Enhancing Therapeutic Efficiency of Poorly Water-Soluble Drugs with Cyclodextrin Derivatives
Key Highlights :
The modern medicine market is characterized by the introduction of new drugs and drug candidates that often show poor water solubility. This low solubility limits the drugs’ absorption in the body, reducing their therapeutic efficiency. To overcome this challenge, solubilizing agents such as cyclodextrins (CDs) are commonly employed to enhance the solubility of such drugs. CDs have a cyclic structure featuring a hydrophilic exterior and a hydrophobic cavity inside that can enclose drug molecules to form inclusion complexes. However, solubilization does not necessarily ensure drug adsorption in the body, as the solubilized drugs cannot readily pass through biological membranes. To improve the permeability of drugs through biological membranes, their concentration in the solution needs to be increased to form a supersaturated state.
Supersaturation is an unstable state as the drug tends to precipitate and form crystals, limiting its effectiveness. To prevent this, the addition of effective crystallization inhibitors is necessary to stabilize drug supersaturation over a long period. CD derivatives are particularly advantageous as they can solubilize drugs as well as inhibit their crystallization. However, the mechanism underlying their crystallization inhibition effect remains poorly understood.
In light of this, a recent study led by researchers from Chiba University, Japan, investigated the impact of 12 different CD derivatives with varying hydrophobic cavity sizes on crystallization inhibition of two poorly water-soluble drugs – carvedilol (CVD) and chlorthalidone (CLT). The researchers evaluated the solubilization and crystal inhibition effect of each CD derivative on the two drugs by performing phase solubility tests and measuring the crystallization induction time.
The phase solubility tests revealed that the addition of β-CD and γ-CD derivatives improved the solubility of CVD. However, CLT's solubility was enhanced only by the β-CD derivative. The degree of solubility improvement depends on the ability to form stable inclusion complexes that, in turn, depends on the size fitness between the drug molecule and the CD cavity. Notably, there was no correlation between the solubilization effect of the different CD derivations and their crystallization inhibition abilities.
Interestingly, the researchers observed that methylated CD derivatives were more effective than their unmethylated counterparts in maintaining the supersaturated state. This was attributed to their highly hydrophobic outer surfaces, which sterically hinder the nucleation and crystal growth processes, and thus maintain the supersaturated state.
The findings of this study shed light on the potential application of CD derivatives in drug-supersaturated formulations, which, in turn, could facilitate the clinical use of poorly water-soluble drug candidates. It also highlights the importance of considering the solubilization effect of CD derivatives while evaluating their crystallization inhibition strength.
Overall, the use of CD derivatives could be a promising approach to enhance the therapeutic efficiency of poorly water-soluble drugs.
