Functional Category
Solubilizing agent; stabilizing agent.
Applications in Pharmaceutical Formulation
Cyclodextrins are crystalline, nonhygroscopic, cyclic oligosaccharides derived from starch. Among the most commonly used forms are a-, b-, and g-cyclodextrin, which have respectively 6, 7, and 8 glucose units; see Section 5. Substituted cyclodextrin derivatives are also available; see Section 17. Cyclodextrins are ‘bucketlike’ or ‘conelike’ toroid molecules, with a rigid structure and a central cavity, the size of which varies according to the cyclodextrin type; see Section 8. The internal surface of the cavity is hydrophobic and the outside of the torus is hydrophilic; this is due to the arrangement of hydroxyl groups within the molecule. This arrangement permits the cyclodextrin to accommodate a guest molecule within the cavity, forming an inclusion complex. Cyclodextrins may be used to form inclusion complexes with a variety of drug molecules, resulting primarily in improvements to dissolution and bioavailability owing to enhanced solubility and improved chemical and physical stability; see Section 18. Cyclodextrin inclusion complexes have also been used to mask the unpleasant taste of active materials and to convert a liquid substance into a solid material. b-Cyclodextrin is the most commonly used cyclodextrin, although it is the least soluble; see Section 10. It is the least expensive cyclodextrin; is commercially available from a number of sources; and is able to form inclusion complexes with a number of molecules of pharmaceutical interest. However, b-cyclodextrin is nephrotoxic and should not be used in parenteral formulations; see Section 14. b-Cyclodextrin is primarily used in tablet and capsule formulations. a-Cyclodextrin is used mainly in parenteral formulations. However, as it has the smallest cavity of the cyclodextrins it can form inclusion complexes with only relatively few, small-sized molecules. In contrast, g-cyclodextrin has the largest cavity and can be used to form inclusion complexes with large molecules; it has low toxicity and enhanced water solubility. In oral tablet formulations, b-cyclodextrin may be used in both wet-granulation and direct-compression processes. The physical properties of b-cyclodextrin vary depending on the manufacturer. However, b-cyclodextrin tends to possess poor flow properties and requires a lubricant, such as 0.1% w/w magnesium stearate, when it is directly compressed.(1,2) In parenteral formulations, cyclodextrins have been used to produce stable and soluble preparations of drugs that would otherwise have been formulated using a nonaqueous solvent. In eye drop formulations, cyclodextrins form water-soluble complexes with lipophilic drugs such as corticosteroids. They have been shown to increase the water solubility of the drug; to enhance drug absorption into the eye; to improve aqueous stability; and to reduce local irritation.(3) Cyclodextrins have also been used in the formulation of solutions,(4,5) suppositories,(6,7) and cosmetics.(8,9)
Description
Cyclodextrins are cyclic oligosaccharides containing at least six D- (þ)-glucopyranose units attached by a(1!4) glucoside bonds. The three natural cyclodextrins, a, b, and g, differ in their ring size and solubility. They contain 6, 7, or 8 glucose units, respectively. Cyclodextrins occur as white, practically odorless, fine crystalline powders, having a slightly sweet taste. Some cyclodextrin derivatives occur as amorphous powders.
Stability and Storage Conditions
b-Cyclodextrin and other cyclodextrins are stable in the solid state if protected from high humidity. Cyclodextrins should be stored in a tightly sealed container, in a cool, dry place
Incompatibilities
The activity of some antimicrobial preservatives in aqueous solution can be reduced in the presence of hydroxypropyl-b- cyclodextrin.(10
Safety
Cyclodextrins are starch derivatives and are mainly used in oral and parenteral pharmaceutical formulations. They are also used in topical and ophthalmic formulations.(3) Cyclodextrins are also used in cosmetics and food products, and are generally regarded as essentially nontoxic and nonirritant materials. However, when administered parenterally, b-cyclodextrin is not metabolized but accumulates in the kidneys as insoluble cholesterol complexes, resulting in severe nephrotoxicity.(13) Cyclodextrin administered orally is metabolized by microflora in the colon, forming the metabolites maltodextrin, maltose, and glucose; these are themselves further metabolized before being finally excreted as carbon dioxide and water. Although a study published in 1957 suggested that orally administered cyclodextrins were highly toxic,(14) more recent animal toxicity studies in rats and dogs have shown this not to be the case, and cyclodextrins are now approved for use in food products and orally administered pharmaceuticals in a number of countries. Cyclodextrins are not irritant to the skin and eyes, or upon inhalation. There is also no evidence to suggest that cyclodextrins are mutagenic or teratogenic. a-Cyclodextrin LD50 (rat, IP): 1.0 g/kg(15) LD50 (rat, IV): 0.79 g/kg b-Cyclodextrin LD50 (mouse, IP): 0.33 g/kg(16) LD50 (mouse, SC): 0.41 g/kg LD50 (rat, IP): 0.36 g/kg LD50 (rat, IV): 1.0 g/kg LD50 (rat, oral): 18.8 g/kg LD50 (rat, SC): 3.7 g/kg g-Cyclodextrin LD50 (rat, IP): 4.6 g/kg(15) LD50 (rat ,IV): 4.0 g/kg LD50 (rat, oral): 8.0 g/kg