Challa R, Ahuja A, Ali J, Khar R. Cyclodextrins in Drug Delivery: An Updated Review. AAPS PharmSciTech. 2005; 06(02): E329-E357. DOI:  10.1208/pt060243

Correspondence to:
Alka Ahuja
Tel: +91 11 26215310
Fax: +91 11 26059663
Email: alkaahuja@yahoo.com

Received: June 11, 2004; Accepted: January 26, 2005; Published: October 14, 2005

Abstract

The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.

Keywords: cyclodextrins, drug formulation, drug delivery, novel delivery systems, excipients

Introduction

Cyclodextrins (CDs), with lipophilic inner cavities and hydrophilic outer surfaces, are capable of interacting with a large variety of guest molecules to form noncovalent inclusion complexes (Figure 1). Chemically they are cyclic oligosaccharides containing at least 6 D-(+) glucopyranose units attached by α-(1, 4) glucosidic bonds. CDs and their derivatives discussed in this article along with their abbreviations are given in Table 1. The 3 natural CDs, α-, β-, and γ-CDs (with 6, 7, or 8 glucose units respectively), differ in their ring size and solubility (Table 2).¹ CDs with fewer than 6 units cannot be formed due to steric hindrances while the higher homologs with 9 or more glucose units are very difficult to purify. However, recently Endo et al established an isolation and purification method for several kinds of large ring CDs and also obtained a relatively large amount of δ-CD (Cyclomaltonose) with 9 glucose units.^2-4

Figure 1.  The chemical structure (A) and the toroidal shape (B) of the â-cyclodextrin molecule.

The cavity size of α-CD is insufficient for many drugs and γ-CD is expensive. In general, δ-CD has weaker complex forming ability than conventional CDs. With drugs like digitoxin and spiranolactone, δ-CD showed greater solubilizing effect than α-CD but the effect of δ-CD was less than that of β- and γ-CDs. β-CD has been widely used in the early stages of pharmaceutical applications because of its ready availability and cavity size suitable for the widest range of drugs. But the low aqueous solubility and nephrotoxicity limited the use of β-CD especially in parenteral drug delivery.⁵

Chemically modified CD derivatives have been prepared with a view to extend the physicochemical properties and inclusion capacity of parent CDs. Several amorphous, noncrystallizable CD derivatives with enhanced aqueous solubility, physical and microbiological stability, and reduced parenteral toxicity have been developed by chemical modification of parenteral CDs.^6,7

Study of CD Complexation and Dilution Effects

The most widely used approach to study inclusion complexation (Figure 2) is the phase solubility method described by Higuchi and Connors,⁸ which examines the effect of a solubilizer, ie, CD or ligand, on the drug being solubilized, ie, the substrate. Phase solubility diagrams are categorized into A and B types; A type curves indicate the formation of soluble inclusion complexes while B type suggest the formation of inclusion complexes with poor solubility. A B_S type response denotes complexes of limited solubility and a B_I curve indicates insoluble complexes. A-type curves are subdivided into A_L (linear increases of drug solubility as a function of CD concentration), A_P (positively deviating isotherms), and A_N (negatively deviating isotherms) subtypes. β-CD often gives rise to B-type curves due to their poor water solubility whereas the chemically modified CDs like HP-β-CD and SBE-β-CD usually produce soluble complexes and thus give A-type systems.

Figure 2.  Theoretical phase solubility diagram.8

In the case of a 1:1 complex, using the following equation one can determine the equilibrium binding or association constant, K, from the slope of the linear portion of the curve.

K a : b   =   s l o p e S 0   ( 1   −   s l o p e )

(1)

Where S_o is the intrinsic solubility of the drug studied under the conditions.

For many drug/CD complexes, binding constant values are in the range of 100 to 20000M^-1. It has been demonstrated that even with tightly bound drugs, a 1:100 dilution reduces the percentage of the complexed drug from 100% to 30%, releasing the free drug that can permeate through biological membranes. A 1:100 dilution can be readily attainable on injection or dilution in the stomach and intestinal contents. Although the competing lipophiles present at ophthalmic, transmucosal, and transdermal delivery sites can displace drugs, the products to these delivery sites are more sensitive to strength of binding or association due to minimal dilution possible. The ratio of free-to-complexed drug upon dilution of a sparingly water-soluble drug/CD complex depends on the phase solubility behavior of the system. Dilution will not result in drug precipitation when the relationship between drug solubility and CD concentration is linear, eg, in a 1:1 interaction of CD and drug. However, dilution may cause drug precipitation when the relationship between drug solubility and CD concentration is nonlinear.⁹ Hence, effects of dilution must be studied before the clinical use of the products containing drug/CD complexes.

Equilibrium binding of drug and CD to form a 1:1 complex can be represented as

D r u g   +   C D   ⇌   D r u g :   C D   C o m p l e x

(2)

Since equilibrium binding usually establishes with half-lives of much less than 1 second, the kinetics of dissociation of drug/CD complexes are generally expected to be much faster than many physiological processes.^10,11

CDs and their derivatives have received considerable attention in the pharmaceutical field for the past few years and an increased number of reviews have been dedicated to their industrial and pharmaceutical applications.^1,12-20

Factors Influencing Inclusion Complex Formation

Type of CD can influence the formation as well as the performance of drug/CD complexes (Tables 3, 4, and 5).^21-23 For complexation, the cavity size of CD should be suitable to accommodate a drug molecule of particular size.^25-29 Compared with neutral CDs, complexation can be better when the CD and the drug carry opposite charge but may decrease when they carry the same charge (Figure 3).^30,31 For many acidic drugs forming anions, the cationic (2-hydroxy-3-[trimethylammonio] propyl)-β-CD acted as an excellent solubilizer.¹ In the case of ionisable drugs, the presence of charge may play a significant role in drug/CD complexation and hence a change in the solution pH can vary the complex constant. In general, ionic forms of drugs are weaker complex forming agents than their nonionic forms.^35,36 but in the case of mebendazole, the un-ionized form was less included in HP-β-CD than the cationic form.³⁷

Figure 3.  Proposed modes for the inclusion complexes of DY-9760e with HP-β-CD (A) and SBE-β-CD (B) at pH 4.0 (upper) and 7.4 (lower).30

Temperature changes can affect drug/CD complexation. In most cases, increasing the temperature decreased the magnitude of the apparent stability constant of the drug/CD complex and the effect was reported to be a result of possible reduction of drug/CD interaction forces, such as van der Waals and hydrophobic forces with rise of temperature.^36,38,39 However, temperature changes may have negligible effect when the drug/CD interaction is predominantly entropy driven (ie, resulting from the liberation of water molecules hydrated around the charges of guest and host molecules through inclusion complexation).³⁰

Method of preparation, viz co-grinding, kneading, solid dispersion, solvent evaporation, co-precipitation, spray drying, or freeze drying can affect drug/CD complexation. The effectiveness of a method depends on the nature of the drug and CD.^28,40,41 In many cases, spray drying,^41-43 and freeze drying^21,22,44 were found to be most effective for drug complexation. However, method of preparation showed no influence on the dissolution performance of tolbutamide:β-CD complexes.⁵³

When added in small amounts, water-soluble polymers or ion pairing agents enhance CD solubilizing effect by increasing the apparent complex stability constant. The polymers or ion pairing agents due to their direct participation in drug complexation, improve both pharmaceutical and biological properties of drug/CD complexes, independent of drug’s physiochemical properties.^20,32,47-51 Certain additives may compete with drug molecules for CD cavities and thus decrease the apparent complex stability constant, eg, additives with positive and negative hydrotropic effect.^54,55 Though water structure forming agents added to CD solutions generally increase the total drug solubility, they showed opposite effects with clotrimazole.⁵² Simultaneous complexation and salt formation with hydroxy carboxylic acid (HA) significantly increased the CD solubilizing power for a sparingly water-soluble amine type drug by forming drug/CD/HA multicomponent systems.⁵⁶ Co-solvents can improve the solubilizing and stabilizing effects of CDs, eg, use of 10% propylene glycol in development of an oral itraconazole preparation containing 40% of HP-β-CD.⁵⁷ Sometimes co-solvents may hinder drug complexation by competitive inclusion, eg, presence of 10% propylene glycol decreased the solubilizing effect of HP-β-CD for itraconazole . On dilution, the presence of propylene glycol favored absorption and precipitation of itraconazole in GI fluids and formulation by providing increased percentage of the free drug. The increased percentage of the free drug in presence of co-solvent was reported to be a result of lesser intrinsic solubility of the drug compared with the dilution concentration line at a given HP-β-CD concentration.⁵⁸

Degree of Substitution

The physicochemical properties of CDs, including their complexation ability, may be greatly affected by the type, number, and position of the substituents on the parent CD molecule. The “degree of substitution” per se does not uniquely characterize a β-CD derivative such as HP-β-CD. When produced under different conditions, the physicochemical properties of HP-β-CD samples with same degree of substitution may not be identical owing to the possible occupancy of hydroxypropyl groups at different positions on the parent CD molecule. Since the purity of CD can have a significant effect on the final quality of the drug product and its marketability, it is necessary to have a proper understanding of the following terms that are used in identification of CD purity.⁵⁹

Degree of substitution (DS): the average number of substituted hydroxyls per glucopyranose unit of CD ring. Since the number of reactive hydroxyls per mole of glucopyranose unit is 3, the maximum numbers of substituents possible for α-, β-, and γ-CDs are 18, 21, and 24, respectively.

Average molar degree of substitution (MS): the average number of moles of the substituting agent, eg, hydroxypropyl, per mole of glucopyranose. It may not necessarily describe the extent to which the reactive sites are substituted when the substituting agent itself has reactive sites, or when new reactive sites are generated during the substitution reaction. Thus the value of MS can be more than 3 for each glycopyranose unit of substituted CDs, or more than 18, 21, and 24 for α-, β-, and γ-CDs, respectively.

Degree of polymerization (DP): the ratio of MS to DS (MS/DS). If no additional reactive sites are produced during the substitution, MS and DS are equal and the DP becomes 1.

Total Degree of Substitution (TDS): It avoids the confusion between DS and MS and represents the average number of substituted groups (eg, hydroxypropyl) per CD molecule. If the MS and DS are known, one can calculate the molecular weight (Mw) of HP-β-CD from the following equation

M w   =   58.08 *   ( T S D )   +   1135

(3)

where 1135 and 58.08 are the molecular weights of β-CD and propylene oxide respectively. In the case of β-CD with 7 glycopyranose units, the TDS is 7*MS and hence the equation becomes

M w   =   406.56 *   ( M S )   +   1135

(4)

HP-β-CDs

Degree of substitution (DS) plays an important role in balancing the CD water solubility and its complexing ability. It was reported that increasing the degree of substitution up to an optimum level improves the CD aqueous solubility, but beyond that, the steric hindrances of the host molecule impair CD complexing (efficiency) capacity. HP-β-CD derivatives with a low degree of substitution showed the best complexing properties with low surface activities. Binding of guests to these CD derivatives was very similar to β-CD at low degrees of substitution, but, as the substitution increased, the steric hindrances weakened the binding and the effect was dependent upon the particular guest. Though increasing the degree of substitution can increase the binding of guests to CDs by increasing the surface area of binding, in many cases the differences in the binding of guests with degree of substitution were small, if detectable.⁶⁰

Sulfoalkyl Ether-β-CDs

The complexation potential of sulfoalkyl ether-β-CDs for the model drugs, testosterone and progesterone, decreased with reduction in the alkyl chain length from butyl (SBE-β-CD) to propyl (sulfopropyl ether-β-CD, SPE-β-CD), but was assisted by increased DS up to a limited extent. With SPE-β-CD, binding constants of the steroids reached an apparent maximum at a DS of 4, but with SBE-β-CD, the same increased until the constants reached a plateau at a DS of ~7. Complexation is an enthalpy-driven process involving expulsion of enthalpy-rich water molecules. Chemical modification of CDs with charged substituents may lower complexation by providing a hydrogen bonding source for the water molecules that decreases the energy difference between the included water molecules and bulk of the solution. It was found that presence of bulky, highly charged, and hydrated sulfonate groups near the CD cavity entrance inhibits the approach of hydrophobic molecules. On the other hand, increasing the distance between the charged substituents on the CD torus by spacer groups reduced the steric interference and raised the CD binding potential, the effect was also sensitive to the substrate structure.⁶¹

Some Important Considerations for Cd Selection in Drug Formulation

Commercial Availability

Out of various CDs discussed in this article, the natural CDs and hydroxypropyl, hydroxylethyl, sulfobutyl, and various methylated CD derivatives are available in bulk quantities. Other CD derivatives are either synthesized in the laboratory for the study or available on laboratory scale. Some of the companies providing CDs and their derivatives are listed in Table 6. For research and investigational purposes, various CDs, natural and modified, including some sugar branched derivatives like Glucosyl and Maltosyl-β-CDs can be obtained from “cyclodex” under the trade name “trappsol.”⁶⁶

Regulatory Status

The global regulatory status of CDs was discussed in the review by Thomson.¹⁴ Regulatory status of natural CDs is given in Table 7. Oral and IV solutions of itraconazole containing 3HP-β -CD (Sporanox, Janssen Pharmaceutica Inc, Titusville, NJ) were approved for marketing in United States and Belgium. 3HP-β-CD containing cisapride suppositories (Prepulsid, Janssen-Cilag) and diclofenac eyedrops (Ciba Vision) were also approved for marketing in Belgium and Switzerland, respectively.⁶⁸ In the United States, in August 1999, a type V DMF, containing information and safety data package of captisol (SBE7-β-CD with average degree of substitution of 6.5 from CyDex) was filed. An intramuscular Captisol-Enabled ziprasidone formulation (Geodon, Zeldox) was the first captisol-containing formulation to receive regulatory approval in Sweden (September 2000), also approved in the United States and the rest of Europe. Pfizer has also obtained European and United States approval for a captisol-enabled IV formulation of voriconazole (Vfend).⁶⁵

Patent Status

Being known for several years, natural CDs would not ordinarily be considered as patentable subject matter, however, there are many unexpired patents claiming specific complexes of drugs with natural CDs, particularly with β-CD.

The patent situation for CD derivatives varies for known derivatives and complexes. HP-β-CD and other hydroxyalkylated β-CD derivatives have been known for nearly 20 years and their basic patents have expired. However, potentially patentable drug complexes of HP-CDs and related derivatives have been developed. In the United States, a patent claiming compositions containing an amorphous drug/CD complex and a method of producing such a complex with description of HP-β-CD as the most promising amorphous CD, was granted to the United States Department of Health and Human Services on 23 February 1988 (United States patent 727 064). In Europe, the dominant patent position with respect to HP-β-CD belongs to Janssen Pharmaceutical Co of Belgium. The Janssen application relates to pharmaceutical compositions containing drugs, which are unstable or sparingly soluble in water, complexed with HP-β-CD or a related β-CD derivative. A European patent was issued to Janssen in 1990 with claims narrowed in the light of earlier work by Pitha.⁶⁹ Between 1996 and 1999, Procter and Gamble filed and received at least 100 patents related to CD use in laundry and deodorizing applications.⁶⁶ CyDex has exclusive rights to patents protecting the use and composition of matter of captisol. Exclusive rights to use captisol for antifungal and some specific ophthalmic applications have been granted by CyDex to its client companies.⁶⁶ Pfizer undertook, in the mid 1990s, to obtain patent protection for another chemically modified β-CD (sulfobutylether) for its own use.⁶⁶

CD Effects on Important Drug Properties in Formulation

Effect on Drug Solubility and Dissolution

CDs have been playing a very important role in formulation of poorly water-soluble drugs by improving apparent drug solubility and/or dissolution through inclusion complexation or solid dispersion, by acting as hydrophilic carriers for drugs with inadequate molecular characteristics for complexation, or as tablet dissolution enhancers for drugs with high dose, with which use of a drug/CD complex is difficult, eg, paracetamol.⁷⁰ The magnitude of apparent stability constant for several drug/CD complexes, K in M^–1, ranges from 0 to 100 000.⁸ CD applications as solubilizing agents are summarized in Table 8.

