Cyclodextrin

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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,[1] drug delivery,[2] 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- 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[edit]

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.[3][4][5]

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.[6] 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.[7] Weight loss supplements are marketed from alpha-cyclodextrin which claim to bind to fat and be an alternative to other anti-obesity medications.[8][9]

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 confectionary 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.[10][11]

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.

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.[12]

Structure[edit]

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.[13] 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.

Synthesis[edit]

The production of cyclodextrins is relatively simple and involves treatment of ordinary starch with a set of easily available enzymes.[14] Commonly cyclodextrin glycosyltransferase (CGTase) is employed along with α-amylase. First starch is liquified either by heat treatment or using α-amylase, then CGTase is added for the enzymatic conversion. CGTases can synthesize all forms of cyclodextrins, thus the product of the conversion results in a mixture of the three main types of cyclic molecules, in ratios that are strictly dependent on the enzyme used: each CGTase has its own characteristic α:β:γ synthesis ratio. Purification of the three types of cyclodextrins takes advantage of the different water solubility of the molecules: β-CD which is very poorly water soluble (18.5 g/l or 16.3mM) (at 25C???) can be easily retrieved through crystallization while the more soluble α- and γ-CDs (145 and 232 g/l respectively) are usually purified by means of expensive and time consuming chromatography techniques. As an alternative a "complexing agent" can be added during the enzymatic conversion step: such agents (usually organic solvents like toluene, acetone or ethanol) form a complex with the desired cyclodextrin which subsequently precipitates. The complex formation drives the conversion of starch towards the synthesis of the precipitated cyclodextrin, thus enriching its content in the final mixture of products. Wacker Chemie AG uses dedicated enzymes, that can produce alpha-, beta- or gamma-cyclodextrin specifically. This is very valuable especially for the food industry, as only alpha- and gamma-cyclodextrin can be consumed without a daily intake limit.

Uses[edit]

Crystal structure of a rotaxane with an α-cyclodextrin macrocycle.[15]

Cyclodextrins are able to form host-guest complexes with hydrophobic molecules given the unique nature imparted by their structure.[16] As a result, these molecules have found a number of applications in a wide range of fields.

Cyclodextrins can solubilize hydrophobic drugs in pharmaceutical applications, and crosslink to form polymers used for drug delivery.[2][17] One example is Sugammadex, a modified γ-cyclodextrin which reverses neuromuscular blockade by binding the drug rocuronium. Other than the above mentioned pharmaceutical applications, cyclodextrins can be employed in environmental protection: these molecules can effectively immobilise inside their rings toxic compounds, like trichloroethane or heavy metals, or can form complexes with stable substances, like trichlorfon (an organophosphorus insecticide) or sewage sludge, enhancing their decomposition.

This ability of forming complexes with hydrophobic molecules has led to their usage in supramolecular chemistry. In particular they have been used to synthesize certain mechanically-interlocked molecular architectures, such as rotaxanes and catenanes, by reacting the ends of the threaded guest. The photodimerization of substituted stilbazoles has been demonstrated using g-cyclodextrin as a host . Based on the photodimer obtained, it is established that the halogen-halogen interactions, which play an interesting role in solid state, can be observed in solution. Existence of such interactions in solution has been proved by selective photodimerization of dichloro substituted stiblazoles in Cyclodextrin and Cucurbiturils.[18]

The application of cyclodextrin as supramolecular carrier is also possible in organometallic reactions. The mechanism of action probably takes place in the interfacial region.[19] Wipff also demonstrated by computational study that the reaction occurs in the interfacial layer. The application of cyclodextrins as supramolecular carrier is possible in various organometallic catalysis.

