`Dermal
`Dexamethasone
`Topical
`Iodine
`Sublingual
`Nicotine
`Oral
`Nimesulide
`Sublingual
`Nitroglycerin
`Oral
`Omeprazole
`Dinoprostone (PGE2)
`Sublingual
`Oral
`Piroxicam
`Oral
`Tiaprofenic acid
`2-Hydroxypropyl-β-cyclodextrin
`Cisapride
`Rectal
`Hydrocortisone
`Buccal
`Indomethacin
`Eye drops
`Itraconazole
`Oral, intravenous
`Mitomycin
`Intravenous
`Randomly methylated β-cyclodextrin
`17β-Oestradiol
`Nasal spray
`Chloramphenicol
`Eye drops
`Sulphobutylether β-cyclodextrin
`Voriconazole
`Intravenous
`Ziprasidone maleate
`Intramuscular
`2-Hydroxypropyl-γ-cyclodextrin
`Europe
`Voltaren
`Diclofenac sodium
`Eye drops
`*Commercial suppliers of pharmaceutical-grade cyclodextrins are Roquette, Cerestar, Wacker Chemie and CyDex. See figures 2 and 5
`for schematic representations of cyclodextrins and functionalized cyclodextrins, respectively.
`
`Ulgut, Lonmiel
`Glymesason
`Mena-Gargle
`Nicorette
`Nimedex, Mesulid
`Nitropen
`Omebeta
`Prostarmon E
`Brexin
`Surgamyl
`
`Propulsid
`Dexocort
`Indocid
`Sporanox
`Mitozytrex
`
`Aerodiol
`Clorocil
`
`Japan
`Japan
`Japan
`Europe
`Europe
`Japan
`Europe
`Japan
`Europe
`Europe
`
`Europe
`Europe
`Europe
`Europe, United States
`United States
`
`Europe
`Europe
`
`Vfend
`Geodon, Zeldox
`
`Europe, United States
`Europe, United States
`
`nucleation and crystallization such that the supersatu-
`rated drug solutions are stable for long enough to allow
`significant absorption and oral bioavailability.
`Given the weakly basic nature of itraconazole, the pH
`of the stomach must be sufficiently low to ensure good
`dissolution and the formation of a stable solution78,79. In
`certain subpopulations, stomach pH can be a limiting
`factor for bioavailability.AIDS patients, for example, often
`suffer from hypochlorhydria and so treating opportunis-
`tic fungal infections with itraconazole in the patients can
`be problematic80. Similarly, the chemotherapeutic agents
`given to cancer patients can reduce gastrointestinal func-
`tion by inducing mucositis, and an individual undergoing
`autologous bone marrow transplants can experience
`graft-versus-host gut disease81.
`To better prevent or treat fungal infections in these
`conditions, a liquid oral formulation of itraconazole
`was developed, in addition to a parenteral dosage form
`for treating disseminated systemic infection, as well as for
`use in administering loading doses. HPβCD was chosen
`as the functional excipient to enable both of these
`
`formulations71. It was reasoned that the oral solution
`might improve bioavailability in the described sub-
`populations because no phase transition is required.
