A drug delivery system is expected to deliver the required amount of drug to the targeted site for the necessary period of time, both efficiently and precisely. Different carrier materials are being constantly developed to overcome the undesirable properties of drug molecules. Amongst them cyclodextrins (CDs) have been found as potential candidates because of their ability to alter physical, chemical and biological properties of guest molecules through the formation of inclusion complexes.
Cyclodextrins (sometimes called cycloamyloses) make up a family of cyclic oligosaccharides, composed of 5 or more a-D-glucopyranoside units, as in amylose (a fragment of starch). The 5-membered macrocycle is not natural. Recently, the largest well-characterized cyclodextrin contains thirty-two 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, even 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, thus denoting:
a-cyclodextrin: six membered sugar ring molecule
ß-cyclodextrin: seven sugar ring molecule
?-cyclodextrin: eight sugar ring molecule
Cyclodextrins are produced from starch by means of enzymatic conversion. Over the last few years they have found a wide range of applications in pharmaceutical and chemical industries as well as agriculture and environmental engineering.
History of cyclodextrins
Cyclodextrins, as they are known today, were called ‘cellulosine’ when first described by A. Villiers in 1891. Soon after, F. Schardinger identified the three naturally occurring cyclodextrins -a, -ß, and -?. 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 1970's, 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.
Structure
ß-cyclodextrin 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 cleavage 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 a-1, 4 linkages between glucose monomers.
3D structure of ß-cyclodextrin
Because of their structure and physico-chemical properties, Cyclodextrins as drug carriers provide following advantages:
They provide a number of potential sites for chemical modification.
Cyclodextrins with different cavity sizes are available which makes it possible to entrap drugs of different molecular dimensions.
The microenvironment in their cavity is relatively non-polar and lipophilic.
They possess low toxicity and low pharmacological activity.
They have a good aqueous solubility.
They are rather resistant to hydrolysis by organic acids and many common alpha amylases, and completely resistant to yeast fermentation and beta amylases.
They are not decomposed by hot alkali.
They exhibit a high thermal stability, with a decomposition temperature approaching 300°C.
They protect the included/conjugated drugs from biodegradation.
They can be used as process aids to remove specific components from a mixture or minerals.
Uses
Cyclodextrins are able to form host-guest complexes with hydrophobic molecules given the unique nature imparted by their structure. As a result these molecules have found a number of applications in a wide range of fields. Other than the above mentioned pharmaceutical applications for drug release, 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 trichloron (an organophosphorus insecticide) or sewage sludge, enhancing their decomposition.
Figure depicting encapsulation of drug molecule into ß-CD cavity
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. Other food applications further include the ability to stabilize volatile or unstable compounds and the reduction of unwanted tastes and odour. Reportedly cyclodextrins are used in alcohol powder, a powder for mixing alcoholic drinks.
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.
Future prospects
Cyclodextrins and its derivatives are quite bright since they possess remarkably unique properties of forming inclusion complexes with drugs. An increasingly number of drugs being developed today have problem of poor solubility, bioavailability and permeability. CDs can serve as useful tools in the hands of pharmaceutical scientists for optimizing the drug delivery of such problematic drugs and also for drugs having other undesirable properties such as poor stability, objectionable taste and odour and irritation potential.
Although, presently only conventional formulations such as tablets, capsules, solutions and ointments have been commercialised using CDs, these are extensively being studied for their utilization in novel formulations such as nanoparticles, liposomes, nasal, ophthalmic and rectal formulations, transdermal products and targeted drug delivery systems and the time is not far when such products will become commercially available.
(Kamal Dua is lecturer, Dept of Pharma Technology, Faculty of Medicine & Health, International Medical University, No. 126, Jalan 19/155B, Bukit Jalil, 57000 KL, Malaysia. VK Sharma and Abdul Samad are with DJ College of Pharmacy, Niwari Road, Modinagar, UP 201024 and Kavita Pabreja is with ISF College of Pharmacy, Moga, Punjab)