β-cyclodextrins are used to produce HPLC columns allowing chiral enantiomers separation,[20] and are also the main ingredient in P&G's product Febreze which claims that the β-cyclodextrins "trap" odor causing compounds, thereby reducing the odor.[21]

Derivatives[edit]

Methyl-β-cyclodextrin[edit]

Both β-cyclodextrin and methyl-β-cyclodextrin (MβCD) remove cholesterol from cultured cells. The methylated form MβCD was found to be more efficient than β-cyclodextrin. The water-soluble MβCD is known to form soluble inclusion complexes with cholesterol, thereby enhancing its solubility in aqueous solution. MβCD is employed for the preparation of cholesterol-free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed. MβCD is also employed in research to disrupt lipid rafts by removing cholesterol from membranes.[22]

History[edit]

Space filling model of β-cyclodextrin.

Cyclodextrins, as they are known today, were called "cellulosine" when first described by A. Villiers in 1891.[23] Soon after, F. Schardinger identified the three naturally occurring cyclodextrins -α, -β, and -γ. These compounds were therefore referred to as "Schardinger sugars". For 25 years, between 1911 and 1935, Pringsheim in Germany was the leading researcher in this area, demonstrating that cyclodextrins formed stable aqueous complexes with many other chemicals. By the mid-1970s, each of the natural cyclodextrins had been structurally and chemically characterized and many more complexes had been studied. Since the 1970s, extensive work has been conducted by Szejtli and others exploring encapsulation by cyclodextrins and their derivatives for industrial and pharmacologic applications.[24] Among the processes used for complexation, the kneading process seems to be one of the best.[25]

In 2009, research from the lab of Michael S. Brown and Joseph L. Goldstein, Nobel Prize winning scientists who pioneered the study of cholesterol metabolism, was published showing how cyclodextrin assists in moving cholesterol out of lysosomes in Niemann-Pick type C disease. Niemann-Pick type C disease is a lysosomal storage disease causing progressive deterioration of the nervous system and dementia. It usually affects young children by interfering with their ability to metabolize cholesterol at the cellular level. Numerous research studies have followed showing that hydroxypropyl-β-cyclodextrin (HPβCD) is not simply an agent to solubilize drugs but has powerful pharmacological properties. In April 2009, investigational new drug (IND) applications were approved by the U.S. Food and Drug Administration (FDA) in a one time clinical trial to treat identical twin girls suffering from Niemann-Pick type C disease with intravenous infusions of HPβCD. On May 17, 2010, the FDA approved an orphan drug application for HPβCD for the treatment of Niemann Pick type C. On July 14, 2010, Children's Hospital & Research Center Oakland filed a second IND application with the FDA to deliver HPβCD directly into the central nervous system of the twins to bypass the blood brain barrier. On September 23, 2010, the hospital announced that the FDA granted clearance of the intrathecal application and will begin the world’s first HPβCD administration into the brain. In 2010, two additional INDs were granted in the U.S. for the treatment of Niemann-Pick type C disease. Intravenous administration began in December 2010 and April 2011. There are over 12 patients receiving HPβCD as treatment for Niemann-Pick type C disease worldwide with a combination of IV and IT treatments. All were initiated by physicians of parent support organizations to move forward to determine efficacy from promising animal model research date. The first Ommaya reservoir was implanted in a Niemann-Pick type C patient in Japan in 2011, to receive ICV injections of HPβCD.

References[edit]

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  4. ^ GRAS Notice No. GRN 000074, beta-cyclodextrin
  5. ^ GRAS Notice No. GRN 000046, gamma-cyclodextrin
  6. ^ COMMISSION DECISION of 26 May 2008 authorising the placing on the market of alpha-cyclodextrin as a novel food ingredient under Regulation (EC) No 258/97 of the European Parliament and of the Council
  7. ^ Commission Regulation (EU) No 536/2013 of 11 June 2013 amending Regulation (EU) No 432/2012 establishing a list of permitted health claims made on foods other than those referring to the reduction of disease risk and to children’s development and health Text with EEA relevance (ANNEX | 2012; 10(6):2713 | 2926 |)
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  21. ^ http://chemistry.about.com/od/cleanerchemistry/f/how-febreze-works.htm
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