Out of various commercially available CDs, methylated CDs with a relatively low molar substitution appear to be the most powerful solubilizers. Reduction of drug crystallinity on complexation or solid dispersion with CDs also contributes to the CD increased apparent drug solubility and dissolution rate.^83,87 CDs, as a result of their ability to form in situ inclusion complexes in dissolution medium, can enhance drug dissolution even when there is no complexation in the solid state.⁷⁵ SBE-β-CD was shown to be an excellent solubilizer for several drugs and was more effective than β-CD but not as effective as DM-β-CD.⁹³ CDs can also act as release enhancers, for example β-CD enhanced the release rate of poorly soluble naproxen and ketoprofen from inert acrylic resins and hydrophilic swellable (high-viscosity hydroxy propyl methyl cellulose [HPMC]) tableted matrices. β-CD also enhanced the release of theophylline from HPMC matrix by increasing the apparent solubility and dissolution rate of the drug.^94,95

Effect on Drug Bioavailability

CDs enhance the bioavailability of insoluble drugs by increasing the drug solubility, dissolution, and/or drug permeability. CDs increase the permeability of insoluble, hydrophobic drugs by making the drug available at the surface of the biological barrier, eg, skin, mucosa, or the eye cornea, from where it partitions into the membrane without disrupting the lipid layers of the barrier. In such cases it is important to use just enough CD to solubilize the drug in the aqueous vehicle since excess may decrease the drug availability (Figure 4).^8,96,97 At low RM-β-CD concentrations, when hydrocortisone was in suspension, increasing the CD concentration increased the drug flux. At higher CD concentrations, when the drug was in solution, increasing the CD concentration decreased the flux.⁹⁸ It was found that addition of polymers can further enhance the drug permeability from aqueous CD solutions. Carboxy methyl cellulose (CMC) enhanced triclosan bioavailability from toothpastes containing β-CD by forming a drug/CD/CMC complex with improved substantivity.⁹⁹ CDs increased the bioavailability of lipophilic itraconazole from both an oral solution and an intravenous formulation by improving the drug solubility and absorption.¹⁰⁰

Figure 4.  Mode of penetration enhancement by CDs.96

In the case of water-soluble drugs, CDs increase drug permeability by direct action on mucosal membranes and enhance drug absorption and/or bioavailability.^7,8 Solubilization of specific membrane lipids of human erythrocytes through inclusion complexation with CDs and their ability to cause perturbation of membrane integrity, were suggested to contribute to CD-induced promotion of drug absorption and toxicity. It was reported that CDs, because of their ability to remove cholesterol, may increase membrane fluidity and induce membrane invagination through a loss of bending resistance and cause cell lysis. On the other hand, removal of phospholipids, especially phosphatidylcholine and sphingomyelin from the outer half of the membrane bilayer by CDs causes bilayer imbalance; the removal may also contribute in part to the formation of stomatocytes through an inward bending of membranes. CD induced lysis of artificial membranes composed of lecithin and cholesterol by a similar solubilization process. Detergents first incorporate themselves into membranes, then extract the membrane components into micelles and cause membrane solubilization/lysis. However, unlike detergents, CDs were reported to solubilize membrane components without entering into the membrane, and hence the perturbing effects of CDs can be mild and reversible. In the presence of CDs, the new lipid-containing compartment in the aqueous phase with extracted components from the erythrocyte surface equilibrated freely with the cell surface by a reversible process. Compared with other absorption-promoting agents and preservatives commonly used in nasal formulations, CDs exerted a rather mild and reversible effect on the ciliary beat frequency of both chicken embryo trachea and human nasal adenoid tissue in vitro in a concentration-dependent manner.¹⁶ DM-β-CD caused enhancement of enoxaparin nasal absorption by solubilizing membrane components and opening tight junctions but the effect was reversible after 6 hours.¹⁰¹ Watanabe et al¹⁰² reported that rectal membrane recovers its barrier function probably ~24 hours after the administration of DM-β-CD (at least 30 mg).⁷ Even at high doses, the effects of HP-β-CD on kidneys were reversible and similar to those of osmotic agents currently used in parenteral formulations.⁸

Labile drug stabilization by CDs^82,86 and their ability to ameliorate drug irritation, and thus improve drug contact time at the absorption site in nasal, ocular, rectal, and transdermal delivery,⁸ are some other important factors that contribute to the CD-improved bioavailability. α-CD improved the rectal bioavailability of morphine by inhibiting the drug’s upward movement from areas impacted by first pass metabolism.⁷

Effect on Drug Safety

CDs have been used to ameliorate the irritation caused by drugs.⁹ The increased drug efficacy and potency (ie, reduction of the dose required for optimum therapeutic activity), caused by CD-increased drug solubility, may reduce drug toxicity by making the drug effective at lower doses. β-CD enhanced the antiviral activity of ganciclovir on human cytomegalovirus clinical strains and the resultant increase in the drug potency reduced the drug toxicity.¹⁰³ The toxicities associated with crystallization of poorly water-soluble drugs in parenteral formulations can often be reduced by formation of soluble drug:CD complexes. Formulation of phenytoin with HP2-β-CD showed considerably reduced tissue irritation compared with a commercial injection of the drug in a BALB/c mouse model.¹⁰⁴ Further CD entrapment of drugs at the molecular level prevents their direct contact with biological membranes and thus reduces their side effects (by decreasing drug entry into the cells of nontargeted tissues) and local irritation with no drastic loss of therapeutic benefits.¹⁸ Inclusion complexation with HP-β-CD reduced the side effects of 2–ethyl hexyl–p–dimethyl aminobenzoate (a UV filter) by limiting the interaction of the UV filter with skin.¹⁰⁵ In a study with patients, piroxicam/β-CD inclusion complex showed better tolerance with lower incidence and severity of gastrointestinal side effects compared with the free drug.¹⁰⁶ HP-β-CD alleviated the intrinsic irritancy effect observed on IV administration of CKD-732 hemioxalate against blood vessels.¹⁰⁷ SBE7-β-CD inhibited DY-9760e-induced cytotoxicity toward human umbilical vein endothelial cells and significantly suppressed the drug-induced vascular damage in rabbits.¹⁰⁸ Inclusion complexation with CDs also reduces ocular drug irritation by limiting the free drug concentration on the precorneal area to a nonirritating level.¹⁰⁹

Effect on Drug Stability

CDs can improve the stability of several labile drugs against dehydration, hydrolysis, oxidation, and photodecomposition and thus increase the shelf life of drugs.¹  Table 9 summarizes CD effects on drug stability. It was reported that CD-induced enhancement of drug stability may be a result of inhibition of drug interaction with vehicles and/or inhibition of drug bioconversion at the absorption site.⁷ By providing a molecular shield, CD complexation encapsulates labile drug molecules at the molecular level and thus insulates them against various degradation processes. SBE-β-CD showed greater stability enhancement of many chemically unstable drugs than other CDs.⁹³

The stabilizing effect of CDs depends on the nature and effect of the included functional group on the drug stability and the nature of the vehicle. Both the catalyzing effect of the nitro group as well as the stabilizing effect of the halogen and cyanogen groups on photodegradation of 1,4 dihydropyrimidine derivatives were reduced by complexation with CDs.¹¹⁸ HP-β-CD significantly reduced the photodegradation of 2–ethyl hexyl p–dimethyl aminobenzoate in solution than in emulsion vehicle.¹⁰⁵ CDs improved the photostability of trimeprazine (when the solution pH is reduced)¹¹⁹ and promethazine.²⁹ CDs also enhanced the solid state stability and shelf life of drugs.^110-112 CDs were reported to enhance the physical stability of viral vectors for gene therapy, and the formulations containing sucrose and CDs were stable for 2 years when stored at 20°C.¹²⁰

Since the hydrolysis of drugs encapsulated in CDs is slower than that of free drugs,¹¹³ the stability of the drug/CD complex, ie, the magnitude of the complex stability constant, plays a significant role in determining the extent of protection.^{30,88,114,121} Very low concentrations of HP-β-CD (1% or lower), due to formation of a more physically unstable complex, did not protect taxol as effectively as higher CD concentrations. The effect of complexation on drug stability can be represented by the following equation (Figure 5):

1 k 0   −   k o b s   =   1 K c   ( k 0 − k c )   [ C D ]   +   1 ( k 0 −   k c )

(5)

Figure 5.  A simple model representing the effect of complex stability constant on drug degradation.115

where k_o is the degradation rate constant of free drug, k_obs is the observed degradation rate constant in the presence of CD, k_c is the degradation rate constant of the drug within CD, K_c is the stability constant for the complex, and [CD] is the concentration of CD.¹¹⁵

Under specific conditions, CD complexation may accelerate drug degradation depending on the type of the CD. CDs catalyzed deacetylation and degradation of spiranolactone, the effect was qualitatively correlated with the ionization state of hydroxyl groups on CDs that were lower in SBE–CDs.¹¹⁶ Structural changes in drug molecules on CD complexation can also accelerate drug degradation.¹¹⁷ β-CD did not improve the photostability of oflaxacin as there was only a partial inclusion of the methyl piperazinyl moiety in the CD.¹²²

CD Applications in Drug Delivery

Oral Drug Delivery

Applications of CDs in oral drug delivery include improvement of drug bioavailability due to increased drug solubility, improvement of rate and extent of dissolution, and/ or stability of the drug at the absorption site, eg, the gastrointestinal tract (GIT) or in formulation, reduction of drug-induced irritation, and taste masking (Table 10). CD complexation was found to decrease local drug irritation and also modify the time of drug release during GI transit.^8,17An itraconazole oral preparation containing 40% (wt/vol) of HP-β-CD (with reduced drug irritation) has been commercialized in the United States and Europe.³⁰

CDs enhance the mucosal drug permeability mainly by increasing the free drug availability at the absorptive surface.^127,128 CD complexation can provide better and uniform absorption of low-soluble drugs with poor and erratic absorption⁹¹ and also enhance the drug activity on oral administration^123,125,126 CD complexation increased the anthelmentic activity of albendazole and provided a high plasma concentration of the active metabolite.¹³³ CD complexation increased the absorption of poorly water-soluble drugs, delivered via buccal or sublingual mucosa.^129-132 Complexation of miconazole, econazole, and clotrimazole with HP-β-CD and genuine CDs increased the toxicity of these drugs on a human buccal cell culture model (TR₁₄₆) by causing drug supersaturation.¹³⁴

Captisol or (SBE)7m-beta-CD, a solubilizer with osmotic property, was used to design osmotic pump tablets of chlorpromazine and prednisolone.^135,136 Complexation can also mask the undesirable taste of drugs. Complexation with CDs suppressed the bitter taste of oxyphenonium bromide. With the assumption that only the free drug molecule exhibits bitter taste, the extent of the suppression was reported to be dependent on the availability of free drug, regardless of the kind and concentration of CD.¹³⁷

The relative safety, efficacy in terms of complexation, cost, and acceptance in pharmacopeias are some important factors to be considered in selecting a CD for drug complexation. HP-β-CDs were shown to have a better oral safety profile than β-CD and other parent CDs, but only limited data are available on the oral safety of the methylated CDs. However, for oral administration all CDs can be considered practically nontoxic due to lack of CD absorption through GIT and, hence, the relative safety profile of CDs is a concern of drug doses used in drug/CD complexes and the LD50 of CD.⁸ β-CD is the most cost-effective compound of all CDs, whereas HP-β- and SBE-β-CDs are more expensive. Monograph of β-CD is already incorporated in various pharmacopeias and national formularies (NF).¹ Hence, β-CD can be considered optimum for oral use when it is effective for drug complexation and modified CDs like HP-, SBE-β-, and DM-β-CDs may be used when they are more effective and when their peculiar property is required in formulation, eg, SBE-β-CD, owing to its osmotic property, was used in the preparation of osmotic pump tablets.^135,136

Parenteral Drug Delivery

CD derivatives such as amorphous HP-β- and SBE-β-CDs have been widely investigated for parenteral use on account of their high aqueous solubility and minimal toxicity. HP-β-CD with much higher aqueous solubility allows parenteral administration of various drugs with no significant toxicity problems and hence is more often used in parenteral formulations. An itraconazole parenteral injection containing HP-β-CD (40% wt/vol) has been commercialized in the United States and Europe.¹³⁸ The solubilizing potentials of both SBE-β- and HP-β-CDs for the drugs melphalan and carmustine were qualitatively similar but the intrinsic reactivities were significantly less with SBE-β-CD.¹¹⁴ Applications of CDs in parenteral delivery are solubilization of drugs, reduction of drug irritation at the site of administration, and stabilization of drugs unstable in the aqueous environment. Singla et al discussed the use of CDs to enhance the solubility and stability of paclitaxel in formulations and mentioned that the approach needs further research to overcome the serious limitations of CD-based formulations.¹¹⁵ An IM dosage form of ziprasidone mesylate with targeted concentration of of 20 to 40 mg/mL was developed by inclusion complexation of the drug with SBE-β-CD.³⁵ Formation of a stable, water-soluble dexamethsone complex with sugar branched β-CDs suggested the potential of these CDs as excellent carriers in steroidal injectable formulations.¹³⁹ Aqueous phenytoin parenteral formulations containing HP-β-CD exhibited reduced drug tissue irritation and precipitating tendency because their pH values were significantly closer to the physiological value (7.4).¹⁴⁰ SBE-β-CD was found to be useful in the preparation of parenteral solutions of poorly water-soluble drugs with positive charge, such as DY–9760e.³⁰

Effects of CDs on drug pharmacokinetics were discussed by Rajewski and Stella.⁹ Miconazole formulations solubilized by HP-β- and SBE7-β-CDs showed no significant effect on the drug pharmacokinetics in sheep compared with the drug micellar solution solubilized by cremophor EL (polyoxyl-35 caster oil). The synergistic effect of CDs with acids like lactic acid was used to solubilize miconazole for safe parenteral delivery.¹⁴¹ In some cases complexation may affect drug pharmacokinetics, eg, complexation with sugar branched β-CDs altered the disposition of dexamethsone in mice. The binding values of diflunisal in plasma solutions containing HP-β-CD were found to be lower than the theoretical because of competitive displacement of the drug from the CD by plasma cholesterol.¹⁴² In rabbits, coadministration of M-β-CD with doxorubicin resulted in reduced distribution half-life and modified renal and hepatic distribution profiles of the drug, but the main pharmacokinetic parameters of the CD were unaltered.¹⁴³

A water-soluble CD derivative with low hemolytic activity was synthesized by substituting acetyl groups for hydroxyl groups of DM-β-CD. The inclusion ability of the obtained heptakis (2,6 di-O-methyl-3-O-acetyl)-β-CD (DMA-β-CD) was the same as that of DM-β-CD, but the new derivative showed less irritation in rabbits with no hemolysis even at 0.1 M concentration.¹⁴⁴

Ocular Delivery

Applications of CDs in aqueous eye drop preparations include solubilization and chemical stabilization of drugs, reduction of ocular drug irritation, and enhancement of ocular drug permeability. Vehicles used in ophthalmic preparations should be nonirritating to the ocular surface to prevent fast washout of the instilled drug by reflex tearing and blinking. Hydrophilic CDs, especially 2HP-β- and SBE-β -CDs, are shown to be nontoxic to the eye and are well tolerated in aqueous eye drop formulations, eg, increased ocular absorption and shelf life of pilocarpine in eye drop solutions by SBE-β-CD and decreased ocular irritation of a lipophilic pilocarpine prodrug by SBE-β- and HP-β-CDs.¹ Reviews on the effects of CDs and aqueous CD-containing formulations on the acular drug bioavailability^96,109 have already discussed the effect of polymers on CD-induced drug solubilization and permeability enhancement (Table 11). The cytotoxicity order of CDs on the human corneal cell line was found to be α-CD > DM-β-CD > SBE-β-CD = HP-β-CD > γ-CD. It was suggested that ocular toxicity with SBE-β-CD (100 mM) after 1 hour of its exposure could be possibly a result of its high osmotic pressure. However, the toxicity with negatively charged SBE-β-CD was greater than that with the control, a neutral hypertonic mannitol solution.¹⁴⁵

CDs enhance drug permeability by making the drug available at the ocular surface. HP-β-CD enhanced the ocular permeability of dexamethasone acetate and also inhibited the conversion of acetate salt to less permeable dexamethasone.¹¹ Since only the free drug can permeate biological membranes, ophthalmic delivery of drugs can be limited by the dissociation of drug/CD complexes in the precorneal area due to the limited dilution in this area. The dissociation of drug/CD complexes depends more on the binding of drugs to precorneal proteins, absorption by corneal tissue, and displacement of drugs from CD complexes by precorneal fluid components.¹⁷ The ability of CDs to decrease membrane lipophilicity by interacting with the lipophilic compounds of epithelium was indicated by the reduction in the bioavailability of highly lipophilic pilocarpine prodrugs on addition of CDs.¹⁴⁶ Complexation with HP-β-CD significantly decreased hydrocortisone (HC) transport from the aqueous to the organic phase, the effect was dependent on the drug partition coefficient and the relative magnitude of the stability constant of the inclusion complex. The polymer interactions with the drug, HC, and its complex in each system were reported to be responsible for the observed solubility and different release behaviors of HC and its inclusion complex from high molecular weight cellulose and polyvinyl alcohol (PVA) polymeric films for ocular delivery.¹⁴⁷ Formulation with HP-β-CD, with and without HPMC, improved the bioavailability and maximal mydriatic response of tropicamide by enhancing the drug’s ocular permeability, but reduced the ocular drug irritation probably by maintaining the pH in physiologic range.⁵⁰ HP-β-CD also enhanced the permeability and miotic response of pilocarpine nitrate without damaging the rabbit corneal tissue.¹⁴⁸

Nasal Drug Delivery

CDs are effective excipients in nasal drug delivery. CDs improve nasal drug absorption either by increasing aqueous drug solubility and/or by enhancing nasal drug permeability. However, large interspecies differences were found in CD-enhanced nasal drug absorption. The safety and nontoxicity of CDs in nasal drug formulations have been demonstrated by the clinical data with CDs showing no adverse effects. Merkus et al¹⁴⁹ demonstrated that CDs can be safely used to improve nasal bioavailability of drugs, especially peptides. DM-β-CD improved the nasal bioavailability of estradiol in rats and rabbits. Nasal absorption of melatonin, a drug with high first pass metabolism was rapid and efficient when administered with β-CD and the peak levels were ~50 times higher than those observed after oral administration. Midazolam was absorbed rapidly when administered as an aqueous nasal spray (pH 4.3) containing SBE-β-CD (14% wt/vol), HPMC (0.1% wt/vol), and other additives.¹⁵⁰

CDs can also be used to reduce the nasal toxicity of other enhancers without affecting their absorption-enhancing property. β-CD or DM-β-CD reduced the serious nasal toxicity of sodium deoxycholate by inhibiting the leucine aminopeptidase activity in nasal mucosa without affecting the absorption-enhancing property of the bile salt for insulin.¹⁵¹ Salbutamol release from the powder inhaler formulations containing γ-CD and DM-β-CD was faster than that from control with lactose; at the amount studied γ-CD was safer than DM-β-CD.¹⁵² Midazolam nasal formulation in aqueous SBE-β-CD solution approached an IV form of the drug in speed of absorption, serum concentration, and sedation effect, with no serious side effects.¹⁵³

Rectal Drug Delivery

Applications of CDs in rectal delivery include enhancing drug absorption from a suppository base either by enhancing drug release from the base or by increasing drug mucosal permeability, increasing drug stability in the base or at the absorption site, providing sustained drug release, and alleviating drug-induced irritation.^7,11

