The cyclodextrin derivative introduces substituents on the natural source cyclodextrin, destroys the hydrogen bond in the cyclodextrin molecule, and changes its physical and chemical properties so that it can selectively accommodate different guest molecules. In recent years, the most researched is to modify the molecular structure of β-CD. There are many types of β-CD derivatives, mainly including methylated or alkylated derivatives, hydroxyalkylated derivatives, branched derivatives, and sulfoalkyl etherified derivatives.
Commonly introduced groups that can increase the solubility of cyclodextrin are: methyl, hydroxypropyl, hydroxyethyl, glucosyl, sulfobutyl and so on. After introducing these groups in β-CD, the water solubility is significantly improved, and water-soluble cyclodextrin derivatives are obtained. For example, β-CD substituted by glucosyl (represented by G), the solubility of G-β-CD and 2G-β-CD (25℃) are respectively 970 and 1400g/L, which is dozens of times higher than β-CD. The solubility of hydroxypropyl-β-CD (HP-β-CD) is also greater than 600g/L. Using water-soluble cyclodextrin derivatives as inclusion materials can improve the solubility of poorly soluble drugs, promote drug absorption, reduce hemolytic activity, and can also be used for injection. Among them, HP-β-CD has been included in the US Pharmacopoeia as injection Use accessories. Dimethyl-β-CD (DM-β-CD) is soluble in water and organic solvents. Its water solubility (25°C) is 26 times that of β-CD, and its solubility in ethanol is 15 times that of β-CD. The clear solution of DM-β-CD will precipitate when heated, which can be dissolved again after cooling. β-CD intermolecular hydrogen bond is the main reason for its low water solubility and nephrotoxicity, but DM-β-CD still has liver and kidney toxicity when administered by injection. The LD50 of β-CD in acute toxicity test in mice is 450mg/kg The LD50 of DM-β-CD is 200mg/kg, and it is also very irritating, so it cannot be used for injection and mucosal administration.
In addition, the type of cyclodextrin will have different effects on the properties of the drug. For example, maltosyl-β-CD can delay the accumulation of insulin in solution, while sulfate-β-CD accelerates the accumulation of insulin, while sulfobutyl ether-β-CD (SBE-β-CD) has an effect on the thermodynamic properties of insulin The change depends on the degree of substitution of its butyl group. A low degree of substitution slows down the accumulation of insulin, and a high degree of substitution speeds up the accumulation of insulin.