Cyclodextrins: Their Future in Drug Formulation and Delivery

Since their discovery, cyclodextrins and their ability to form inclusion complexes have fascinated chemists, formulators and recently, entrepreneurs. This mini-review has as its objective, a critical assessment of the current status of cyclodextrins in the formulation and delivery of pharmaceuticals and commentary on their potential future uses. The emphasis will be on answers to common questions often asked of pharmaceutical scientists working in this area. Why use cyclodextrins for drug solubilization and stabilization when alternative techniques are available? Why the greater interest in modified cyclodextrins and not the parent cyclodextrins? If a drug forms a strong cyclodextrin inclusion complex, how is the drug releasedin vivo? Does the injection of a cyclodextrin/drug complex alter the pharmacokinetics of the drug? Are there drug products on the market which contain cyclodextrins? What is the regulatory status of cyclodextrins? Although definitive answers to all these questions are not possible at this time, many of these questions are answerable, and educated and informed responses are possible for the rest.

[1]  A. Karara,et al.  Effect of 2-Hydroxypropyl-β-cyclodextrin on the Ocular Absorption of Dexamethasone and Dexamethasone Acetate , 1991, Pharmaceutical Research.

[2]  A. Hedges,et al.  Subchronic Toxicity of Orally Administered Beta-Cyclodextrin in Rats , 1991 .

[3]  G. Fricker,et al.  Cyclodextrins : Useful excipients for oral peptide administration ? , 1996 .

[4]  V. Stella,et al.  Preliminary safety evaluation of parenterally administered sulfoalkyl ether beta-cyclodextrin derivatives. , 1995, Journal of pharmaceutical sciences.

[5]  W. Saenger,et al.  Inclusion Compounds. XIX.1a The Formation of Inclusion Compounds of α-Cyclodextrin in Aqueous Solutions. Thermodynamics and Kinetics , 1967 .

[6]  T. G. Smith,et al.  β-Cyclodextrin : 52-week toxicity studies in the rat and dog , 1995 .

[7]  G. Schmid,et al.  Toxicological Comparison of Cyclodextrins , 1996 .

[8]  F. Hirayama,et al.  In‐vivo and In‐vitro Correlation for Delayed‐release Behaviour of a Molsidomine/O‐carboxymethyl‐O‐ethyl‐β‐cyclodextrin Complex in Gastric Acidity‐controlled Dogs , 1995, The Journal of pharmacy and pharmacology.

[9]  N. Bodor,et al.  The use of 2-hydroxypropyl-β-cyclodextrin as a vehicle for intravenous administration of dexamethasone in dogs , 1990 .

[10]  A. Hersey,et al.  Mechanism of inclusion-compound formation for binding of organic dyes, ions and surfactants to α-cyclodextrin studied by kinetic methods based on competition experiments , 1986 .

[11]  I. Szatmári,et al.  Pharmacokinetics of Dimethyl-Beta-Cyclodextrin in Rats , 1988 .

[12]  V. Stella,et al.  Differential Effects of Sulfate and Sulfobutyl Ether of β-Cyclodextrin on Erythrocyte Membranes in Vitro , 2004, Pharmaceutical Research.

[13]  N. Bodor,et al.  Preparation, Characterization, and Anesthetic Properties of 2-Hydroxypropyl-β-cyclodextrin Complexes of Pregnanolone and Pregnenolone in Rat and Mouse , 1995 .

[14]  K. Uekama,et al.  Effects of beta- and gamma-cyclodextrins on the pharmacokinetic behavior of prednisolone after intravenous and intramuscular administrations to rabbits. , 1987, Journal of pharmacobio-dynamics.

[15]  J. Szejtli,et al.  Absorption and Elimination of Cyclodextrin Derivatives by Rabbits and Rats , 1982 .

[16]  M. Borgers,et al.  Beta-cyclodextrins as vehicles in eye-drop formulations: an evaluation of their effects on rabbit corneal epithelium. , 1990, Lens and eye toxicity research.

[17]  A. Urtti,et al.  Ophthalmic arachidonylethanolamide decreases intraocular pressure in normotensive rabbits. , 1995, Current eye research.

[18]  J. K. Palmer,et al.  Enzymic degradation of .alpha.- and .beta.-cyclodextrins by Bacteroides of the human colon , 1984 .

[19]  K. Uekama,et al.  Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation. , 1997, Journal of pharmaceutical sciences.

[20]  J. Pitha Amorphous water soluble derivatives of cyclodextrins: From test tube to patient , 1987 .

[21]  Thorsteinn Loftsson,et al.  The effect of hydroxypropyl methylcellulose on the release of dexamethasone from aqueous 2-hydroxypropyl-β-cyclodextrin formulations , 1994 .

[22]  J. Pitha,et al.  Effect of bile on the intestinal absorption of α-cyclodextrin in rats , 1988 .

[23]  F. Hirayama,et al.  In vitro and in vivo evaluation of delayed-release behavior of diltiazem from its O-carboxymethyl-O-ethyl-β-cyclodextrin complex , 1993 .

[24]  A. Sato,et al.  Nutritional significance of cyclodextrins: indigestibility and hypolipemic effect of alpha-cyclodextrin. , 1985, Journal of nutritional science and vitaminology.