Drug release from the suppository base is important in rectal absorption because of the high viscosity of rectal fluids. The effect of CDs on rectal drug absorption can be influenced by partition coefficient of the drug and its CD complex, magnitude of the complex stability constant, and nature of the suppository base (oleaginous or hydrophilic). Hydrophilic CDs (especially methylated and hydroxylpropyl CDs) enhance the absorption of lipophilic drugs by improving the drug release from oleaginous vehicles and/or by increasing the drug dissolution rate in rectal fluids. Formation of hydrophilic CD complexes was found to inhibit the reverse diffusion of drugs into oleaginous vehicles by reducing the drug/vehicle interaction. Rectal absorptions of flurbiprofen and biphenylacetic acid were improved by DM-β-CD and HP-β-CD, respectively. CDs may not affect drug release if the drug/CD complex dissociates in the vehicle itself. For example, although the dissolution rate of ethyl 4-biphenylylacetate (EBA) was highest from the DM-β-CD complex, only the HP-β-CD complex enhanced EBA release from the oleaginous suppository base because of lower dissociation of the HP-β-CD complex in the vehicle. The CD complex, once released from the base, mostly releases the free drug for absorption. The competing sites for the free drug released at the absorption site are CD cavity, suppository base, and the rectal mucosa. The extent of drug diffusion into these sites depends on drug’s partition coefficient, magnitude of the stability constant of the drug/CD complex, and the relative lipophilicity of the competing sites. In the case of lipophilic drugs with a high partition coefficient, there might be some back diffusion of the released free drug into the lipophilic base. Since a part of drug may get absorbed as the CD complex, the partition coefficient of the complex also becomes important, eg, rectal absorption of a part of EBA as HP-β-CD complex. In the presence of hydroxyl propyl methyl cellulose (HPMC), β-CD markedly reduced the bioavailability of acetaminophen from both aqueous solution and hydrogels by forming a complex with a lower partition coefficient or higher hydrophilicity.⁷

CDs enhance the rectal absorption of inabsorbable, hydrophilic drugs such as antibiotics, peptides, and proteins by their direct action on the rectal epithelial cells.⁷ α-CD enhanced the rectal absorption of morphine and human chorionic gonadotropin by increasing their mucosal permeability and reducing their degradation.^154,155

CDs enhance rectal drug stability either by inhibiting the drug/vehicle interaction (by making the drug insoluble in oleaginous base) or by inhibiting the drug bioconversion in the rectum. α-CD improved the rectal bioavailability of morphine by inhibiting the upward movement of the drug from areas impacted by first pass metabolism.⁷

Controlled Drug Delivery

CDs, due to their ability either to complex drugs or to act as functional carrier materials in pharmaceutical formulations, can serve as potential candidates for efficient and precise delivery of required amounts of drugs to targeted site for a necessary period of time. β-CD derivatives are classified as hydrophilic, hydrophobic, and ionizable derivatives. The hydrophilic derivatives improve the aqueous solubility and dissolution rate of poorly soluble drugs, while the hydrophobic derivatives retard the dissolution rate of water-soluble drugs from vehicles. Hence hydrophilic and hydrophobic CD derivatives are used in immediate and prolonged release type formulations, respectively. The ionizable CD derivatives, on the other hand, improve inclusion capacity, modify drug dissolution rate, and alleviate drug irritation, eg, use of CME-β-CD to obtain delayed release–type formulations. Highly hydrophilic derivatives, such as 2HP-β-, G2-β-, and SBE-β-CDs were used in immediate release formulations that dissolve readily in the GIT and enhance the oral bioavailability of poorly soluble drugs. CDs, both natural and chemically modified, are used in the design of immediate, delayed release, and targeted drug delivery systems (Table 12).

The pH-dependent solubility of CME-β-CD (ie, limited solubility under the acidic conditions of stomach with the complex solubility increasing with pH), which provides selective dissolution of drug/CD complex, makes it useful in the design of enteric formulations. When molsidomine tablets containing CME-β-CD were studied in gastric acidity–controlled dogs, the absorption of the drug was significantly retarded under high gastric acidity compared with low gastric acidity conditions.^156,157

Hydrophobic CDs, such as alkylated and acylated derivatives, are useful as slow-release carriers in prolonged release formulations of water-soluble drugs. Applications of various CD derivatives in formulation of modified-release preparations are summarized in Table 13. Among the alkylated CDs, DE-β- and TE- β-CDs were the first used slow release carriers and their hydrophobic complexes with diltiazem¹⁵⁸ and isosorbide dinitrate¹⁵⁹ provided slow drug release on oral administration in dogs. Peracylated CDs, particularly those with medium alkyl chain lengths (C₄–C₆) are useful as hydrophobic carriers (Table 14) and have broad applicability in various routes of administration. Combination of short-chain and long-chain peracylated β-CDs in an appropriate molar ratio was suggested to be useful to provide an effectively controlled release rate of water-soluble drugs, eg, markedly retarded release rate of molsidomine on complexation with peracylated β-CDs.¹⁶⁰ TB-β-CD was suggested to be a useful carrier for oral administration of water-soluble drugs, especially those that are metabolized in the GIT. In beagle dogs, oral administration molsidomine as TB-β-CD complexes resulted in suppressed peak plasma level of the drug while maintaining sufficient drug levels for long periods. The increased hydrophobicity and mucoadhesive properties on complexation were reported to be responsible for the observed sustained effect with TB-β-CD. Nanospheres of amphiphilic CDs such as DH-β-CD were also reported to have bioadhesive effects on gastrointestinal mucosa.¹⁵⁶

CDs can also be used along with other carrier materials to optimize drug release rate. Improved nifedipine bioavailability with reduced first pass metabolism was observed from a modified oral dosage form containing a fast release portion of the drug with HP–β-CD and HCO-60, a nonionic surfactant (ie, amorphous drug form obtained by spray drying with the CD and surfactant) and a slow release portion with hydroxy propyl celluloses (HPCs) of different viscosity grades.¹⁶¹ Quaglia et al¹⁶² reported that CDs can be used to modulate drug delivery from swellable systems, eg, β-CD significantly affected the delivery of nicardipine from swellable crosslinked polyethylene glycol matrix by decreasing effective drug diffusivity through the matrix. SBE-β-CD has been used in the design of sustained release matrix tablets of poorly soluble drugs. Directly compressed tablets containing prednisolone with SBE-β-CD and polymer physical mixture showed more enhanced drug release than the control (with lactose instead of the CD) due to formation of an in situ drug:CD complex in the gel layer.¹⁶³ HP-β-CD, because of its dissolution enhancing effect, was found to be more effective than β-CD in the development of controlled release nicardipine formulations.¹⁶⁴

Combination of drug complexes with hydrophilic and hydrophobic CDs in appropriate ratios can be a promising drug delivery system for prolonged therapeutic effect and balanced bioavailability. In rabbits, a sustained release nicardipine formulation, developed by mixing the drug complexes with HP-β-CD (fast release fraction) and with hydrophobic TA-β-CD (sustained releasing portion) in appropriate ratios, showed markedly retarded drug release with prolonged maintenance of plasma levels.¹⁶⁵ A sustained release 2-layered nifedipine tablet formulation was developed by using the drug complexes with β- and HP-β-CDs.¹⁶⁶ Use of CDs with a hydroxyapatite matrix was indicated to control the release of chemotherapeutic agents containing toxic metals, such as Rhodium II citrate and butyrate, and to provide localized antitumor chemotherapy with minimal side effects.¹⁶⁷

Colon-Specific Drug Delivery

CDs are barely hydrolyzed and only slightly absorbed in the stomach and small intestine but are absorbed in the large intestine after fermentation into small saccharides by colonic microbial flora. The peculiar hydrolyzing property of CDs makes them useful for colon drug targeting. Biphenyl acetic acid (BPAA) prodrugs for colon-specific delivery were developed by conjugation of the drug onto one of the primary hydroxyl groups of α-, β-, and γ-CDs through an ester or amide linkage. In the case of ester prodrugs, the maltose and triose conjugates released the free drug after initial hydrolysis of the susceptibile ester linkage, but in the case of amide prodrugs, the conjugates remained as such providing delayed release due to the resistance of the amide bond to hydrolysis. The CD-based prodrug approach was used for colon-specific and delayed drug delivery, eg, when tested in rats with carageenan-induced inflammation, the absorption of BPAA from γ-CD prodrugs was found to be from cecum and colon in contrast to that from the highly soluble β-CD complex, which was mainly from the small intestine.¹⁶⁸ When studied in rats, it was found that both sugar-degrading and ester-hydrolyzing enzymes are necessary for colon-specific release of butyric acid from its β-CD ester conjugates.¹⁶⁹ Drug conjugation with α-CD resulted in a delayed release–type prodrug formulation for colon-specific delivery that alleviates the side effects of drugs while maintaining their therapeutic effect, eg, site-specific degradation of prednisolone/α-CD conjugates in the large intestine alleviated the side effects of the drug while maintaining its anti-inflammatory action.¹⁷⁰

Complexation of triamcinolone acetonide (TA) with β-CD improved the sphericity of microcrystalline cellulose (MCC)–β-CD-TA spherical pellets (5:90:5) prepared by extrusion and spheronization for colon targeting. TA complexation with the CD also facilitated the application of coating resistant to gastric and small intestinal media and maintained the pellet integrity in dissolution medium with no premature bursting of coatings on granule swelling.¹⁷¹

Peptide and Protein Delivery

Various problems associated in practical use of therapeutic peptides and proteins are their chemical and enzymatic instability, poor absorption through biological membranes, rapid plasma clearance, peculiar dose response curves, and immunogenicity. CDs, because of their bioadaptability in pharmaceutical use and ability to interact with cellular membranes, can act as potential carriers for the delivery of proteins, peptides, and oligonucleotide drugs.¹⁷²

The existence of efflux pumps may serve as an additional barrier for nonspecific uptake of peptides and thus can cause low peptide bioavailability. P-glycoprotein (P-gp) is an efflux transporter present in the apical region of epithelial cells in the brain, kidney, liver, and GI tract. P-gp opposes the transcellular drug movement in the epithelial cells and many peptide drugs, especially hydrophobic peptides like cyclosporin A,¹⁷³ D, N-acetyl-leucyl-leucylnorleucinal,¹⁷⁴ valinomycin,¹⁷⁵ gramicidin,¹⁷⁶ and ditekiren¹⁷⁷ are reported to be substrates for this efflux transporter. Therapeutic use of peptides across the blood brain barrier (BBB) is greatly hindered by their very low penetration and it was reported that P-gp substrates, such as synthetic hydrophobic peptides, can stimulate the transport of drugs across the BBB. An apically polarized verapamil sensitive efflux system for small hydrophobic peptides has been found in the BBB of rats. It was also reported that P-gp–mediated transport of peptides might play an important role in greatly reducing their delivery to the central nervous system in vivo.¹⁷⁸ Hence, whenever unexplainable poor peptide absorption is seen, the role of efflux pumps should be examined.¹⁷⁹

It was found that CDs can inhibit or impair the efflux function of P-gp and multidrug resistance associated proteins (MRP2). Out of various β-CD derivatives studied, DM-β-CD was found to be most effective and significantly impaired the efflux function of P-gp and MRP2 in Caco cell monolayers (Caco2, Caco-2R) without changing the cell viability and membrane integrity. The inclusion ability of DM-β-CD, causing the release of the transporters (P-gp, MRP2) from the apical membranes of monolayers, was reported to be the possible reason for the observed impaired efflux function of the transporters in the presence of the CD. Not only the extraction of cholesterol but also that of phospholipids from the monolayers were found to be required for the CD-induced inhibitory effect on the efflux function.¹⁸⁰ In addition to the solubilizing effect of DM-β-CD, its ability to inhibit P-gp efflux of tacrolimus from intestinal epithelial cells contributed to the CD-induced enhancement of the drug’s oral bioavailability. Pretreatment of the apical membranes of the Caco cell monolayers with DM-β-CD decreased the efflux of tacrolimus and rhodamine with no associated cytotoxicity. DM-β-CD also decreased the level of P-gp in the apical membranes of the monolayers probably by allowing its release from the apical membranes into the transport buffer.¹⁸¹

CDs were found to be useful in the absorption enhancement of calcitonin, glucagon, insulin, and recombinant human granulocyte colony-stimulating factor. DM-β-CD (5%) enhanced the intranasal calcitonin absorption in rats and rabbits. In rabbits the intranasal absorption was comparable to intravenous or subcutaneous calcitonin absorption. In rabbits, a nasal spray of liquid and powder formulations of glucagons containing DM-β-CD provided improved bioavailability (> 80%) of glucagons compared with their subcutaneous administration. The absolute bioavailability of insulin in rats was also increased to ~100% on nasal administration with DM-β-CD (3% to 5%).¹⁴⁹ β-CD or DM-β-CD reduced the serious nasal toxicity of sodiumdeoxycholate (a bile salt) by inhibiting the leucine aminopeptidase activity in the nasal mucosa without affecting the absorption-enhancing property of the bile salt for insulin.¹⁵¹ The various established mechanisms for CD-improved nasal absorption of peptides are interaction with membrane lipids and proteins in the nasal epithelium that reduces the membrane barrier function, inhibition of proteolytic enzyme activities in the nasal mucosa, and finally inhibition of protein or peptide aggregation by direct action upon these molecules. Since the absorption-enhancing effects of CDs are reversible, as enhancers they are less toxic than other widely used enhancers, eg, the effect of CDs on the nasal cilliary beat frequency were observed to be mild, reversible, and less toxic. However, substantial interspecies differences were observed in the absorption enhancement of peptides from CD solutions. DM-β-CD, the only effective nasal absorption enhancer out of the CDs studied (β-, HP-β-, γ-, and DM-β-CDs), largely improved the nasal absorption of insulin and adreno crotico tropic hormone (ACTH) from solutions in rats (bioavailability ~70% to 100%) but in rabbits and healthy human volunteers, the same CD/insulin solution was found to be ineffective. Improved bioavailability of insulin (up to 13%) was observed on nasal administration of powder formulations containing DM-β-CD compared with the control containing lactose instead of the CD.¹⁸²

CDs can enhance physical and chemical stability of protein and peptide drugs, and the maximum enhancing effects were reported at low CD concentrations. The proteolytic degradation of basic fibroblast growth factor was decreased by water-soluble β-CD sulfate.¹

β-CD improved insulin loading of alginate microspheres prepared by an emulsion-based process. The process was suggested to be useful in the development of an oral insulin drug delivery system as the absorption of insulin from optimized microspheres was found to take place from the GI region.¹⁸³

Gene and Oligonucleotide Delivery

The toxicity and immunogenicity associated with viral vectors led to the development of nonviral vectors for gene delivery. Besides the plasmid or virus-based vector systems, “naked” nucleotide derivatives have also been investigated for possible use as therapeutic agents through several routes of administration. Gene delivery technologists are now testing CD molecules in the hope of finding an optimal carrier for the delivery of therapeutic nucleic acids, however, the limitations of CDs, such as CD-associated toxicity (eg, DM-β-CD) have to be considered before their clinical use.¹⁸⁴

CDs can solve many of the problems associated with in vivo delivery of oligonucleotides (Ons), such as their limited ability to extravasate from blood stream and traverse cellular membranes, high degree of susceptibility to endonucleases with potential toxicity of their breakdown products, polyanionic nature leading to nonspecific interactions with extracellular and intracellular cationic molecules, and potential immunogenicity. CDs can improve cellular uptake of ONs and also delay their degradation by increasing their stability against endonucleases. ON-adamatane conjugates associated with HP-β-CD provided significantly increased cellular uptake of ONs. Substitution of at least a single nucleotide of ONs with CDs improved the cellular uptake and/or stability of ONs. On conjugation with CDs, ONs may be delivered to the colon, an advantageous absorption site to achieve acceptable therapeutic levels of ONs. CDs can also modulate undesirable side effects of ON treatment such as immune stimulation and reduction of platelet counts.^185,186

Neutral and amphipilic as well as cationic CDs have been used for synthesis of novel gene delivery vectors. Neutral CDs like β-, DM-β-, and HP-β-CDs were reported to increase DNA cellular uptake by increasing its permeability. The increased DNA permeability was reported to be a result of interaction of the CDs with membrane components such as cholesterol, but not due to their complexing ability for DNA. Cationic polyamino CDs, because of their polycationic polyanionic interaction with mononucleotides, neutralized the multiple charges on DNA and thus made DNA compact into a particle of suitable size for cellular internalization. Amphiphilic CDs, because of their vesicle-forming potential, offer an additional possibility for polar nucleotides to complex into aqueous vesicle core while allowing hydrophobic agents to complex into individual cavities or interior of the bilayer with multiple lipophilic hydrocarbon chains.¹⁸⁶ Polyplexes (polycation polymer/DNA composite structures) of linear, cationic, β-CD–containing polymers (βCDPs) were found to be suitable for DNA delivery due to their increased transfection efficiency and stability against enzymatic degradation with low in vitro and in vivo toxicity.¹⁸⁷ The ability of CDs to complex hydrophobic adamantane was exploited for steric stabilization of βCDPs with hydrophilic polymers like poly(ethylene glycol). Steric stabilization of βCDPs prevents their self-aggregation but facilitates their targeted delivery by preventing their undesired interactions with non–self-entities.¹⁸⁸

CDs were also found to enhance plasmid or viral-vector–based delivery of genes. Positively charged quarternary amino and tertiary amino β-CDs significantly enhanced the transfection efficiency of negatively charged adenoviral vector-based gene formulations. It was reported that the transfection enhancement by the cationic β-CDs could be a result of increased viral internalization caused by increased viral binding to cell and improved cell membrane permeability.¹⁸⁹ CDs also enhanced the physical stability of viral vector formulations for gene therapy.¹²⁰

Dermal and Transdermal Delivery

CDs have been used to optimize local and systemic dermal drug delivery. Applications of CDs in transdermal drug delivery include enhancement of drug release and/or permeation, drug stabilization in formulation or at absorptive site, alleviation of drug-induced local irritation, sustaining of drug release from vehicle, and alteration of drug bioconversion in the viable skin. Parent CDs (α-, β-, and γ-CDs) and various chemically modified CD derivatives with extended physicochemical properties and inclusion capacity have been used in transdermal drug delivery.⁷

