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Cyclodextrins: Emerging Medicines of the New Millennium

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  • Time of issue:2021-09-29
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(Summary description)

Cyclodextrins: Emerging Medicines of the New Millennium

(Summary description)

  • Categories:News
  • Author:
  • Origin:
  • Time of issue:2021-09-2911
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Cyclodextrins (CDs), first reported by Villiers in 1891 , have completed their 128th anniversary. Described by Villiers as carbohydrates that precipitate slowly (amidst the fermentation products of starch) in the form of beautiful radiant crystals(Figure 1), these molecules have kept as much attractiveness as mystery through the first five decades that followed their discovery.

In the early 50 years of their knowledge to humans, cyclodextrins were the subject of intense scientific curiosity . Scientists of different groups sought to understand the origins of their formation, their reactivity (including the ability to host other molecules) and, most importantly, their structure. The cyclic nature of cyclodextrins was postulated in 1939 ; however, this first proposal, based on modelling alone, has also erroneously defined α-CDthe smallest cyclodextrinas having five glucose units . It was not until 1948, with the adequate purification and crystal structure resolution of each of the native cyclodextrins, that their composition was accurately defined, being of six, seven, and eight glucose units for α-CD, β-CD, and γ-CD .

 

In the second half of the 20th century, as the structure and properties of cyclodextrins became known with greater detail, studies were directed towards the exploration of their ability to form inclusion complexes with various molecules . Cyclodextrins were found to protect sensitive organic guest molecules from volatilization and from oxidation and their solubilizing action on apolar guests made them attractive for a variety of applications . When the industrial production of cyclodextrins started to make them available in larger quantities and the toxicological safety was ascertained (details in the Section 1.2.), applications in the pharmaceutical, cosmetic, and food chemistry have blossomed, and, more recently, applications expanded to (re-)emerging areas as nutraceutics and natural products . In all of these products, cyclodextrins were essentially regarded as excipients or inert materials.

 

With the turn of the new millennium, developments in cyclodextrin biomedical research have once more surprised the scientific community by demonstrating that these molecules are not quite so inert and they that may, in fact, be used to treat some human ailments. Such medicinal properties are the main topic of this review and are presented in detail in Section 2.

 

Regulatory Status of Cyclodextrins

Native CDs are regarded in Japan as natural products, and for this reason they are used without many restrictions both in medicines and in foods. In western countries, the ingestion of native cyclodextrins is regulated by the JECFA (Joint WHO/FAO Expert Committee on Food Additives) , with the pharmaceutical applications falling under the European Medicines Agency (EMA) in Europe and under the Food and Drug Administration in the United States of America. Native CDs can be ingested without significant absorption, being thus Generally Regarded As Safeby the FDA ; they are commonly referred to as molecules with GRAS status. α-CD and γ-CD can be taken without restrictions  while the oral intake of β-CD should be limited to a maximum of 5 mg per kilogram of weight each day . Regarding parenteral use, native cyclodextrins suffer from much stronger restrictions. Indeed, the EMA recommends against the administration of α-CD and β-CD directly into the bloodstream due to renal toxicity . In addition, native CDs are known to cause hemolysis in vitro, at concentrations of 6, 3, and 16 mM for α-, β-, and γ-CDs, respectively , due to extraction of phospholipids and cholesterol from the erythrocyte membrane .

 

Native CDs can be functionalized to afford a large variety and number of derivatives, surpassing 1500 different molecules according to a report of 2012 . Of these, only a few are approved for human use in the fields of pharmaceutics. The U.S. Food and Drug Administration (FDA) lists 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 2-hydroxypropyl-γ-CD (HPγCD) as approved inert materials (excipients), with HPβCD being suited for oral and intravenous administration while HPγCD can only be used in topical products and in a maximal concentration of 1.5% (w/v) (FDA, 2016). Within O-methylated CDs, the approval status varies from one molecule to the next. For instance, heptakis-2,3,6-tris-O-methyl β-CD (TRIMEB) is deemed unsafe for human use due to its hemolytic action and renal toxicity. Its sister cyclodextrin, heptakis-2,6-di-O-methyl-β-CD (DIMEB), also features some toxicity, mostly targeting the liver: Doses of 300 mg/kg in mice caused elevated levels of glutamate-pyruvate transaminase (GPT) and glutamate-oxaloacetate transaminase (GOT) , two biomarkers of hepatic injury. Despite this, DIMEB is approved by the FDA for commercial use in a few injectable vaccines , probably due to the fact that it is present in low amounts in such products.

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