`The oral and intravenous formulations that were
`developed proved to be safe and effective in numerous
`clinical trials, and this resulted in their market introduc-
`tion in the United States and Europe (the oral solution
`in 1997 and the intravenous product in 1999)81–83. The
`oral product is indicated in empiric therapy of febrile
`patients with suspected fungal infections, as well as
`for the treatment of oropharyngeal and oesophageal
`candidiasis81,84. The aqueous 40% w/v HPβCD solution
`contains 10 mg per ml itraconazole, which represents an
`increase in apparent solubility of five to six orders of
`magnitude. The oral bioavailability of itraconazole is
`more consistent in the subpopulations described
`(fraction absorbed 85% and oral bioavailability
`55%)81,85. On the basis of an oral dose of 200 mg itra-
`conazole, the dose of HPβCD is 8 g per day. The
`intravenous product is also approved for empiric
`therapy as well as for blastomycosis (pulmonary and
`
`1028 | DECEMBER 2004 | VOLUME 3
`
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`
`6
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`

`

`CH2OR
`O
`
`ROCH2
`
`O
`
`O
`OR
`
`RO
`
`RO
`
`O
`
`CH2OR
`
`OR
`
`O
`
`O
`
`OR
`
`ROCH2
`
`OR
`
`O
`
`RO
`
`RO
`
`O
`
`RO
`
`CH2OR
`
`O
`
`OR
`
`OR
`
`O
`
`O
`
`RO
`
`RO
`
`O
`
`RO
`
`O
`
`R E V I E W S
`
`Dimethyl-β-cyclodextrin (DMβCD)
`Trimethyl-β-cyclodextrin (TMβCD)
`Randomly methylated-β-cyclodextrin (RMβCD)
`Hydroxyethyl-β-cyclodextrin (HEβCD)
`2-Hydroxypropyl-β-cyclodextrin (HPβCD)
`3-Hydroxypropyl-β-cyclodextrin (3HPβCD)
`2,3-Dihydroxypropyl-β-cyclodextrin (DHPβCD)
`2-Hydroxyisobutyl-β-cyclodextrin (HIBβCD)
`Sulphobutylether-β-cyclodextrin (SBEβCD)
`Glucosyl-β-cyclodextrin (G1βCD)
`Maltosyl-β-cyclodextrin (G2βCD)
`
`-CH3 or -H
`-CH3
`-CH3 or -H
`-CH2CH2OH or -H
`-CH2CHOHCH3 or -H
`-CH2CH2CH2OH or -H
`-CH2CHOHCH2OH or -H
`-CH2C(CH3)2OH or -H
`-(CH2)4SO3Na or -H
`-glucosyl or -H
`-maltosyl or -H
`
`CH2OR
`Figure 5 | Graphical representations of β-cyclodextrin and its pharmaceutically relevant chemical derivatives.
`
`O
`
`CH2OR
`
`extra-pulmonary), histomycosis (pulmonary and dis-
`seminated, non-meningeal) and aspergillosis (pul-
`monary and non-pulmonary), in the latter case in
`individuals refractory or intolerant to amphotericin
`B81,84. Based on intravenous doses of itraconazole
`between 200 and 400 mg and a formulation containing
`10 mg itraconazole in a 40% HPβCD solution, the intra-
`venous dose of HPβCD is between 8 and 16 g per day.
`
`Applications of sulphobutyl ether βCD. The sulphobutyl
`ether derivatives of β-CD (SBEβCD; FIG. 5) represent the
`newest CD derivative to be approved25,86–88. In addition,
`γ-CD derivatives of these useful excipients are also
`available. Two products were introduced in 2002 in the
`United States and Europe, including an intravenous
`formulation of the antifungal agent voriconazole
`(Vfend; Pfizer) and an intramuscular dosage form for
`the antipsychotic agent ziprasidone (Zeldox; Pfizer).
`In addition, a number of compounds are under devel-
`opment in areas including parenteral, oral sustained
`release, pulmonary and ophthalmalogical drug delivery.
`Voriconazole is a triazole antifungal agent that, unlike
`itraconazole, which evolved from the miconazole-
`ketoconazole series, is structurally related to flucon-
`azole89–91.Voriconazole is effective against Candida spp. as
`well as Aspergillus spp., and is also reported to be effective
`against such emerging pathogens as Scedospotium and
`Fusarium spp.89–91. As with itraconazole, it can partici-
`pate in numerous drug interactions. The compound is
`also poorly water soluble (~0.2 mg per ml at pH 3) and
`is not stable in aqueous solutions because it forms an
`inactive enantiomer. Unlike itraconazole, which has a
`log P >5, voriconazole is more amphiphilic and has
`a log P of 1.8. These factors complicate the preparation
`of a parenteral dosage form92.
`SBEβCD was used in this formulation problem
`and resulted in a dosage form containing 3.2 g of the
`CD and 200 mg of the active principle84. The supplied
`vial is diluted with water for injection to give a 10 mg
`per ml solution of voriconazole in a 16% w/v
`SBEβCD solution; this is then further diluted such
`that the administration solution contains 5 mg per
`ml or less of the active principle. The intravenous dose
`suggested is 3–6 mg per kg, which means