Drug thermodynamic activity in vehicles as well as its skin/vehicle partition coefficients can significantly affect CD-induced changes in the drug permeability through skin. CDs, by enhancing apparent drug solubility, enhance the drug thermodynamic activity in vehicles and thus cause enhancement of drug release from vehicles. The enhancement of drug release from vehicles by CDs in turn enhances the dermal drug absorption by improving the drug availability at the lipophilic absorptive barrier surface (ie, skin).^7,18 Although the drug partition coefficient (eg, a lipophilic drug) may be decreased on complexation with CDs (eg, with hydrophilic CDs), the increased drug solubility and thermodynamic activity in vehicles can lead to increased drug permeability through skin, eg, increased skin permeability of dexamethasone by HP-β-CD.¹⁹⁰ The vehicle type used, because of its main influence on the drug’s membrane/vehicle partition coefficient, can markedly affect CD-induced enhancement of drug release. Diffusion rate of ketoprofen from its β-CD and HP-β-CD inclusion complexes was in the order of carbopol gel > oil/water emulsion > fatty ointment.¹⁹¹ Hydrophilic CDs improve the release rate of lipophilic drugs from hydrophilic aqueous vehicles. Hydrophilic CDs markedly increased the in vitro release rate of corticosteroids from aqueous bases (hydrophilic, absorptive, or polyacrylic) but retarded the same from nonaqueous bases (fatty alcohol, propylene glycol, or macrogol). Complexation with β-, DM-β-, and HP-β-CDs increased the release of 4-biphenylacetic acid from hydrophilic ointment. β- and HP-β-CDs significantly enhanced the anti-inflammatory effects of indomethacin in hydroxyethyl cellulose hydrogels in healthy volunteers.¹⁸ It was reported that CDs may not affect or even hamper drug release from nonaqueous vehicles and the effect may be due to lowered drug solubility in vehicle on complexation. The release of prednisolone from non–water-containing ointment bases was abated on complexation with DM-β-CD. Hydrophilic β- and HP-β-CDs enhanced the release of hydrocortisone from oil/water cream and hydrogel but retarded the same from petrolatum vehicle or water/oil cream.¹⁹²

CDs enhance drug delivery by increasing the drug availability at the barrier surface, where the free drug partitions from the CD cavity into lipophilic barrier. The free drug fraction at the barrier surface depends on the drug dissolution rate, relative magnitude of the stability constants of the CD complexes with the drug and the competing agent at the absorption site, and the drug absorption rate constant. In ointments, just as in suppositories, a drug in the CD complex may be displaced by ointment components, depending on the magnitude of the stability constant of the drug/CD complex. Hence, for optimum drug release, the vehicle or the CD complex chosen should be such that the complex barely dissociates but still maintains a high drug thermodynamic activity in the vehicle.¹⁸ The order of prednisolone release rate from a hydrophilic ointment was drug alone < γ-CD complex < β-CD complex < DM-β-CD complex, which was reflective of the order of the complex stability constants.⁷ For absorption, the CD complex has to dissociate to release free drug, the actual absorbable species and the dissociation of CD complex depends on the magnitude of the complex stability constant. If the complex stability constant is too high, the complex may not release the free drug at the absorptive site and thus may decrease or inhibit drug absorption.¹⁸ The effect of HP-β-CD concentration on the iontophoretic delivery of hydrocortisone (ie, higher drug amount delivered at lower CD concentration [1%] compared with higher CD concentrations [3% or 5%]) indicated the delivery of only the free drug with the CD acting as a carrier.¹⁹³

CDs have also been used to reduce drug degradation in topical preparations. β-CD maintained the stability of tixoxortol 17-butyrate 21-propionate in vaseline and oil/water emulsion bases even after 30 days.⁷ Complexation with CDs was suggested to be a rational way to improve physicochemical properties of drugs for transdermal delivery. β- and HP-β-CDs increased the skin permeability of dexamethasone and also improved its stability in skin by protecting it against skin metabolism.¹⁹⁰ CDs, by increasing solubility, facilitate drug incorporation into formulation and thus increase the drug concentration in the formulation. HP-β-CD increased the amount of piroxicam transported through skin but pretreatment of skin with the CD showed no effect on drug retention in skin. Hence the CD effect on the drug’s skin permeability was reported to be due to increased drug concentration in gel and not due to enhancement of drug iontophoretic flux.¹⁹⁴

CDs may alleviate drug-induced skin irritation by lowering the extent of free drug resulting from inclusion equilibrium. β- and DM-β-CDs significantly reduced chlorpromazine-induced skin irritation and their alleviating efficacy; DM-β-CD > β-CD was consistent with the magnitude of their complex stability constants. Suppression of drug penetration into skin caused by the reduction of drug/skin partition coefficient on CD complexation was reported to be the possible reason for the reduction of chlorpromazine-induced skin irritation. β-CD also attenuated the skin irritation induced by tretinoin and menadione.⁷

Hydrophobic CDs can modulate drug release from vehicles. Nitroglycerin complexation with DE-β-CD accelerated the drug release rate from ointments but the same with β-CD retarded the drug release. Hence a combination of the drug complexes with DE-β-CD and β-CD was suggested to obtain sustained release percutaneous preparations of the drug.⁷

Though only insignificant amounts of CDs and drug/CD complexes can penetrate into biological barriers because of their size and hydrophilicity, CDs may interact with some of the skin components. It was reported that the free CDs released on complex dissociation, due to their ability to remove some membrane surface components, can modify the membrane transport properties and thus can facilitate absorption of drugs, especially water-soluble drugs. Interaction of RM-β-CD with skin components was directly implicated to its effect on drug diffusion. It is also important to pay careful attention toward possible irritation effects of CDs on skin, eg, RM-β-CD extracted all major classes of lipids from an isolated stratum corneum of hairless rats and thereby reduced the barrier function of the skin.¹⁸

CDs, the safer solubilizing agents with bioadaptability and multifunctional characteristics, have been evaluated for formulation of poorly water-soluble cosmetic materials. HP-CDs increased the aqueous solubility of cosmetic materials, retarded the release rate of fragrance materials with no toxicity in topical liquid preparations,^7,195 and also reduced permeation rate of eugenol and methyl paraben through hairless mouse skin. Other CD applications in cosmetics include masking of smell and stench, stabilization of cosmetic materials (eg, loyal jelly and antiplasmin drugs), assisting in preparation of stable emulsion and suspension, inhibition of foaming caused by amphiphilic materials, and powderization of oily materials.⁷ Being nontoxic polysaccharides with solubilizing and stabilizing effects and further advantages, CDs and their complexes have been used to formulate cosmetic products, making possible those effects that were not realizable with common techniques. The ability of CDs to increase stability (against light and oxygen) and solubility of sparingly water-soluble molecules made them useful in the formulation of cosmetic products.¹⁹⁶

Brain Drug Delivery or Brain Targetting

The concept of Bodor’s chemical delivery system (CDS) (ie, covalent coupling of drugs to 1-methyl-1, 4-dihydronicotinic acid through an enzymatically labile linkage, which increases drug lipophilicity) was applied for targeting drugs such as steroids, antitumor agents, and calcium channel antagonists to brain. However, presence of the lipophilic moiety makes prodrugs of CDS poorly water-soluble. HP-β-CD, due to its ability to solubilize drugs and also to enhance the chemical stability of dihydronicotinic acid in aqueous solution solved the solubility problems of CDS.¹⁵⁶ Formulation is an important and integral concern in the development of CDS, especially those for brain targeting. Formulation development of CDS is based on the need for appropriate dosage form, stability, solubility, and dissolution characteristics. Brewster and Loftsson¹⁹⁷ discussed the use of chemically modified, especially water-soluble, CD derivatives such as HP-β-CD in the formulation development of CDS. HP-β-CD contributed to the development and preclinical testing of several CDS by providing a stable and water-soluble dosage form suitable for parenteral administration. Use of CDs in the formulation of CDS can be demonstrated by the significantly improved solubility, stability, and pharmacologic activity of CDS of thyrotropin-releasing hormone analogs on complexation with HP-β-CD.¹⁹⁸

The very low penetration across the BBB greatly hinders the therapeutic use of peptides, and whenever unexplainable poor peptide absorption is seen the role of the efflux pumps should be examined. It was reported that P-gp–mediated peptide transport may play an important role in greatly reducing the peptide delivery to the central nervous system in vivo.^178,179 It was also indicated that CDs such as DM-β-CD, due to their inhibitory effect on P-gp efflux function, may enhance drug delivery to brain.¹⁸¹

CD Applications in the Design of Some Novel Delivery Systems

Liposomes

In drug delivery, the concept of entrapping CD-drug complexes into liposomes combines the advantages of both CDs (such as increasing the solubility of drugs) and liposomes (such as targeting of drugs) into a single system and thus circumvents the problems associated with each system. Liposomes entrap hydrophilic drugs in the aqueous phase and hydrophobic drugs in the lipid bilayers and retain drugs en route to their destination. The fact that some lipophilic drugs may interfere with bilayer formation and stability limits the range and amount of valuable drugs that can be associated with liposomes. By forming water-soluble complexes, CDs would allow insoluble drugs to accommodate in the aqueous phase of vesicles and thus potentially increase drug-to-lipid mass ratio levels, enlarge the range of insoluble drugs amenable for encapsulation (ie, membrane-destabilizing agents), allow drug targeting, and reduce drug toxicity. Problems associated with intravenous administration of CD complexes such as their rapid removal into urine and toxicity to kidneys, especially after chronic use, can be circumvented by their entrapment in liposomes.^199-202

When the concept of entrapping CD complexes into liposomes was applied to HP-β-CD complexes of dexamethasone, dehydroepiandrosterone, retinal, and retinoic acid, the obtained dehydration-rehydration vesicles (DRV liposomes) retained their stability in the presence of blood plasma.¹⁹⁹ Liposomal entrapment can also alter the pharmacokinetics of inclusion complexes. Liposomal entrapment drastically reduced the urinary loss of HP-β-CD/drug complexes but augmented the uptake of the complexes by liver and spleen, where after liposomal disintegration in tissues, drugs were metabolized at rates dependent on the stability of the complexes.^200,203

CD complexation can increase liposomal entrapment of lipophilic drugs and also reduce their release from the carrier, ie, liposomes. Complexation with CDs increased the liposomal entrapment of nifedipine by reducing its interaction with lipid bilayers and also improved the liposomal stability in plasma.²⁰⁴ To encapsulate large amounts of lipophilic drugs in liposomes, a CD molecule forming an inclusion complex with a high drug:CD ratio should be selected. Liposomal entrapment of prednisolone was higher when incorporated as HP-β-CD complex than as free drug. Selection of CD can also have a significant effect on the amount of drug associated with vesicles, eg, HP-β-CD, with a more lipophilic interior and considerably higher aqueous solubility incorporated higher drug amounts in vesicles than β-CD. However, HP-β-CD, as a result of its ability to get entrapped in higher amounts in the vesicles, also showed a higher velocity of destabilizing effect on vesicles than β-CD.²⁰⁵

Complexation with CDs can improve the stability of liposomes, eg, most stable liposomal formulations of metronidazole and verapamil were obtained by direct spray drying of lipid, drug, and HP-β-CD mixture.²⁰⁶ Inclusion complexation can greatly increase the chemical stability of labile drugs in multilamellar liposomes. Multilamellar DRV liposomes containing a riboflavin/γ-CD complex provided optimal protection to the photosensitive drug.²⁰⁷ Similarly, multilamellar liposomes containing indomethacin/HP-β-CD inclusion complex showed increased stability of the hydrolysable drug (~75-fold).²⁰⁸

Parent CDs (α-, β-, and γ-) along with sulfated glycolipids were used as starting materials in the synthesis of specific erythrocyte-like liposomes having excellent self-assembling capacity to form stable monolayers at an air water interface.²⁰⁹

Microspheres

In the presence of a high percentage of highly soluble hydrophilic excipients, complexation may not improve the drug dissolution rate from microspheres. Nifedipine release from chitosan microspheres was slowed down on complexation with HP-β-CD in spite of the improved drug-loading efficiency. Since it is highly unlikely for CD molecules to diffuse out of the microspheres, even with a low stability constant, the complex must first release the free drug that can permeate out of the microspheres. Hence the observed slow nifedipine release from the microspheres was reported to be due to lesser drug availability from the complex and also due to formation of hydrophilic chitosan/CD matrix layer around the lipophilic drug that further decreases the drug matrix permeability.²¹⁰ Sustained hydrocortisone release with no enhancement of its dissolution rate was observed from chitosan microspheres containing its HP-β-CD complex. The sustained hydrocortisone release was reported to be due to formation of a layer adjacent to the interface by the slowly dissolving drug during the dissolution process that makes the microsphere surface increasingly hydrophobic.²¹¹

Study of in vivo release behavior (over 24 hours) of β-CD from β-CD/poly (acrylic acid) (PAA) microspheres, prepared by a water/oil solvent evaporation technique, indicated a high encapsulating efficiency (>90%) with potential covalent binding of the CD.²¹² β-CD caused no alteration of the in vitro release kinetics of dyes, phenolphthalein, and rhodamine B (with different solubilities and strengths of association with β-CD) from the microspheres. The reasons suggested for the unaltered release kinetics were rapid hydration of the polymer matrix because of limited cross-linking; perturbation of dye/β-CD complex by oil, organic solvent residues and/or conformational changes; and reduction of β-CD complexing ability on covalent binding with PAA due to steric hindrance of its cavity.²¹³

HP-β-CD acted as a promising agent for stabilizing lysozyme and bovine serum albumin (BSA) during primary emulsification of poly (d, l-lactide-co-glycolide) (PLGA) microsphere preparation. The stabilizing effect was reported to be a result of increased hydrophilicity of the proteins caused by shielding of their hydrophobic residues by HP-β-CD; this also reduces their aggregation and denaturation by keeping them away from methylene chloride water interface. HP-β-CD enhanced BSA conformational stability and also increased its recovery from water/oil emulsion by preventing the adsorption of the protein to PLGA.^214,215 CDs were also used to modulate peptide release rate from microspheres, eg, HP-β-CD co-encapsulation in PLGA microspheres slowed down insulin release rate. Microspheres, prepared by spray drying of a water/oil emulsion containing the CD provided a constant insulin release up to 45 days without initial burst and maintained the peptide stability during the entire release phase. The slowing down of overall release rate of the peptide was reported to be due to its decreased matrix diffusivity caused by its higher apparent molecular weight and size on complexation. Co-encapsulation of the CD also reduced the apparent particle size of the microspheres.²¹⁶

A high entrapment efficiency of gabexate mesylate (GM) was observed with all types of bioadhesive and biodegradable starch/CD microspheres prepared by chemical crosslinking of an alkaline solution of a mixture of starch and CD (α-, β-, or γ-CD) with epichlorohydrin. The amount of GM included and its proportion in microspheres after storage were in agreement with its affinity for the CDs and the order of association constants of its complexes.²¹⁷ All PVA/CD microspheres, prepared by crosslinking of an acidified aqueous mixture solution of PVA and CD (α-, β-, or γ-CD) with gluteraldehyde, displayed good affinity for different drugs (diclofenac, indomethacin, metronidazole, and propranolol).²¹⁸ The amount of CD linked in microspheres was in the order β- > γ- > α-CD and the dimensions of the microspheres with γ-CD were much higher than those with α- or β-CDs.

Microcapsules

It was suggested that crosslinked β-CD microcapsules, because of their ability to retard the release of water-soluble drugs through semipermeable membranes, can act as release modulators to provide efficiently controlled release of drugs. Terephthaloyl chloride (TC) crosslinked β-CD microcapsules were found to complex p-nitrophenol rapidly and the amount complexed increased as the size of the microcapsules decreased. TC crosslinked β-CD microcapsules retarded the diffusion of propranolol hydrochloride through dialysis membrane. Double microcapsules, prepared by encapsulating methylene blue with different amounts of β-CD microcapsules inside a crosslinked human serum albumin (HSA), showed decreasing release rate of methylene blue with increasing amount of β-CD microcapsules. Dissociation of methylene blue complex with β-CD microcapsules was found to serve as an additional mechanism in controlling the release kinetics of HSA double microcapsules. In the case of HSA microcapsules with parent β-CD, the hydrating property of the CD, by promoting the diffusion of water into the microcapsules, caused an increased release rate of methylene blue compared with those without the CD. However, in the case of HSA double microcapsules (ie, with β-CD microcapsules), the hydrophobic groups introduced during crosslinking suppressed the CD hydration and provided controlled release without enhancing the diffusion of water that can impair the complexation of methylene blue.²¹⁹

Nanoparticles

Nanoparticles are stable systems suitable to provide targeted drug delivery and to enhance the efficacy and bioavailability of poorly soluble drugs. However, the safety and efficacy of nanoparticles are limited by their very low drug loading and limited entrapment efficiency (with classical water emulsion polymerization procedures) that may lead to excessive administration of polymeric material.^220,221 Two applications of CDs have been found very promising in the design of nanoparticles: one is increasing the loading capacity of nanoparticles and the other is spontaneous formation of either nanocapsules or nanospheres by nanoprecipitation of amphiphilic CDs diesters. Both the new techniques were reported to be useful due to great interest of nanoparticles in oral and parenteral drug administration. CDs increased the loading capacity of poly (isobutylcyanoacrylate) nanoparticles. The increased loading capacity was reported to be a result of increased drug concentration in the polymerization medium on addition of the drug:CD complex and increased number of hydrophobic sites in the nanosphere structure on association of large amounts of CDs to the nanoparticles.^221,222 HP-β-CD increased saquinavir loading into poly (alkylcyanoacrylate) nanoparticles by providing a soluble drug reservoir in polymerization medium that feeds the nanoparticle-formation process. A dynamic equilibrium was observed between the complex, the dissociated species, and the forming polymeric particle. It was indicated that during nanoparticle formation the free drug gets progressively incorporated into polymer network, driven by the drug partition coefficient between the polymer and polymerization medium though there may be a simultaneous direct entrapment of some drug/CD complex.^222,223