[25]  B. Müller,et al.  Hydroxypropyl-beta-cyclodextrin derivatives: influence of average degree of substitution on complexing ability and surface activity. , 1986, Journal of pharmaceutical sciences.

[26]  V. Stella,et al.  The effect of SBE4-β-CD on i.m. prednisolone pharmacokinetics and tissue damage in rabbits: Comparison to a co-solvent solution and a water-soluble prodrug , 1995 .

[27]  F. Merkus,et al.  Effects of Absorption Enhancers on Rat Nasal Epithelium in Vivo: Release of Marker Compounds in the Nasal Cavity , 1995, Pharmaceutical Research.

[28]  F. Merkus,et al.  Cyclodextrins in Nasal Drug Delivery: Trends and Perspectives , 1996 .

[29]  K. Uekama,et al.  [Improvement in pharmacological properties of thiopental by gamma-cyclodextrin complexation]. , 1983, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan.

[30]  G. Salvioli,et al.  Improvement of ursodeoxycholic acid bioavailability by 2-hydroxypropyl-beta-cyclodextrin complexation in healthy volunteers. , 1995, Pharmacological research.

[31]  H. Vandoorne INTERACTIONS BETWEEN CYCLODEXTRINS AND OPHTHALMIC DRUGS , 1993 .

[32]  D. Frank,et al.  Cyclodextrin nephrosis in the rat. , 1976, The American journal of pathology.

[33]  Valentino J. Stella,et al.  β‐Cyclodextrin Derivatives, SBE4‐β‐CD and HP–β‐CD, Increase the Oral Bioavailability of Cinnarizine in Beagle Dogs , 1995 .

[34]  A. Fónagy,et al.  Absorption, distribution, excretion and metabolism of orally administered 14C-beta-cyclodextrin in rat. , 1985, Arzneimittel-Forschung.

[35]  Valentino J. Stella,et al.  The effect of SBE4-β-CD on i.v. methylprednisolone pharmacokinetics in rats: Comparison to a co-solvent solution and two water-soluble prodrugs , 1995 .

[36]  M. Brewster,et al.  Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. , 1996, Journal of pharmaceutical sciences.

[37]  A. C. Eissens,et al.  The Effects of Cyclodextrins on the Disposition of Intravenously Injected Drugs in the Rat , 1991, Pharmaceutical Research.

[38]  V. Stella,et al.  The effect of a modified beta-cyclodextrin, SBE4-beta-CD, on the aqueous stability and ocular absorption of pilocarpine. , 1994, Current eye research.

[39]  B. Lindberg,et al.  Distribution of substituents in O-(2-hydroxypropyl) derivatives of cyclomalto-oligosaccharides (cyclodextrins: influence of increasing substitution of the base used in the preparation, and of macrocyclic size. , 1992, Carbohydrate research.

[40]  V. Stella,et al.  Effect of Alkyl Chain Length and Degree of Substitution on the Complexation of Sulfoalkyl Ether β-Cyclodextrins with Steroids , 1997 .

[41]  J. Szejtli,et al.  Cyclodextrins in Pharmacy , 1993 .

[42]  A. Urtti,et al.  Sulfobutyl ether β-cyclodextrin (SBE-β-CD) in eyedrops improves the tolerability of a topically applied pilocarpine prodrug in rabbits , 1995 .

[43]  W. Löscher,et al.  New Injectable Aqueous Carbamazepine Solution Through Complexing with 2‐Hydroxypropyl‐β‐Cyclodextrin: Tolerability and Pharmacokinetics After Intravenous Injection in Comparison to a Glycofurol‐Based Formulation , 1995, Epilepsia.

[44]  D O Thompson,et al.  Cyclodextrins--enabling excipients: their present and future use in pharmaceuticals. , 1997, Critical reviews in therapeutic drug carrier systems.

[45]  A. Urtti,et al.  Modified β‐Cyclodextrin (SBE7‐β‐CyD) with Viscous Vehicle Improves the Ocular Delivery and Tolerability of Pilocarpine Prodrug in Rabbits , 1996 .

[46]  B. Müller,et al.  In vitro corneal permeability of diclofenac sodium in formulations containing cyclodextrins compared to the commercial product voltaren ophtha. , 1994, Journal of pharmaceutical sciences.

[47]  E. Stefánsson,et al.  Topically effective ocular hypotensive acetazolamide and ethoxyzolamide formulations in rabbits , 1994, The Journal of pharmacy and pharmacology.

[48]  V. Stella,et al.  Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery. , 1996, Journal of pharmaceutical sciences.

[49]  C. Lutton,et al.  Hypolipidemic effects of β-cyclodextrin in the hamster and in the genetically hypercholesterolemic rico rat , 1993, Lipids.

[50]  Kennath A. Connors Cyclodextrins and their industrial uses: Dominique Duchêne (Editor), Editions de Santé, 19 rue Louis-le-Grand, 75002 Paris, France, 1987, 448 pages, ISBN 2-86411-019-9. , 1988 .

[51]  C. Crosson,et al.  Beta-cyclodextrins enhance bioavailability of pilocarpine. , 1993, Current eye research.

[52]  F. Merkus,et al.  Intranasal administration of estradiol in combination with progesterone to oophorectomized women: a pilot study. , 1992, European journal of obstetrics, gynecology, and reproductive biology.