Cyclodextrins (CD) were discovered by Vellier in 1891. It has been more than a century since the discovery of cyclodextrins, which has developed into the most important subject of supramolecular chemistry, containing the wisdom and labor of many scientists and technologists. Villiers was the first to isolate 3 g of a substance that could be recrystallized from water from 1 kg of starch digest of Bacillus amylobacter (Bacillus), determining its composition to be (C 6 H 10 O 5)2*3H 2 O, which was called -wood flour.
Cyclodextrin (hereinafter referred to as CD) is a white crystalline powder with non-toxic, non-harmful, water-soluble, porous and stable characteristics, which is a cyclic oligosaccharide with a complex cavity structure composed of multiple glucose molecules connected at the head and tail. The molecular structure of cyclodextrin is cyclic cavity type, because of its special structure, external hydrophilic and internal hydrophobic properties, it is often used to form inclusion or modifier to improve the physical and chemical properties of the embedded material. Cyclodextrins containing 6, 7 and 8 glucose units, namely α-CD, β-CD and γ-CD, are commonly used in practical applications, as shown in Fig. 1. Cyclodextrins are widely used in the fields of stabilization of food flavors and fragrances, protection of photosensitive components, pharmaceutical excipients and targeting agents, and fragrance holding in daily chemicals. Among the common cyclodextrins, β-CD, compared with α-CD and γ-CD, is widely used in various fields due to the moderate size of cavity structure, mature production technology and lowest cost.
Betadex Sulfobutyl Ether Sodium(SBE-β-CD) is an ionized β-cyclodextrin (β-CD) derivative which was successfully developed by Cydex in the 1990s, and it is the product of the substitution reaction between β-CD and 1,4-butanesulfonolactone. The substitution reaction can take place on the 2,3,6 carbon hydroxyl group of β-CD glucose unit. SBE-β-CD has the advantages of good water solubility, low nephrotoxicity and small hemolysis, etc., it is a pharmaceutical excipient with excellent performance, and it has passed the approval of the U.S. FDA to be used as an excipient for injection.
1. How to prepare inclusion complexes between API/drugs/NME/NCE and cyclodextrins?
Inclusion complexes containing cyclodextrins can be prepared in a variety of ways, such as spray drying, freeze drying, kneading, and physical mixing. The preparation method can be selected from a number of preliminary tests to determine the efficiency of the inclusion for a given method. In order to prepare the complex in solid form, the solvent needs to be removed in the last step of the process. Preparation of the inclusion or complex in an aqueous medium is very simple using hydroxypropyl-β-cyclodextrin (HPBCD). The general principle involves dissolving a quantitative amount of HPBCD, obtaining an aqueous solution, adding the active ingredient to this solution and mixing until a clarified solution is formed. Ultimately, the complex can be freeze-dried or spray-dried.
2. When should I consider using cyclodextrins in my formulations?
① This may affect bioavailability when the active ingredient is poorly water soluble.
② When the time required to reach effective blood levels of an oral drug is excessive due to slow dissolution rates and/or incomplete absorption.
③ When it is necessary to formulate aqueous eye drops or injections containing insoluble active ingredients.
④ When the active ingredient is unstable in physicochemical properties.
⑤ When the acceptability of a drug is poor due to an unpleasant odor, bitter, astringent, or irritating taste.
⑥ When needed to relieve side effects (such as throat, eye, skin, or stomach irritation).
⑦ When the active ingredient is provided in liquid form, however, the preferred form of the drug is stabilized tablets, powders, aqueous sprays, and the like.
3. Do target compounds form complexes with cyclodextrins?
(1) General prerequisites for the formation of pharmaceutically useful inclusion complexes with target compounds. First, it is important to know the nature of the target compound, and in the case of small molecules, the following properties can be considered:
① Usually more than 5 atoms (C, O, P, S and N) form the backbone of the molecule.
② Usually less than 5 condensed rings in the molecule
③ Solubility less than 10 mg/ml in water
④ Melting temperature below 250°C (otherwise the cohesion between molecules is too strong)
⑤ Molecular weight between 100-400 (the smaller the molecule, the lower the drug content of the complex, large molecules will not fit into the cyclodextrin cavity)
⑥ Electrostatic charge present on the molecule
(2) For large molecules, most cases will not allow for complete encapsulation within the cyclodextrin cavity. However, side chains in macromolecules can contain suitable groups (e.g., aromatic amino acids in peptides) that can interact with and form partial complexes with cyclodextrins in aqueous solution. It has been reported that the stability of aqueous solutions of insulin or other peptides, proteins, hormones and enzymes has been significantly improved in the presence of suitable cyclodextrins. Considering the above factors, the next step would be to conduct laboratory tests to assess whether cyclodextrins achieve functional properties (e.g., improved stability, improved solubility).