Addition of HP-β-CD in the polymerization medium of poly (ethylcyanoacrylate) (PECA) nanospheres improved the subcutaneous absorption of metoclopramide in rats. PECA nanospheres with HP-β-CD provided the highest drug concentration and enhanced drug absorption compared with those with dextran or with drug solution. However, in addition to drug absorption from subcutaneous (sc) sites, HP-β-CD also enhanced the drug elimination by enhancing the drug absorption to reticluoendothelial tissues.²²⁴

Addition of steroid drugs, hydrocortisone (HC), and progesterone (PN) as β-CD or HP-β-CD complexes maintained the sizes of solid lipid nanoparticles (SLN) below 100 nm with the steroids dispersed in an amorphous state. CD complexation increased the incorporation of the more hydrophilic drug, HC than PN but provided lower release of both the drugs from SLN compared with the release from SLN containing the free drugs. It was suggested that the process of incorporating drugs partly in free form and partly in complexed form may be used to modulate release kinetics of drugs from SLN.²²⁵

Amphiphilic β-CDs (β-CDsa), synthesized by introducing substituents of varying chain lengths (C₆-C₁₄) and bond types (ester and amide) on the primary face of the CD, have been characterized and evaluated as potential novel excipients in the preparation of nanocapsules.²²⁶ Compared with natural CDs, β-CDsa, particularly those derivatives with 6C aliphatic chains on the primary face, form biodegradable, nonsurfactant, highly loaded nanospheres and nanocapsules with low hemolytic activity.^220,226,227 The chemical structure of β-CDsa derivatives was found to influence their ability to nanoassociate or form stable nanospheres. Partial acylation of β-CDsa allowed self-assembly into stable nanosphere suspension but peracylation with 14 alkyl chains on secondary hydroxyl groups failed to do the same even in the presence of a nonionic surfactant in the aqueous phase. The amount of partially acylated species in β-CDsa was also found to play an important role in regulating the mean diameter size and suspension stability of nanospheres.²²⁸

Amphiphilic β-CD (β-CDa) derivatives, 6-N-CAPRO-β-CD and β-CDC6 with 6C aliphatic chains on the primary and secondary face respectively, enhanced the solubility and therapeutic efficacy of model drugs, bifonazole and clotrimazole. The β-CDa derivatives formed inclusion complexes with the drugs and with the nanoprecipitation technique the derivatives gave nanospheres of less than 300 nm with no use of surfactants. 6-N-CAPRO-β-CD, due to its ability to hold drugs longer in its cavity, displayed a higher loading capacity and slower release profile than β-CDC6. A slightly higher loading capacity observed with 6-N-CAPRO-β-CD was attributed to the higher drug adsorption onto its particle surface caused by the higher affinity of the 14 alkyl chains surrounding the CD molecule. Affinity of β-CD to model drugs also played a major role in affecting the drug release from the β-CDa nanospheres.²²⁷ Loading techniques and also the type of β-CDa can influence the loading and release properties of the nanospheres. Inclusion complexation of progesterone with β-CDa prior to its entrapment in nanospheres increased the drug loading into nanospheres. Progesterone-loaded β-CDa nanospheres acted as a promising nonsurfactant injectable delivery system to provide rapidly a high quantity of the water-insoluble drug (within 1 hour).²²⁰

CD Use as Excipients in Drug Formulation

As excipients, CDs have been finding different applications in the formulation and processing of drugs. β-CD, due to its excellent compactability (varied with source) and minimal lubrication requirements, showed considerable promise as a filler binder in tablet manufacturing but its fluidity was insufficient for routine direct compression. β-CD was also found to be useful as a solubility enhancer in tablets. The ability of β-CD to complex progesterone by wet granulation was found to be dependent on both binder solution and mixture type.²²⁹ Complexation can cause subtle changes in the tabletting properties of drugs or CDs that can substantially affect the stability and tabletting performance of tablet formulations containing drug/CD complexes. Complexation of tolbutamide with HP-β-CD (freeze-dried or spray-dried) altered the water sorption-desorption and tabletting properties of the CD, and the resultant complex showed worse compactability than the pure CD or the drug/CD physical mixture.²³⁰ CDs also affect the tabletting properties of other excipients, eg, microcrystalline cellulose codried with β-CD showed improved flowability, compactability, and disintegration properties suitable for direct compression.²³¹ In the case of high-swelling wheat starches, β-CD (1%) increased the peak viscosity (PV) but decreased the cool paste viscosity (CPV) and in the case of low-swelling starches, the same CD slightly decreased the PV but increased the CPV. However, β-CD reduced the heat paste viscosity of both the starches.²³² Avicel/β-CD codried product showed improved flowability and disintegration properties but its rounder particles, because of their sensitivity to lubrication, gave tablets weaker than those with avicel. But on addition of magnesium stearate, the codried excipient with improved powder flowability served as a better excipient in wet granulation.²³³

CDs can be used to mask the taste of drugs in solutions, eg, suppression of bitter taste of 4 mm oxyphenonium bromide by CDs. With the assumption that only the free drug molecule exhibits bitter taste regardless of the kind and concentration of CD, the suppression of drug bitter taste by CDs was reported to be in the order of α-CD < γ-CD < β-CD, reflecting the stability constants of the complexes.¹³⁷

CDs were used as pellatization agents in extrusion and spheronization processes and in the presence of β-CD up to 90% by weight, the process provided satisfactory products.²³⁴ CDs were also indicated to stabilize protein and peptide pharmaceuticals during spray drying, eg, inhibition of spray drying induced inactivation of β-galactoside by HP-β-CD.²³⁵

CDs were found to inhibit adsorption or absorption of drugs to container walls. SBE-β-CD and HP-β-CD reduced the adsorption of DY-9760e to PVC tubes but the effect was more significant with SBE-β-CD reflecting the stability constants of the CD complexes. Compared with HP-β-CD, SBE-β-CD was found to exhibit a greater masking effect against the hydrophobic interaction between the surface of PVC tubes and the drug.³⁰ Hydrophilic CDs, including maltosyl-β-CD, inhibited the adsorption of bovine insulin to containers and also inhibited insulin aggregation by interacting with the hydrophilic regions of the peptide.²³⁶ β-CD inhibited the adsorption of FK 906, a surface active drug, from aqueous solution onto container walls by shifting the critical micellar concentration of the drug to a higher value.²³⁷

Carbomers, owing to their ionic nature and large number of acidic groups, tend to interact with cationic substances and hydrophilic polymers with alcoholic groups. CDs were found to inhibit carbomer-drug interactions in hydrogel. Carbopol, as a result of its interaction with the cationic drug, propranolol HCl, formed an insoluble complex that causes modification of all the hydrogel properties of the polymer. β-CD, by reducing carbopol interaction with the cationic drug, maintained the hydrogel properties of carbopol.²³⁸

Large differences were observed in the powder and particle characteristics of β-, α-, γ-, and HP-β-CDs. With these CDs, the order of sphericity was β-CD < α-CD < γ-CD < HP-β-CD and that of shape uniformity was α-CD < β-CD < γ-CD < HP-β-CD. Water content of CDs was found to be variable with storage conditions and can be removed by evaporation at 160°C. It was reported that a characteristic peak shown in the DSC profile of α-CD, unaffected even at high temperature, was representative of a “feasible structural change” in the CD molecule.²³⁹

The osmolality of SBE-CDs was found to increase with the total degree of substitution and was also considerably higher than that of HP-CDs. The observations with these CD derivatives provided a useful insight into their behavior in solutions and in characterization of drug release mechanisms from osmotic pump tablets.²⁴⁰ SBE- and HP- derivatives of β- and α-CDs, with different total degree of substitution (TDS), exhibited different colligative properties, especially their osmotic pressure (OP) increased with their TDS. With substituted CDs, the OP was above their theoretical values but with unsubstituted γ-CD, the OP was below the expected value. Self-association of the unsubstituted γ-CD molecules was reported to be the possible reason for the observed low OP value of the CD. These findings relating the OP properties of CDs can be useful in the formulation of parenteral and ophthalmic solutions, where maintenance of OP is an important consideration.²⁴¹

Interaction of CDs with the preservatives in the formulation is an important factor and should be investigated. It was reported that such interaction can result in reduction of both the solubilizing effect of CD and the antimicrobial activity of preservatives, eg, interaction of HP-β-CD with preservatives like benzalkonium chloride, chlorhexidine gluconate, chlorambutanol, methylparaben, and propylparaben.²⁴²

Conclusion

CDs, as a result of their complexation ability and other versatile characteristics, are continuing to have different applications in different areas of drug delivery and pharmaceutical industry. However, it is necessary to find out any possible interaction between these agents and other formulation additives because the interaction can adversely affect the performance of both. It is also important to have knowledge of different factors that can influence complex formation in order to prepare economically drug/CD complexes with desirable properties. Since CDs continue to find several novel applications in drug delivery, we may expect these polymers to solve many problems associated with the delivery of different novel drugs through different delivery routes.

References

1. Loftsson T, Brewester M.  Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J Pharm Sci. 1996;85:1017-1025.
PubMed  DOI: 10.1021/js950534b

2. Endo T, Nagase H, Ueda H, Kobayashi S, Nagai T.  Isolation, purification, and characterization of Cyclomaltodecaose (curly epsilon-Cyclodextrin), Cyclomaltoundecaose (zeta-Cyclodextrin) and Cyclomaltotridecaose (é-Cyclodextrin). Chem Pharm Bull (Tokyo). 1997;45:532-536.

3. Endo T, Nagase H, Ueda H, Shigihara A, Kobayashi S, Nagai T.  Isolation, purification and characterization of Cyclomaltooctadecaose (v-Cyclodextrin), Cyclomaltononadecaose (xi-Cyclodextrin), Cyclomaltoeicosaose (o-Cyclodextrin) and Cyclomaltoheneicosaose (ã-Cyclodextrin. Chem Pharm Bull (Tokyo). 1998;46:1840-1843.

4. Miyazawa H, Ueda H, Nagase T, Endo T, Kobayashi S, Nagai T.  Physicochemical properties and inclusion complex formation of δ-cyclodextrin. Eur J Pharm Sci. 1995;3:153-162.
DOI: 10.1016/0928-0987(95)00006-Y

5. Szejtli J.  Cylodextrin in drug formulations: Part I. Pharm Technol Int. 1991;3:15-23.
PubMed 

6. Szente L, Szejtli J.  Highly soluble cyclodextrin derivatives: chemistry, properties, and trends in development. Adv Drug Deliv Rev. 1999;36:17-38.
PubMed  DOI: 10.1016/S0169-409X(98)00092-1

7. Matsuda H, Arima H.  Cyclodextrins in transdermal and rectal delivery. Adv Drug Deliv Rev. 1999;36:81-99.
PubMed  DOI: 10.1016/S0169-409X(98)00056-8

8. Higuchi T, Connors KA.  Phase-solubility techniques. Adva Anal Chem Instr. 1965;4:212-217.
PubMed 

9. Rajewski RA, Stella VJ.  Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery. J Pharm Sci. 1996;85:1142-1168.
PubMed  DOI: 10.1021/js960075u

10. Hersey A, Robinson BH, Kelly HC.  Mechanism of inclusion compound formation for binding of organic dyes, ions and surfactants to alpha cyclodextrin studied by kinetic methods based on competition experiments. J Chem Soc, Faraday Trans 1. 1986;82:1271-1287.
PubMed  DOI: 10.1039/f19868201271

11. Cramer F, Saenger W, Satz HC.  Inclusion compounds. ΧΙХ.The formation of inclusion compounds of alpha cyclodextrin in aqueous solutions, thermodynamics and kinetics. J Am Chem Soc. 1967;89:14-20.
DOI: 10.1021/ja00977a003

12. Uekama K, Otagiri M.  Cyclodextrins in drug carrier systems. Crit Rev Ther Drug Carrier Sys. 1987;3:1-40.
PubMed 

13. Szejtli J.  Medicinal applications of cyclodextrins. Med Res Rev. 1994;14:353-386.
PubMed 

14. Thomson DO.  Cyclodextrins–enabling excipients: their present and future use in pharmaceuticals. Crit Rev Ther Drug Carr Sys. 1997;14:1-104.
PubMed 

15. Jayachandra Babu R, Pandit JK.  Cyclodextrin inclusion complexes: oral applications. Eastern Pharmacist. 1995;38:37-42.
PubMed 

16. Irie T, Uekama K.  Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation. J Pharm Sci. 1997;86:147-162.
PubMed  DOI: 10.1021/js960213f

17. Stella VJ, Rajeswski RA.  Cyclodextrins: their future in drug formulation and delivery. Pharm Res. 1997;14:556-567.
PubMed  DOI: 10.1023/A:1012136608249

18. Uekama K, Hirayama F, Irie T.  Cyclodextrin drug carrier systems. Chem Rev. 1998;98:2045-2076.
PubMed  DOI: 10.1021/cr970025p

19. Loftsson T, Ólafsson JH.  Cyclodextrins: new drug delivery system in dermatology. Int J Dermatol. 1998;37:241-246.
PubMed  DOI: 10.1046/j.1365-4362.1998.00369.x

20. Loftsson T.  Increasing the cyclodextrin complexation of drugs and drug bioavailability through addition of water-soluble polymers. Pharmazie. 1998;53:733-740.
PubMed 

21. Castillo JA, Canales JP, Garcia JJ, Lastres JL, Bolas F, Torrado JJ.  Preparation and characterization of albendazole beta-cyclodextrin complexes. Drug Dev Ind Pharm. 1999;25:1241-1248.
PubMed  DOI: 10.1081/DDC-100102294

22. Diaz D, Escobar Llanos CM, Bernad MJB.  Study of the binding in an aqueous medium of inclusion complexes of several cyclodextrins involving fenoprofen calcium. Drug Dev Ind Pharm. 1999;25:107-110.
PubMed  DOI: 10.1081/DDC-100102150

23. Mura P, Faucci MT, Parrini PL, Furlanetto S, Pinzauti S.  Influence of the preparation method on the physicochemical properties of ketoprofen-cyclodextrin binary systems. Int J Pharm. 1999;179:117-128.
PubMed  DOI: 10.1016/S0378-5173(98)00390-1

24. Nesna N, Lou J, Breslow R.  The binding of cocaine to cyclodextrins. Bioorg Med Chem Lett. 2000;10:1931-1933.
PubMed  DOI: 10.1016/S0960-894X(00)00371-1

25. Arias-Blanco MJA, Moyano JR, Martinez JIP, Gines JM.  Study of inlusion complex of gliclazide in α-cyclodextrin. J Pharm Biomed Anal. 1998;18:275-279.
PubMed  DOI: 10.1016/S0731-7085(98)00179-4

26. Ueda H, Wakamiya T, Endo H, Nagase H, Tomono K, Nagai T.  Interaction of cyclomaltononaose (delta-CD) with several drugs. Drug Dev Ind Pharm. 1999;25:951-954.
PubMed  DOI: 10.1081/DDC-100102256

27. Akasaka H, Endo T, Nagase H, Ueda H, Kobayashi S.  Complex formation of cyclomaltononaose delta-cyclodextrin (delta-CD) with macrocyclic compounds. Chem Pharm Bull (Tokyo). 2000;48:1986-1989.
PubMed 

28. Mura P, Adragna E, Rabasco AM, et al.  Effects of the host cavity size and the preparation method on the physicochemical properties of ibuproxam-cyclodextrin systems. Drug Dev Ind Pharm. 1999;25:279-287.
PubMed  DOI: 10.1081/DDC-100102172

29. Lutka A.  Investigation of interaction of promethazine with cyclodextrins in aqueous solution. Acta Pol Pharm. 2002;59:45-51.
PubMed 

30. Nagase Y, Hirata M, Wada K, et al.  Improvement of some pharmaceutical properties of DY-9760e by sulfobutyl ether beta-cyclodextrin. Int J Pharm. 2001;229:163-172.
PubMed  DOI: 10.1016/S0378-5173(01)00851-1

31. Jain AC, Adeyeye MC.  Hygroscopicity, phase solubility and dissolution of various substituted sulfobutylether beta-cyclodextrins (SBE) and danazol-SBE inclusion complexes. Int J Pharm. 2001;212:177-186.
PubMed  DOI: 10.1016/S0378-5173(00)00607-4

32. Loftsson T, Peterson DS.  Cyclodextrin solubilization of ETH-615, a zwitterionic drug. Drug Dev Ind Pharm. 1998;24:365-370.
PubMed 

33. Dalmora MEA, Oliveira AG.  Inclusion complex of piroxicam with beta-cyclodextrin and incorporation in hexadecyltrimethylammonium bromide based microemulsion. Int J Pharm. 1999;184:157-164.
PubMed  DOI: 10.1016/S0378-5173(99)00099-X

34. McCandless R, Yalkowsky SH.  Effect of hydroxypropyl-beta-cyclodextrin and pH on the solubility of levemopamil HCl. J Pharm Sci. 1998;87:1639-1642.
PubMed  DOI: 10.1021/js9802143

35. Kim Y, Oksanen DA, Massefski W, Blake JF, Duffy EM, Chrunyk B.  Inclusion complexation of ziprasidone mesylate with beta-cyclodextrin sulfobutyl ether. J Pharm Sci. 1998;87:1560-1567.
PubMed  DOI: 10.1021/js980109t

36. Tros de Ilarduya MC, Martin C, Goni MM, Martinez-Oharriz MC.  Solubilization and interaction of sulindac with beta-cyclodextrin in the solid state and in aqueous solution. Drug Dev Ind Pharm. 1998;24:301-306.
PubMed 

37. Diaz D, Bernad MJB, Mora JG, Llaons CME.  Solubility, 1H-NMR, and molecular mechanics of mebendazole with different cyclodextrins. Drug Dev Ind Pharm. 1999;25:111-115.
PubMed  DOI: 10.1081/DDC-100102151

38. Zarzycki PK, Lamparczyk H.  The equilibrium constant of β-cyclodextrin-phenolphtalein complex; influence of temperature and tetrahydrofuran addition. J Pharm Biomed Anal. 1998;18:165-179.
PubMed  DOI: 10.1016/S0731-7085(98)00150-2

39. Jain AC, Adeyeye MC.  Hygroscopicity, phase solubility and dissolution of various substituted sulfobutylether beta-cyclodextrins (SBE) and danazol-SBE inclusion complexes. Int J Pharm. 2001;212:177-186.
PubMed  DOI: 10.1016/S0378-5173(00)00607-4

40. Chowdary KPR, Nalluri BN.  Nimesulide and beta-cyclodextrin inclusion complexes: physicochemical characterization and dissolution rate studies. Drug Dev Ind Pharm. 2000;26:1217-1220.
PubMed  DOI: 10.1081/DDC-100100995

41. Palmeiri GF, Angeli DG, Giovannnucci G, Martelli S.  Inclusion of methoxytropate in β− and hydroxylpropyl β-cyclodextrins: Comparision of preparation methods. Drug Dev Ind Pharm. 1997;23:27-37.

