The Overview of Cyclodextrins

Cyclodextrins (sometimes called cycloamyloses) are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides).

Cyclodextrins are produced from starch by means of enzymatic conversion. They are used in food, pharmaceutical,drug delivery,and chemical industries, as well as agriculture and environmental engineering.

Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose (a fragment of starch). The 5-membered macrocycle is not natural. Recently, the largest well-characterized cyclodextrin contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape:

α (alpha)-cyclodextrin:    6-membered sugar ring molecule.

β (beta)-cyclodextrin:      7-membered sugar ring molecule.

γ (gamma)-cyclodextrin:  8-membered sugar ring molecule.

α, β,and γ-cyclodextrin are being used in the food industry. As α-cyclodextrin is a soluble dietary fiber, it can be found as Alpha Cyclodextrin (soluble fiber) on the list of ingredients of commercial products.

Chemical structure of the three main types of cyclodextrins.

APPLICATIONS

INCREASING BIOAVAILABILITY

Because cyclodextrins are hydrophobic inside and hydrophilic outside, they can form complexes with hydrophobic compounds. Thus they can enhance the solubility and bioavailability of such compounds. This is of high interest for pharmaceutical as well as dietary supplement applications in which hydrophobic compounds shall be delivered. Alpha-, beta-, and gamma-cyclodextrin are all generally recognized as safe by the FDA.

CHOLESTEROL FREE PRODUCTS

In the food industry, cyclodextrins are employed for the preparation of cholesterol free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed.

MULTIFUNCTIONAL DIETARY FIBER

α-Cyclodextrin has been authorized for use as a dietary fiber in the European Union since 2008. In 2013 the EU commission has verified a health claim for alpha-cyclodextrin. The EU assessment report confirms that consumption of alpha-cyclodextrin can reduce blood sugar peaks following a high-starch meal. Weight loss supplements are marketed from alpha-cyclodextrin which claim to bind to fat and be an alternative to other anti-obesity medications.

Due to its surface-active properties, α-cyclodextrin can also be used as emulsifying fiber, for example, in mayonnaise as well as a whipping aid, for example, in desserts and confectionery applications.

OTHER FOOD APPLICATIONS

Applications further include the ability to stabilize volatile or unstable compounds and the reduction of unwanted tastes and odour. Beta-cyclodextrin complexes with certain carotenoid food colorants have been shown to intensify color, increase water solubility and improve light stability.

The strong ability of complexing fragrances can also be used for another purpose: first dry, solid cyclodextrin microparticles are exposed to a controlled contact with fumes of active compounds, then they are added to fabric or paper products. Such devices are capable of releasing fragrances during ironing or when heated by human body. Such a device commonly used is a typical 'dryer sheet'. The heat from a clothes dryer releases the fragrance into the clothing.

Cyclodextrins are also used to produce alcohol powder by encapsulating ethanol. The powder produces an alcoholic beverage when mixed with water.

AEROSOLS

Aqueous cyclodextrin solutions can generate aerosols in particle size ranges suitable for pulmonary deposition. Large quantities of aerosol can be nebulized in acceptable nebulization times. The cyclodextrin concentration does not modify nebulization efficiency in the range tested.

Clinical

In April 2009, compassionate use investigational new drug (IND) applications were filed by Benioff Children's Hospital Oakland and Mr. Hugh and Chris Hempel, parents of Addison and Cassidy Hempel, identical twin girls suffering from Niemann-Pick disease, type C. This was the second time in history that cyclodextrin alone was proposed to treat a fatal disease. In 1987, cyclodextrin was used in a medical case involving a boy suffering from a fatal form of hypervitaminosis A.

On January 23, 2013, a formal clinical trial to evaluate HPβCD cyclodextrin therapy as a treatment for Niemann-Pick disease, type C was announced by scientists from the NIH’s National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). A Phase I clinical trial is currently being conducted at the NIH Clinical Center.

Structure

 γ-CD toroid structure showing spatial arrangement.

Typical cyclodextrins are constituted by 6-8 glucopyranoside units, can be topologically represented as toroids with the larger and the smaller openings of the toroid exposing to the solvent secondary and primary hydroxyl groups respectively. Because of this arrangement, the interior of the toroids is not hydrophobic, but considerably less hydrophilic than the aqueous environment and thus able to host other hydrophobic molecules. In contrast, the exterior is sufficiently hydrophilic to impart cyclodextrins (or their complexes) water solubility.

The formation of the inclusion compounds greatly modifies the physical and chemical properties of the guest molecule, mostly in terms of water solubility. This is the reason why cyclodextrins have attracted much interest in many fields, especially pharmaceutical applications: because inclusion compounds of cyclodextrins with hydrophobic molecules are able to penetrate body tissues, these can be used to release biologically active compounds under specific conditions. In most cases the mechanism of controlled degradation of such complexes is based on pH change of water solutions, leading to the loss of hydrogen or ionic bonds between the host and the guest molecules. Alternative means for the disruption of the complexes take advantage of heating or action of enzymes able to cleave α-1,4 linkages between glucose monomers.