42. Palmieri GF, Wehrle P, Stamm A.  Inclusion of vitamin D₂ in β-cyclodextrin: evaluation of different complexation methods. Drug Dev Ind Pharm. 1993;19:875-885.

43. Moyano JR, Arias MJ, Gines JM, Perez JI, Rabasco AM.  Dissolution behavior of oxazepam in the presence of cyclodextrins: evaluation of oxazepam dimeb binary system. Drug Dev Ind Pharm. 1997;23:379-385.

44. Pose-Vilarnovo B, Perdomo-Lopez I, Echezarreta-Lopez M, Schroth-Pardo P, Estrada E, Torres-Labandeira JJ.  Improvement of water solubility of sulfamethizole through its complexation with β- and hydroxypropyl-β-cyclodextrin—Characterization of the interaction in solution and in solid state. Eur J Pharm Sci. 2001;13:325-331.
PubMed  DOI: 10.1016/S0928-0987(01)00131-2

45. Mitrevej A, Sinchaipanid N, Junyaprasert V, Warintornuwat L.  Effect of grinding of β-cyclodextrin and glibenclamide on tablet properties. Drug Dev Ind Pharm. 1996;22:1237-1241.

46. Senoferjan AM, Nanjundaswamy NG, Mahesh S, Murthy SN.  Formulation and evaluation of β- cyclodextrin complexes of tenoxicam. Indian J Pharm Sci. 2000;62:119-121.

47. Loftsson T, Guomundsdottir TK, Frioriksdottir H.  The influence of water-soluble polymers and pH on hydroxypropyl-α-cyclodextrin complexation of drugs. Drug Dev Ind Pharm. 1996;22:401-406.

48. Nath BS, Shivkumar HN.  A 2(3) Factorial studies on factors influencing Meloxicam β-cyclodextrin complexation for better solubility. Indian J Pharm Sci. 2000;62:129-132.

49. Cappello B, Carmignani C, Iervolino M, La Rotonda MI, Saettone MF.  Solubilization of tropicamide by hydroxypropyl-beta-cyclodextrin and water-soluble polymers: in vitro/ in vivo studies. Int J Pharm. 2001;213:75-81.
PubMed  DOI: 10.1016/S0378-5173(00)00648-7

50. Faucci MT, Mura P.  Effect of water-soluble polymers on naproxen complexation with natural and chemically modified beta-cyclodextrins. Drug Dev Ind Pharm. 2001;27:909-917.
PubMed 

51. Granero G, de Bertorello NM, Longhi M.  Solubilization of a naphthoquinone derivative by hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and polyvinylpyrrolidone (PVP-K30). The influence of PVP-K30 and pH on solubilizing effect of HP-beta-CD. Boll Chim Farm. 2002;141:63-66.
PubMed 

52. Pedersen M.  Effect of hydrotropic substances on the complexation of clotrimazole with beta cyclodextrin. Drug Dev Ind Pharm. 1993;19:439-448.

53. Veiga F, Fernandes C, Maincent P.  Influence of the preparation method on the physicochemical properties of tolbutamide/cyclodextrin binary systems. Drug Dev Ind Pharm. 2001;27:523-532.
PubMed  DOI: 10.1081/DDC-100105177

54. Tokumura T, Nanda M, Tsushima Y, et al.  Enhancement of bioavailability of cinnarizine from its beta-cyclodextrin complex on oral administration with DL-phenylalanine as a competing agent. J Pharm Sci. 1986;75:391-394.
PubMed 

55. Muller BW, Albers E.  Effect of hydrotropic substances on the complexation of sparingly soluble drugs with cyclodextrin derivatives and the influence of cyclodextrin complexation on the pharmacokinetics of the drugs. J Pharm Sci. 1991;80:599-604.
PubMed 

56. Redenti E, Szente L, Szetli J.  Drug/cyclodextrin/hydroxy acid multicomponent systems. Properties and pharmaceutical applications. J Pharm Sci. 2000;89:1-8.
PubMed  DOI: 10.1002/(SICI)1520-6017(200001)89:1<1::AID-JPS1>3.0.CO_2-W

57. Li P, Zhao L, Yalkowsky SH.  Combined effect of cosolvent and cyclodextrin on solubilization of nonpolar drugs. J Pharm Sci. 1999;88:1107-1111.
PubMed  DOI: 10.1021/js990159d

58. Miyake K, Irie T, Arima H, et al.  Characterization of itraconazole/2-hydroxypropyl-beta-cyclodextrin inclusion complex in aqueous propylene glycol solution. Int J Pharm. 1999;179:237-245.
PubMed  DOI: 10.1016/S0378-5173(98)00393-7

59. Blanchard J, Stefan P.  Some important considerations in the use of cyclodextrins. Pharm Res. 1999;16:1796-1798.
PubMed  DOI: 10.1023/A:1011930821801

60. Muller BW, Brauns U.  Hydroxypropyl-beta-cyclodextrin derivatives: influence of average degree of substitution on complexing ability and surface activity. J Pharm Sci. 1986;75:571-572.
PubMed 

61. Zia V, Rajeswski RA, Bornancini ER, Luna EA, Stella VJ.  Effect of alkyl chain length and degree of substitution on the complexation of sulfoalkyl ether beta-cyclodextrins with steroids. J Pharm Sci. 1997;86:220-224.
PubMed  DOI: 10.1021/js960236u

62. CycloLab Cyclodextrin Research & Development Laboratory Web site.   Available at: http://www.cyclolab.hu. Accessed May 25, 2005. 

63. Wacker-Chemie GmbH Products and Trademarks Web site.   Available at: http://www.wacker.com. Accessed May 25, 2005. 

64. Sigma-Aldich Web site.   Available at: http://www.sigmaaldrich.com/. Accessed May 25, 2005. 

65. CyDex Inc Web site.   Available at: http://www.cydexinc.com. Accessed May 25, 2005. 

66. Inc CTC. Web site.   Available at: http://www.cyclodex.com. Accessed May 25, 2005. 

67. Cyclodextrins for Pharmaceutical Applications [technical brochure].  2000; Available at: http://www.ispcorp.com/products/pharma/content/forwhatsnew/cyclodex/cyclodex.pdf. Accessed May 25, 2005. 

68. Mosher G, Thompson DO. Complexation and Cyclodextrins. In: Swarbrick J, Boylan JC,  eds. Encyclopedia of Pharmaceutical Technology 2^nd ed. New York, NY: Marcell Dekker; 2002:531-558. 

69. Pitha J, inventor. Pharmaceutical preparations containing cyclodextrin derivatives.. US patent 4 727 064. February 23, 1988.

70. Tasic LM, Jovanovic MD, Djuric ZR.  The influence of beta-cyclodextrin on the solubility and dissolution rate of paracetamol solid dispersions. J Pharm Pharmacol. 1992;44:52-55.
PubMed 

71. Sanghavi NM, Choudhari KB, Matharu RS, Viswanathan L.  Inclusion complexation of Lorazepam with beta-cyclodextrin. Drug Dev Ind Pharm. 1993;19:701-712.

72. Ahn HJ, Kim KM, Choi SJ, Kim CK.  Effects of cyclodextrin derivatives on bioavailability of ketoprofen. Drug Dev Ind Pharm. 1997;23:397-401.

73. Dhanaraju MD, Santil Kumaran K, Baskaran T, Moorthy MSR.  Enhancement of bioavailability of griseofulvin by its complexation with beta-cyclodextrin. Drug Dev Ind Pharm. 1998;24:583-587.
PubMed 

74. Veiga MD, Diaz PJ, Ahsan F.  Interactions of griseofulvin with cyclodextrins in solid binary systems. J Pharm Sci. 1998;87:891-900.
PubMed  DOI: 10.1021/js970233x

75. Becket G, Schep LJ, Tan MY.  Improvement of the in vitro dissolution of praziquantal by complexation with alpha-, beta- and gamma-cyclodextrins. Int J Pharm. 1999;179:65-71.
PubMed  DOI: 10.1016/S0378-5173(98)00382-2

76. Lotter J, Krieg HM, Keizer K, Breytenbach JC.  The influence of beta-cyclodextrin on the solubility of chlorthalidone and its enantiomers. Drug Dev Ind Pharm. 1999;25:879-884.
PubMed  DOI: 10.1081/DDC-100102248

77. Askrabic JM, Rajic DS, Tasic L, Djuric S, Kasa P, Hodi KP.  Etodolac and solid dispersion with β-cyclodextrin. Drug Dev Ind Pharm. 1997;23:1123-1129.

78. Cavallari C, Abertini B, Rodriguez MLG, Rodriguez L.  Improved dissolution behavior of steam granulated piroxicam. Eur J Pharm Biopharm. 2002;54:65-73.
PubMed  DOI: 10.1016/S0939-6411(02)00021-8

79. Chowdary KPR, Rao SS.  Investigation of dissolution enhancement of itraconazole by complexation with β-, and hydroxypropyl-β-cyclodextrins. Indian J Pharm Sci. 2001;63:438-441.
PubMed 

80. Ghorab MK, Adeyeye MC.  Enhancement of ibuprofen dissolution via wet granulation with beta cyclodextrin. Pharm Dev Technol. 2001;6:305-314.
PubMed  DOI: 10.1081/PDT-100002611

81. Arias MJ, Moyano JR, Munoz P, Gines JM, Justo A, Giordano F.  Study of omeprazole-gamma-cyclodextrin complexation in the solid state. Drug Dev Ind Pharm. 2000;26:253-259.
PubMed  DOI: 10.1081/DDC-100100353

82. Uekama K, Fujinaga T, Hirayama F, et al.  Improvement of the oral bioavailability of digitalis glycosides by cyclodextrin complexation. J Pharm Sci. 1983;72:1338-1341.
PubMed 

83. Londhe V, Nagarsenker M.  Comparision between Hydroxypropyl-β-cyclodextrin and polyvinyl pyrrolidine as carriers for carbamazepine solid dispersions. Indian J Pharm Sci. 1999;61:237-240.
PubMed 

84. Trapani G, Latrofa A, Franco M, et al.  Complexation of zolpidem with 2-hydroxypropyl-β-, methyl-β-, 2-hydroxypropyl-γ-cyclodextrins: Effect on aqueous solubility, dissolution rate and ataxic activity in rats. J Pharm Sci. 2000;89:1443-1451.
PubMed  DOI: 10.1002/1520-6017(200011)89:11<1443::AID-JPS7>3.0.CO_2-Q

85. Latrofa A, Trapani G, Franco M, et al.  Complexation of phenytoin with some hydrophilic cyclodextrins: Effect on aqueous solubility, dissolution rate and anti-covulsant activity in mice. Eur J Pharm Biopharm. 2001;52:65-73.
PubMed  DOI: 10.1016/S0939-6411(01)00144-8

86. Miyake K, Arima H, Hiramaya F, et al.  Improvement of solubility and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin. Pharm Dev Technol. 2000;5:399-407.
PubMed  DOI: 10.1081/PDT-100100556

87. Bettinetti G, Gazzaniga A, Mura P, Giordano F, Setti M.  Thermal behavior and dissolution properties of naproxen in combinations with chemically modified beta-cyclodextrins. Drug Dev Ind Pharm. 1992;18:39-53.

88. Kang J, Kumar V, Yang D, Chowdhury PR, Hohl RJ.  Cyclodextrin complexation: influence on the solubility, stability, and cytotoxicity of camptothecin, an antineoplastic agent. Eur J Pharm Sci. 2002;15:163-170.
PubMed  DOI: 10.1016/S0928-0987(01)00214-7

89. Zhao L, Li P, Yalkowsky SH.  Solubilization of fluasterone. J Pharm Sci. 1999;88:967-969.
PubMed  DOI: 10.1021/js9901413

90. Kaukonen AM, Lennernas H, Mannermaa JP.  Water-soluble Beta cyclodextrin in paediatric oral solutions of spiranolactone: preclinical evalution of spiranolactone bioavailability from solutions of beta cyclodextrin derivatives in rats. J Pharm Pharmacol. 1998;50:611-619.
PubMed 

91. Arima H, Yunomae K, Miyake K, Irie T, Hirayama F, Uekama K.  Comparative studies of the enhancing effects of cyclodextrins on the solubility and oral bioavailability of tacrolimus in rats. J Pharm Sci. 2001;90:690-701.
PubMed  DOI: 10.1002/jps.1025

92. Bettinetti G, Mura P, Faucci MT, Sorrenti M, Setti M.  Interaction of naproxen with noncrystalline acetyl beta- and acetyl gamma-cyclodextrins in the solid and liquid state. Eur J Pharm Sci. 2002;15:21-29.
PubMed  DOI: 10.1016/S0928-0987(01)00199-3

93. Ueda H, Ou D, Endo T, Nagase H, Tomono K, Nagai T.  Evaluation of a sulfobutyl ether beta-cyclodextrin as a solubilizing/stabilizing agent for several drugs. Drug Dev Ind Pharm. 1998;24:863-867.
PubMed 

94. Sangalli ME, Zema L, Moroni A, Foppoli A, Giordano F, Gazzania A.  Influence of β-cylodextrin on the release of poorly soluble drugs from inert and hydrophilic heterogeneous polymeric matrices. Biomaterials. 2001;22:2647-2651.
PubMed  DOI: 10.1016/S0142-9612(01)00005-9

95. Pina ME, Veiga F.  The influence of diluent on the release of theophylline from hydrophilic matrix tablets. Drug Dev Ind Pharm. 2000;26:1125-1128.
PubMed  DOI: 10.1081/DDC-100100279

96. Loftsson T, Stefánsson E.  Effect of cyclodextrins on topical drug delivery to the eye. Drug Dev Ind Pharm. 1997;23:473-481.

97. Van Dorne H.  Interaction between cyclodextrins and ophthalmic drugs. Eur J Pharm Biopharm. 1993;39:133-139.

98. Loftsson T, Másson M, Stefánsson E. Cyclodextrins as permeation enhancers. 17th Pharmaceutical Technology Conference and Exhibition; March 24-26, 1997; Dublin, Ireland. 

99. Loftsson T, Leeves N, Bjornsdottir B, Duffy L, Masson M.  Effect of cyclodextrins and polymers on triclosan availability and substantivity in toothpastes in vivo. J Pharm Sci. 1999;88:1254-1258.
PubMed  DOI: 10.1021/js9902466

100. Willems L, Geest RV, de Beule K.  Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics. J Clin Pharm Ther. 2001;26:159-169.
PubMed  DOI: 10.1046/j.1365-2710.2001.00338.x

101. Yang T, Hussain A, Paulson J, Abbruscato TJ, Ahsan F.  Cyclodextrins in nasal delivery of low-molecular-weight heparins: in vivo and in vitro studies. Pharm Res. 2004;21:1127-1136.
PubMed  DOI: 10.1023/B:PHAM.0000032998.84488.7a

102. Watanabe Y, Kiriyama M, Ito R, et al.  Pharmacodynamics and pharmacokinetics of recombinant human granulocyte colony-stimulating factor (rhG-CSF) after administration of a rectal dosage vehicle. Biol Pharm Bull. 1996;19:1059-1063.
PubMed 

103. Nicolazzi C, Venard V, Le Faou A, Finance C.  In vitro antiviral activity of the gancyclovir complexed with beta cyclodextrin on human cytomegalovirus strains. Antiviral Res. 2002;54:121-127.
PubMed  DOI: 10.1016/S0166-3542(01)00218-2

104. Blanchard J, Ugwu SO, Bhardwaj R, Dorr RT.  Development and testing of an improved of phenytoin using 2-hydroxypropyl-beta-cyclodextrin. Pharm Dev Technol. 2000;5:333-338.
PubMed  DOI: 10.1081/PDT-100100548

105. Scalia S, Villani S, Casolari A.  Inclusion complexation of the sunscreening agent 2–ethyl hexyl–p–dimethyl aminobenzoate with hydroxypropyl-β-cyclodextrin: effect on photostability. J Pharm Pharmacol. 1999;51:1367-1374.
PubMed  DOI: 10.1211/0022357991777182

106. Serni U.  Rheumatic diseases—clinical experience with piroxicam-beta-cyclodextrin. Eur J Rheumatol Inflamm. 1993;12:47-54.
PubMed 

107. Kim JH, Lee SK, Ki MH, et al.  Development of parenteral formulation for a novel angiogenesis inhibitor, CKD-732 through complexation with hydroxypropyl-β-cyclodextrin. Int J Pharm. 2004;272:79-89.
PubMed  DOI: 10.1016/j.ijpharm.2003.11.034

108. Nagase Y, Arima H, Wada K, et al.  Inhibitory effect of sulfobutyl ether beta-cyclodextrin on DY-9760e-induced cellular damage: In vitro and in vivo studies. J Pharm Sci. 2003;92:2466-2474.
PubMed  DOI: 10.1002/jps.10517

109. Loftssona T, Jarvinen T.  Cyclodextrins in ophthalmic drug delivery. Adv Drug Deliv Rev. 1999;36:59-79.
PubMed  DOI: 10.1016/S0169-409X(98)00055-6

110. Babu R, Pandit JK.  Effect of aging on the dissolution stability of glibenclamide/beta-cyclodextrin complex. Drug Dev Ind Pharm. 1999;25:1215-1219.
PubMed  DOI: 10.1081/DDC-100102291

111. Cwiertnia B, Hladon T, Stobiecki M.  Stability of Diclofenac sodium in the inclusion complex in the beta cyclodextrin in the solid state. J Pharm Pharmacol. 1999;51:1213-1218.
PubMed  DOI: 10.1211/0022357991776930

112. Li J, Guo Y, Zografi G.  The solid-state stability of amorphous quinapril in the presence of beta-cyclodextrins. J Pharm Sci. 2002;91:229-243.
PubMed  DOI: 10.1002/jps.10014

113. Brewster ME, Loftsson T, Estes KS, Lin JL, Friðriksdóttir H.  Effects of various cyclodextrins on solution stability and dissolution rate of doxorubicin hydrochloride. Int J Pharm. 1992;79:289-299.
DOI: 10.1016/0378-5173(92)90121-H

114. Ma DQ, Rajewski RA, Velde DV, Stella VJ.  Comparative effects of (SBE) _7m-beta-CD and HP-beta-CD on the stability of two anti-neoplastic agents, melphalan and carmustine. J Pharm Sci. 2000;89:275-287.
PubMed  DOI: 10.1002/(SICI)1520-6017(200002)89:2<275::AID-JPS15>3.0.CO_2-C

115. Singla AK, Garg A, Aggarwal D.  Paclitaxel and its formulations. Int J Pharm. 2002;235:179-192.
PubMed  DOI: 10.1016/S0378-5173(01)00986-3

116. Jarho P, Vander Velde D, Stella VJ.  Cyclodextrin-catalyzed deacetylation of spironolactone is pH and cyclodextrin dependent. J Pharm Sci. 2000;89:241-249.
PubMed  DOI: 10.1002/(SICI)1520-6017(200002)89:2<241::AID-JPS11>3.0.CO_2-0

117. Sortino S, Giuffrida S, De Guldi G, et al.  The photochemistry of flutamide and its inclusion complex with beta-cyclodextrin: Dramatic effect of the microenvironment on the nature and on the efficiency of the photodegradation pathways. Photochem Photobiol. 2001;73:6-13.
PubMed  DOI: 10.1562/0031-8655(2001)073<0006:TPOFAI>2.0.CO_2

118. Mielcarek J.  Photochemical stability of the inclusion complexes formed by modified 1, 4-dihydropyridine derivatives with beta-cyclodextrin. J Pharm Biomed Anal. 1997;15:681-686.
PubMed  DOI: 10.1016/S0731-7085(96)01900-0

119. Lutka A, Koziara J.  Interaction of trimeprazine with cyclodextrins in aqueous solution. Chem Pharm Bull (Tokyo). 2000;57:369-374.

120. Croyle MA, Cheng X, Wilson JM.  Development of formulations that enhance physical stability of viral vectors for gene therapy. Gene Ther. 2001;8:1281-1290.
PubMed  DOI: 10.1038/sj.gt.3301527

121. Dwivedi AK, Kulkarni D, Khanna M, Singh S.  Effect of cyclodextrins on the stability of new antimalarial compound N¹–3¹ –Acetyl/ - 4¹, 5¹ – Dihydro – 2¹ Furanyl – N⁴–(6–Methoxy, 8-Quinolinyl)–1– 4–Pentane diamine. Ind J Pharm Sci. 1999;61:175-177.
PubMed 

122. Koester LS, Guterres SS, Le Roch M, Lima VLE, Zuanazzi JA.  Bassani Vl. Ofloxacin/ beta-cyclodextrin complexation. Drug Dev Ind Pharm. 2001;27:533-540.
PubMed  DOI: 10.1081/DDC-100105178

123. Choi HG, Lee BJ, Han JH, et al.  Terfenadine-beta-Cyclodextrin inclusion complex with antihistaminic activity enhancement. Drug Dev Ind Pharm. 2001;27:857-862.
PubMed  DOI: 10.1081/DDC-100107250

124. Aggarwal S, Singh PN, Mishra B.  Studies on solubility and hypoglycemic activity of gliclazide beta-cyclodextrin-hydroxypropylmethylcellulose complexes. Pharmazie. 2002;57:191-193.
PubMed 

125. Veiga F, Fernandes C, Teixeira F.  Oral bioavailability and hypoglycaemic activity of tolbutamide/cyclodextrin inclusion complexes. Int J Pharm. 2000;202:165-171.
PubMed  DOI: 10.1016/S0378-5173(00)00445-2

126. Fathy M, Sheha M.  In vitro and in vivo evaluation of amylobarbitone/ hydroxypropyl-β-cyclodextrin complex prepared by a freeze-drying method. Pharmazie. 2000;55:513-517.
PubMed 

127. Zuo Z, Kwon G, Stevenson B, Diakur J, Wiebe LI.  Flutamide- Hydroxy proyl- β-cyclodextrin complex: formulation, physical characterization, and absorption studies using the Caco-2 in vitro model. J Pharm Pharm Sci. 2000;3:220-227.
PubMed 

128. Yoo SD, Yoon BM, Lee HS, Lee KC.  Increased bioavailability of clomipramine after sublingual administration in rats. J Pharm Sci. 1999;88:1119-1121.
PubMed  DOI: 10.1021/js990163p

129. Pitha J, Harman SM, Michel ME.  Hydrophilic cyclodextrin derivatives enable effective oral administration of steroidal hormones. J Pharm Sci. 1986;75:165-167.
PubMed 

130. Pitha J, Anaissie EJ, Uekama K.  Gamma-cyclodextrin: testosterone complex suitable for sublingual administration. J Pharm Sci. 1987;76:788-790.
PubMed 

131. Farag Badawy SI, Ghorab MM, Adeyeye CM.  Bioavailability of danazol-hydroxypropyl-á-cylodextrin complex by different routes of administration. Int J Pharm. 1996;145:137-143.
DOI: 10.1016/S0378-5173(96)04763-1

132. Jain AC, Aungust BJ, Adeyeye MC.  Development and in vivo evaluation of buccal tablets prepared using danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complexes. J Pharm Sci. 2002;91:1659-1668.
PubMed  DOI: 10.1002/jps.10163

133. Garcia-Rodriguez JJ, Torrado J, Bolas F.  Improving bioavailability and anthelmentic activity of albendazole by preparing albendazole cyclodextrin complex. Parasite. 2001;8:S188-S190.
PubMed 

134. Jacobsen J, Bjerregaard S, Pedersen M.  Cyclodextrin inclusion complexes of antimycotics intended to act in the oral cavity-drug supersaturation, toxicity on TR146 cells and release from a delivery system. Eur J Pharm Biopharm. 1999;48:217-224.
PubMed  DOI: 10.1016/S0939-6411(99)00043-0

135. Okimoto K, Ohike A, Ibuki R, et al.  Design and evaluation of an osmotic pump tablet (OPT) for chlorpromazine using (SBE)7m-beta-CD. Pharm Res. 1999;16:549-554.
PubMed  DOI: 10.1023/A:1018827214223

136. Okimoto K, Miyake M, Ohnishi N, et al.  Design and evaluation of an osmotic pump tablet (OPT) for prednisolone, a poorly water soluble drug, using (SBE)7m-beta-CD. Pharm Res. 1998;15:1562-1568.
PubMed  DOI: 10.1023/A:1011955117026

137. Funasaki N, Kawaguchi R, Hada S, Neya S.  Ultraviolet spectroscopic estimation of microenvironments and bitter tastes of oxyphenonium bromide in cyclodextrin solutions. J Pharm Sci. 1999;88:759-762.
PubMed  DOI: 10.1021/js990026s

138. Stevens DA.  Intraconazole in cyclodextrin solution. Pharmacotherapy. 1999;9:603-611.

139. Shinoda T, Kagatani S, Maeda A, et al.  Sugar-branched-cyclodextrins as injectable drug carriers in mice. Drug Dev Ind Pharm. 1999;25:1185-1192.
PubMed  DOI: 10.1081/DDC-100102286

140. Blanchard J, Ugwu SO, Bhardwaj R, Dorr T.  Anhydrous carbopol polymer gels for the topical delivery of oxygen/water sensitive compounds. Pharm Dev Technol. 2000;7:249-255.

141. Piel G, Evrard B, Van Hees T, Delattre L.  Comparison of the IV pharmacokinetics in sheep of miconazole-cyclodextrin solutions and a micellar solution. Int J Pharm. 1999;180:41-45.
PubMed  DOI: 10.1016/S0378-5173(98)00403-7

142. Sideris EE, Koupparis MA, Macheras PE.  Effect of cyclodextrins on protein binding of drugs: the diflunisal/ hydroxypropyl-beta-cyclodextrin model case. Pharm Res. 1994;11:90-95.
PubMed  DOI: 10.1023/A:1018901912619

143. Grosse PY, Bressoile F, Rouanet P, Joulia JM, Pinguest F.  Methyl-beta-cyclodextrin and doxorubicin pharmacokinetics and tissue concentrations following bolus injection of these drugs alone or together in the rabbit. Int J Pharm. 1999;180:215-223.
PubMed  DOI: 10.1016/S0378-5173(99)00008-3

144. Hirayama F, Mieda S, Miyamoto Y, Arima H, Uekama K.  Heptakis (2, 6-di-O-methyl-3-O-acetyl)-beta-cyclodextrin: a water-soluble cyclodextrin derivative with low hemolytic activity. J Pharm Sci. 1999;88:970-975.
PubMed  DOI: 10.1021/js990128i

145. Saarinen-Savolainen P, Jarvinen T, Araki-Sasaki K, Watanabe H, Urtti A.  Evaluation of cytotoxicity of various ophthalmic drugs, eye drop excipients and cyclodextrins in an immortalized human corneal epithelial cell line. Pharm Res. 1998;15:1275-1280.
PubMed  DOI: 10.1023/A:1011956327987

146. Siefert B, Keipert S.  Influence of alpha-cyclodextrin and hydroxyalkylated β-cyclodextrin derivatives on the corneal uptake and permeation aqueous pilocarpine-HCL solutions. J Pharm Sci. 1997;86:716-720.
PubMed  DOI: 10.1021/js960389h

147. Becirevic-Lacan M, Filipovic-Grcic J.  Effect of hydroxypropyl-beta-cyclodextrin on hydrocortisone dissolution from films intended for ocular drug delivery. Pharmazie. 2000;55:518-520.
PubMed 

148. Aktas Y, Unlu N, Orhan M, Irkec M, Hincal AA.  Influence of hydroxypropyl β-cyclodextrin on the corneal permeation of pilocarpine. Drug Dev Ind Pharm. 2003;29:223-230.
PubMed 

149. Merkus FW, Verhoef JC, Marttin E, et al.  Cyclodextrins in nasal drug delivery. Adv Drug Deliv Rev. 1999;36:41-57.
PubMed  DOI: 10.1016/S0169-409X(98)00054-4

150. Loftsson T, Gudmundsdottir H, Sigurjonsdottir JF, et al.  Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray. Int J Pharm. 2001;212:29-40.
PubMed  DOI: 10.1016/S0378-5173(00)00580-9

151. Zhang Y, Jiang XG, Yao J.  Nasal absorption enhancement of insulin by sodium deoxycholate in combination with cyclodextrins. Acta Pharmacol Sin. 2001;22:1051-1056.
PubMed 

152. Srichana T, Suedee R, Reanmongkol W.  Cyclodextrin as a potential drug carrier in salbutamol dry powder aerosols: the in vitro deposition and toxicity studies of the complexes. Respir Med. 2001;95:513-519.
PubMed  DOI: 10.1053/rmed.2001.1079

153. Gudmundsdottir H, Sigurjonsdottir JF, Masson M, Fjalldal O, Stefansson E, Loftsson T.  Intranasal administration of midazolam in a cyclodextrin based formulation: bioavailability and clinical evaluation in humans. Pharmazie. 2001;56:963-966.
PubMed 

154. Uekama K, Kondo T, Nakamura K, et al.  Modification of rectal absorption of morphine from hollow-type suppositories with a combination of alpha-cyclodextrin and viscosity-enhancing polysaccharide. J Pharm Sci. 1995;84:15-20.
PubMed 

155. Kowari K, Hirosawa I, Kurai H, Utoguchi N, Fujii M, Watanabe Y.  Pharmacokinetics and pharmacodynamics of human chorionic gonadotropin (hCG) after rectal administration of hollow-type suppositories containing hCG. Biol Pharm Bull. 2002;25:678-681.
PubMed  DOI: 10.1248/bpb.25.678

156. Hirayama F, Uekama K.  Cyclodextrin-based controlled drug release system. Adv Drug Deliv Rev. 1999;36:125-141.
PubMed  DOI: 10.1016/S0169-409X(98)00058-1

157. Sinha VR, Nanda A, Kumria R. Cyclodextrins as sustained-release carriers. Pharmaceutical Technology.  2002; Available at: http://www.pharmtech.com. Accessed May 25, 2005. 

158. Horiuchi Y, Hirayama F, Uekama K.  Slow-release characteristics of diltiazem from ethylated β-cyclodextrin complex. J Pharm Sci. 1990;79:128-132.
PubMed 

159. Hirayama F, Hirashima N, Abe K, Uekama K, Ijitsu T, Ueno M.  Utilization of diethyl-beta-cyclodextrin as a sustained-release carrier for isosorbide dinitrate. J Pharm Sci. 1988;77:233-236.
PubMed 

160. Uekama K, Horikawa T, Yamanaka M, Hirayama F.  Peracylated β-cyclodextrins as novel sustained-release carriers for a water-soluble drug, molsidomine. J Pharm Pharmacol. 1994;46:714-717.
PubMed 

161. Wang Z, Horikawa T, Hirayama F, Uekama K.  Design and in vitro evaluation of a modified-release oral dosage form of nifedipine by hybridization of hydroxypropyl-beta-cyclodextrin and hydroxypropylcellulose. J Pharm Pharmacol. 1993;45:942-946.
PubMed 

162. Quaglia F, Varricchio G, Miro A, La Rotonda MI, Larobina D, Mensitieri G.  Modulation of drug release from hydrogels by using cyclodextrins: the case of nicardipine/ beta-cyclodextrin system in crosslinked polyethylenglycol. J Control Release. 2001;71:329-337.
PubMed  DOI: 10.1016/S0168-3659(01)00242-5

163. Rao VM, Haslam JL, Stella VJ.  Controlled and complete release of a model poorly water-soluble drug, prednisolone from hydroxypropyl methylcellulose matrix tablets using (SBE) (7m)-beta-cyclodextrin as a solubilizing agent. J Pharm Sci. 2001;90:807-816.
PubMed  DOI: 10.1002/jps.1034

164. Fernandes CM, Teresa Viera M, Veiga FJ.  Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds. Eur J Pharm Sci. 2002;15:79-88.
PubMed  DOI: 10.1016/S0928-0987(01)00208-1

165. Fernandes CM, Ramos P, Falcao AC, Veiga FJ.  Hydrophilic and hydrophobic cyclodextrins in a new sustained release oral formulation of nicardipine: in vitro evaluation and bioavailability studies in rabbits. J Control Release. 2003;88:127-134.
PubMed  DOI: 10.1016/S0168-3659(02)00465-0

166. Chowdary KPR, Reddy GK.  Complexes of nifedipine with β- and hydroxypropyl-β-cyclodextrin in the design of nifedipine SR tablets. Ind J Pharm Sci. 2002;64:142-146.
PubMed 

167. Burgos AE, Belchior JC, Sinisterra RD.  Controlled release of rhodium (II) carboxylates and their association complexes with cyclodextrins from hydroxyapatite matrix. Biomaterials. 2002;23:2519-2526.
PubMed  DOI: 10.1016/S0142-9612(01)00386-6

168. Minami K, Hirayama F, Uekama K.  Colon-specific drug delivery based on a cyclodextrin prodrug: release behavior of biphenylylacetic acid from its cyclodextrin conjugates in rat intestinal tracts after oral administration. J Pharm Sci. 1998;87:715-720.
PubMed  DOI: 10.1021/js9704339

169. Hirayama F, Ogata T, Yano H, et al.  Release characteristics of a short-chain fatty acid, n-butyric acid from its beta-cyclodextrin ester conjugate in rat biological media. J Pharm Sci. 2000;89:1486-1495.
PubMed  DOI: 10.1002/1520-6017(200011)89:11<1486::AID-JPS11>3.0.CO_2-D

170. Yano H, Hirayama F, Kamada M, Arima H, Uekama K.  Colon-specific delivery of prednisolone-appended alpha-cyclodextrin conjugate: alleviation of systemic side effect after oral administration. J Control Release. 2002;79:103-112.
PubMed  DOI: 10.1016/S0168-3659(01)00532-6

171. Lopez MEV, Reyes LN, Igea SA, Espinar FJO, Mendez JB.  Formulation of triamcinolone acetonide pellets suitable for coating and colon targeting. Int J Pharm. 1999;79:229-235.

172. Irie T, Uekama K.  Cyclodextrins in peptide and protein delivery. Adv Drug Deliv Rev. 1999;36:101-123.
PubMed  DOI: 10.1016/S0169-409X(98)00057-X

173. Augustijns PF, Bradshaw TP, Gan LSL, Hendren RW, Thakker DR.  Evidence for a polarized efflux system in caco-2 cells capable of modulating cyclosporin a transport. Biochem Biophys Res Commun. 1993;197:360-365.
PubMed  DOI: 10.1006/bbrc.1993.2487

174. Burton PS, Conradi RA, Hilgers AR, Ho NFH.  Evidence for a polarized efflux system for peptides in the apical membrane of caco-2 cells. Biochem Biophys Res Commun. 1993;190:760-766.
PubMed  DOI: 10.1006/bbrc.1993.1114

175. Ueda K, Shimabuku AM, Konishi H, et al.  Functional expression of human P-glycoprotein in Schizosaccharomyces pombe. FEBS Lett. 1993;330:279-282.
PubMed  DOI: 10.1016/0014-5793(93)80888-2

176. Loe DW, Sharom FJ.  Interaction of multidrug-resistant Chinese hamster ovary cells with the peptide ionophore gramicidin D. Biochim Biophys Acta. 1994;1190:72-84.
PubMed 

177. Takahashi H, Kim RB, Perry PR, Wilkinson GR.  Characterization of the hepatic canalicular membrane transport of a model oligopeptide: ditekiren1. J Pharm Exp Therapeutics. 1997;281:297-303.
PubMed 

178. Sharom FJ, Xiaohong YU.  DioDiodato G, Chu JWK. Synthetic hydrophobic peptides are substrates for P-glycoprotein and stimulate drug transport. Biochem J. 1996;320:421-428.
PubMed 

179. McNally EJ, Park JY. Peptides and Proteins - Oral Absorption. In: Swarbrick J, Boylan JC,  eds. Encyclopedia of Pharmaceutical Technology 2^nd ed. New York, NY: Marcell Dekker; 2002:2096-2113. 

180. Arima H, Yunomae K, Morikawa T, Hirayama F, Uekama K.  Contribution of cholesterol and phospholipids to inhibitory effect of dimethyl-β-cyclodextrin on efflux function of P-glycoprotein and multidrug resistance–associated protein 2 in vinblastine-resistant Caco-2 cell monolayers. Pharm Res. 2004;21:625-634.
PubMed  DOI: 10.1023/B:PHAM.0000022409.27896.d4

181. Arima H, Yunomae K, Hirayama F, Uekama K.  Contribution of P-glycoprotein to the enhancing effects of dimethyl-β-cyclodextrin on oral bioavailability of Tacrolimus. J Pharm Exp Therapeutics. 2001;297:547-555.
PubMed 

182. Verhoef JC, Schipper NGM, Romeijn SG, Merkus FWHM.  The potential of cyclodextrins as absorption enhancers in nasal delivery of peptide drugs. J Control Release. 1994;29:351-360.
DOI: 10.1016/0168-3659(94)90080-9

183. Jerry N, Anitha Y, Sharma CP, Sony P.  In vivo absorption studies of insulin from an oral delivery system. Drug Deliv. 2001;8:19-23.
PubMed  DOI: 10.1080/107175401300002711

184. Dass CR.  Vehicles for oligonucleotide delivery. J Pharm Pharmacol. 2002;54:3-27.
PubMed  DOI: 10.1211/0022357021771887

185. Redenti E, Pietra C, Gerlozy A, Szente L.  Cyclodextrins in oligonucleotide delivery. Adv Drug Deliv Rev. 2001;53:235-244.
PubMed  DOI: 10.1016/S0169-409X(01)00230-7

186. Driscoll CO, Darcy R. Cyclodextrin constructs for delivery of genotherapeutic agents. Business Briefing: Pharmatech2002  Available at: http://www.bbriefings.com/pdf/17/ACF9C6C.pdf. Accessed May 25, 2005. 

187. Hwang SJ, Bellocq NC, Davis ME.  Effects of structure of β-cyclodextrin-containing polymers on gene delivery. Bioconjugate Chem. 2001;12:280-290.
PubMed  DOI: 10.1021/bc0001084

188. Pun SH, Davis DE.  Development of a nonviral gene delivery vehicle for systemic application. Bioconjugate Chem. 2002;13:630-639.
PubMed  DOI: 10.1021/bc0155768

189. Croyle MA, Roessler BJ, Hsu CP, Sun R, Amidon GL.  Beta cyclodextrins enhance adenoviral-mediated gene delivery to the intestine. Pharm Res. 1998;15:1348-1355.
PubMed  DOI: 10.1023/A:1011985101580

190. Lopez RF, Collett JH, Bently MV.  Influence of cyclodextrin complexation on the in vitro permeation and skin metabolism of dexamethasone. Int J Pharm. 2000;200:127-132.
PubMed  DOI: 10.1016/S0378-5173(00)00365-3

191. Orienti I, Zecchi V, Bernabei S, Sentimenti S, Fini A.  Diffusion of ketoprofen from coprecipitates through a non porous lipidic membrane. Boll Chim Farm. 1989;128:336-343.
PubMed 

192. Loftsson T, Masson M.  Cyclodextrins in topical drug formulations: theory and practice. Int J Pharm. 2001;225:15-30.
PubMed  DOI: 10.1016/S0378-5173(01)00761-X

193. Chang SL, Banga AK.  Transdermal iontophoretic delivery of hydrocortisone from cyclodextrin solutions. J Pharm Pharmacol. 1998;50:635-640.
PubMed 

194. Doliwa A, Santoyo S, Ygartua P.  Transdermal iontophoresis and skin retention of piroxicam from gels containing piroxicam: hydroxypropyl-beta-cyclodextrin complexes. Drug Dev Ind Pharm. 2001;27:751-758.
PubMed  DOI: 10.1081/DDC-100107238

195. Tanaka M, Matsuda H, Sumiyoshi H, et al.  2-Hydroxy- propylated cyclodextrins as a sustained release carrier for fragrance materials. Chem Pharm Bull (Tokyo). 1996;44:416-420.

196. Buschmann HJ, Schollmeyer E.  Applications of cyclodextrins in cosmetic products: a review. J Cosmet Sci. 2002;53:185-191.
PubMed 

197. Brewster ME, Loftsson T.  The use of chemically modified cyclodextrins in the development of formulations for chemical delivery systems. Pharmazie. 2002;57:94-101.
PubMed 

198. Wu WM, Wu J, Bodor N.  Effect of 2-hydroxypropyl-beta-cyclodextrin on the solubility, stability, and pharmacological activity of the chemical delivery system of TRH analogs. Pharmazie. 2002;57:130-134.
PubMed 

199. McCormack B, Gregoriadis G.  Entrapment of cyclodextrin-drug complexes into liposomes: potential advantages in drug delivery. J Drug Target. 1994;2:449-454.
PubMed 

200. McCormack B, Gregoriadis G.  Drugs-in-cyclodextrins-in-liposomes: an approach to controlling the fate of water insoluble drugs in vivo. Int J Pharm. 1998;162:59-69.
DOI: 10.1016/S0378-5173(97)00413-4

201. McCormack B, Gregoriadis G.  Drugs-in-cyclodextrins-in liposomes: a novel concept in drug delivery. Int J Pharm. 1994;112:249-258.
DOI: 10.1016/0378-5173(94)90361-1

202. Duchene D, Ponchel G, Wouessidjewe D.  Cyclodextrins in targeting. Application to nanoparticles. Adv Drug Del Rev. 1999;36:29-40.
PubMed  DOI: 10.1016/S0169-409X(98)00053-2

203. McCormack B, Gregoriadis G.  Comparative studies of the fate of free and liposome-entrapped hydroxypropyl-/3-cyclodextrin/drug complexes after intravenous injection into rats: implications in drug delivery. Biochim Biophys Acta. 1996;1291:237-244.
PubMed 

204. Skalko N, Brandl M, Ladan MB, Grid JF, Genjak IJ.  Liposomes with nifedipine and nifedipine-cyclodextrin complex: calorimetrical and plasma stability comparison. Eur J Pharm Sci. 1996;4:359-366.
DOI: 10.1016/S0928-0987(96)00180-7

205. Fatouros DG, Hatzidimitriu K, Antimisiaris SG.  Liposomes encapsulating prednisolone- cyclodextrin complexes: comparision of membrane integrity and drug release. Eur J Pharm Sci. 2001;13:287-296.
PubMed  DOI: 10.1016/S0928-0987(01)00114-2

206. Skalko-Basnet N, Pavelic Z, Becirevic-Lacan M.  Liposomes containing drug and cyclodextrin prepared by the one-step spray-drying method. Drug Dev Ind Pharm. 2000;26:1279-1284.
PubMed  DOI: 10.1081/DDC-100102309

207. Loukas YL, Jayasekera P, Gregoriadis G.  Novel liposome-based multicomponent systems for the protection of photolabile agents. Int J Pharm. 1995;117:85-94.
DOI: 10.1016/0378-5173(94)00320-5

208. Loukas YL, Vraka V, Gregoriadis G.  Drugs, in cyclodextrins, in liposomes: a novel approach to the chemical stability of drugs sensitive to hydrolysis. Int J Pharm. 1998;162:137-142.
DOI: 10.1016/S0378-5173(97)00421-3

209. Sukegawa T, Furuike T, Niikura K, Yamagishi A, Monde K, Nishimura S.  Erythrocyte-like liposomes prepared by means of amphiphilic cyclodextrin sulfates. Chem Commun. 2002;5:430-431.
PubMed  DOI: 10.1039/b110673b

210. Filipovic-Grcic J, Laan MB, Skalko N, Jalsenjak I.  Chitosan microspheres of nifedipine and nifedipine-cyclodextrin inclusion complexes. Int J Pharm. 1996;135:183-190.
DOI: 10.1016/0378-5173(96)04470-5

211. Filipovic-Grcic J, Voinovich D, Moneghini M, Becirevic-Lacan M, Magarotto L, Jalsenjak I.  Chitosan microspheres with hydrocortisone and hydrocortisone–hydroxypropyl-b-cyclodextrin inclusion complex. Eur J Pharm Sci. 2000;9:373-379.
PubMed  DOI: 10.1016/S0928-0987(99)00078-0

212. Bibby DC, Davies NM, Tucker IG.  Investigations into the structure and composition of beta-cyclodextrin/poly (acrylic acid) microspheres. Int J Pharm. 1999;180:161-168.
PubMed  DOI: 10.1016/S0378-5173(99)00004-6

213. Bibby DC, Davies NM, Tucker IG.  Poly (acrylic acid) microspheres containing β-cyclodextrin: loading and in vitro release of two dyes. Int J Pharm. 1999;187:243-250.
PubMed  DOI: 10.1016/S0378-5173(99)00190-8

214. Kang F, Jiang G, Hinderliter A, Luca PPD, Singh J.  Lysozyme stability in primary emulsion for PLGA microsphere preparation: effect of recovery methods and stabilizing excipients. Pharm Res. 2002;19:629-633.
PubMed  DOI: 10.1023/A:1015354028908

215. Kang F, Singh J.  Conformational stability of a model protein (bovine serum albumin) during primary emulsification process of PLGA microspheres synthesis. Int J Pharm. 2003;260:149-156.
PubMed  DOI: 10.1016/S0378-5173(03)00263-1

216. Quaglia F, De Rosa G, Granata E, Ungaro F, Fattal E, La Rotonda MI.  Feeding liquid, non-ionic surfactant and cyclodextrin affect the properties of insulin-loaded poly(lactide-co-glycolide) microspheres prepared by spray-drying. J Control Release. 2003;86:267-278.
PubMed  DOI: 10.1016/S0168-3659(02)00414-5

217. Fundueanu G, Constantin M, Dalpiaz A, et al.  Preparation and characterization of starch/cyclodextrin bioadhesive microspheres as platform for nasal administration of Gabexate Mesylate (Foy®) in allergic rhinitis treatment. Biomaterials. 2004;25:159-170.
PubMed  DOI: 10.1016/S0142-9612(03)00477-0

218. Constantin M, Fundueanu G, Bortolotti F, Cortesi R, Ascenzi P, Menegatti E.  Preparation and characterisation of poly(vinyl alcohol)/ cyclodextrin microspheres as matrix for inclusion and separation of drugs. Int J Pharm. 2004;285:87-96.
PubMed  DOI: 10.1016/j.ijpharm.2004.07.025

219. Pariot N, Levy FE, Andry MC, Levy MC.  Cross-linked beta-cyclodextrin microcapsules. II. Retarding effect on drug release through semi-permeable membranes. Int J Pharm. 2002;232:175-181.
PubMed  DOI: 10.1016/S0378-5173(01)00899-7

220. Memisoglu E, Bochot A, Sen M, Duchene D, Hıncal AA.  Non-surfactant nanospheres of progesterone inclusion complexes with amphiphilic β-cyclodextrins. Int J Pharm. 2003;251:143-153.
PubMed  DOI: 10.1016/S0378-5173(02)00593-8

221. Monza da Silveira A, Ponchel G, Puisieux F, Duchene D.  Combined poly (isobutylcyanoacrylate) and cyclodextrins nanoparticles for enhancing the encapsulation of lipophilic drugs. Pharm Res. 1998;15:1051-1055.
PubMed  DOI: 10.1023/A:1011982211632

222. Duchene D, Ponchel G, Wouessidjewe D.  Cyclodextrins in targeting Application to nanoparticles. Adv Drug Deliv Rev. 1999;36:29-40.
PubMed  DOI: 10.1016/S0169-409X(98)00053-2

223. Boudad H, Legrand P, Lebas G, Cheron M, Duchene D, Ponchel G.  Combined hydroxypropyl-beta-cyclodextrin and poly (alkylcyanoacrylate) nanoparticles intended for oral administration of saquinavir. Int J Pharm. 2001;218:113-124.
PubMed  DOI: 10.1016/S0378-5173(01)00622-6

224. Radwan MA.  Preparation and in vivo evaluation of parenteral metoclopramide-loaded poly (alkylcyanoacrylate) nanospheres in rats. J Microencapsul. 2001;18:467-477.
PubMed  DOI: 10.1080/02652040010018146

225. Cavalli R, Peira E, Caputo O, Gasco MR.  Solid lipid nanoparticles as carriers of hydrocortisone and progesterone complexes with beta-cyclodextrins. Int J Pharm. 1999;182:59-69.
PubMed  DOI: 10.1016/S0378-5173(99)00066-6

226. Memisoglu E, Bochot A, Sen M, Charon D, Duchene D, Hincal AA.  Amphiphilic beta-cyclodextrins modified on the primary face: synthesis, characterization, and evaluation of their potential as novel excipients in the preparation of nanocapsules. J Pharm Sci. 2002;91:1214-1224.
PubMed  DOI: 10.1002/jps.10105

227. Memisoglu E, Bochot A, Ozalp M, Sen M, Duchene D, Hincal AA.  Direct formation of nanospheres from amphiphilic beta-cyclodextrin inclusion complexes. Pharm Res. 2003;20:117-125.
PubMed  DOI: 10.1023/A:1022263111961

228. Gèze A, Aous S, Baussanne I, Putaux JL, Defaye J, Wouessidjewe D.  Influence of chemical structure of amphiphilic β-cyclodextrins on their ability to form stable nanoparticles. Int J Pharm. 2002;242:301-305.
PubMed  DOI: 10.1016/S0378-5173(02)00192-8

229. Shangraw RF, Pande GS, Gala P.  Charactarisation of the tableting properties of beta cyclodextrin: the effects of processing variableson the inclusion complex formation, compactability and dissolution. Drug Dev Ind Pharm. 1992;18:1831-1851.

230. Suihko E, Korhoneno O, Jarvinen T, et al.  Complexation with tolbutamide modifies the physicochemical and tableting properties of hydroxypropyl-beta-cyclodextrin. Int J Pharm. 2001;215:137-145.
PubMed  DOI: 10.1016/S0378-5173(00)00682-7

231. Tsai T, Wu JS, Ho HO, Sheu MT.  Modification of physical characteristics of microcrystalline cellulose by codrying with beta-cyclodextrins. J Pharm Sci. 1998;87:117-122.
PubMed  DOI: 10.1021/js960486a

232. Li WD, Huang JC, Corke H.  Effect of beta-cyclodextrin on pasting properties of wheat starch. Nahrung. 2000;44:164-167.
PubMed  DOI: 10.1002/1521-3803(20000501)44:3<164::AID-FOOD164>3.0.CO_2-X

233. Wu J, Ho H, Sheu M.  Influence of wet granulation and lubrication on the powder and tableting properties of codried product of microcrystalline cellulose with beta-cyclodextrin. Eur J Pharm Biopharm. 2001;51:63-69.
PubMed  DOI: 10.1016/S0939-6411(00)00137-5

234. Gazzaniga A, Sangalli ME, Bruni G, Zema L, Vecchio C, Giordano F.  The use of beta-cyclodextrin as a pelletization agent in the extrusion/spheronization process. Drug Dev Ind Pharm. 1998;24:869-873.
PubMed 

235. Branchu S, Forbes RT, York P, Petren S, Nyquest H, Camber O.  Hydroxypropyl-beta-cyclodextrin inhibits spray-drying-induced inactivation of beta-galactosidase. J Pharm Sci. 1999;88:905-911.
PubMed  DOI: 10.1021/js9804819

236. Tokihiro K, Irie T, Uekama K.  Varying effects of cyclodextrin derivatives on aggregation and thermal behavior of insulin in aqueous solution. Chem Pharm Bull (Tokyo). 1997;45:525-531.
PubMed 

237. Kitamura S, Fujimura T, Kohda S.  Interaction between surface-active drug (FK906, rennin inhibitor) and cyclodextrins in aqueous solution. J Pharm Sci. 1999;88:327-330.
PubMed  DOI: 10.1021/js980278d

238. Blanco-Fuente H, Esteban-Fernandez B, Blanco-Mendez J, Otero-Espinar FJ.  Use of beta-cyclodextrins to prevent modifications of the properties of carbopol hydrogels due to carbopol-drug interactions. Chem Pharm Bull (Tokyo). 2002;50:40-46.
PubMed  DOI: 10.1248/cpb.50.40

239. Muñoz-Ruiz AM, Paronen P.  Particle and powder properties of cyclodextrins. Int J Pharm. 1997;148:33-39.
DOI: 10.1016/S0378-5173(96)04820-X

240. Zannou EA, Streng WH, Stella VJ.  Osmotic properties of sulfobutylether and hydroxypropyl cyclodextrins. Pharm Res. 2001;18:1226-1231.
PubMed  DOI: 10.1023/A:1010947631380

241. Proniuk S, Blanchard J.  Influence of degree of substitution of cyclodextrins on their colligative properties in solution. J Pharm Sci. 2001;90:1086-1090.
PubMed  DOI: 10.1002/jps.1062

242. Loftsson T, Stefansdottir O, Friariksdottir H, Guomundsson O.  Interaction between preservatives and 2-hydroxypropyl β-cyclodextrin. Drug Dev Ind Pharm. 1992;18:1477-1484.