Preparation and characterization of inclusion complexes of antitumor camptothecin with cucurbit[n = 7, 8]urils

Abstract

The slightly water-soluble anticancer drug camptothecin (CPT) and its inclusion complexes with cucurbit[n = 7, 8]uril (Q[n] (n = 7, 8)) were investigated. The formation of 1:2 complexes with Q[n] (n = 7, 8) in aqueous solution was confirmed by fluorescence spectroscopy and the apparent stability constants were determined to be higher than 3.01 × 10 12 L 2 /mol 2 . The solid inclusion complexes of CPT and Q[n] (n = 7, 8) were also prepared by the co-evaporation method and characterized by Fourier transformation-infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction. Aqueous solubility and dissolution studies indicate that the complexes exhibited significantly increased dissolution rates compared with the pure drug and physical mixtures. The potential of Q[7] or Q[8] for stabilizing lactone modality of CPT was investigated by the High Performance Liquid Chromatography (HPLC) method. The results reveal more than 63% CPT lactone form (active form) in or Q[8] complexes compared to only 36% CPT lactone form in the absence of Q[7] or Q[8] after being incubated in the phosphate buffer solution (pH 7.4 at 37 °C) for 5 h. complexes, camptothecin, cucurbit[n]uril (n = 7, 8), dissolution properties, stability

Cucurbit[7]uril: an emerging candidate for pharmaceutical excipients

“…34 Notably, in the previously discussed example of CPT complexation by CB [7], the guest drug CPT was found to exhibit a pK a shift of almost five units (from 1.2 to 6.2) in the presence of CB [7]. 27 Likewise, a CB[7]-induced pK a shift was demonstrated with the epidermal growth factor receptor inhibitor gefitinib; the complexation of gefitinib with CB [7] decreased the acidity of the protonated drug, resulting in an upward pK a shift moderately by 0.6-1.3 units. 35 CB[7] also induced a pK a shift of the ocular therapeutic tropicamide (ß0.5 pK a units), promoting the dominance of the cationic form of this mydriatic drug in ocular pH (pH ß7), thus potentially enhancing its permeation to the corneal epithelium, suggesting that CB [7] could serve as an alternative to acidified tropicamide, which has caused significant discomfort to the eyes.…”

“…For example, upon complexation with CB[7], the p K a of the pyridine nitrogen of milrinone shifted upward from 4.5 to 7.1, thus stabilizing the cationic and keto forms of milrinone . Notably, in the previously discussed example of CPT complexation by CB[7], the guest drug CPT was found to exhibit a p K a shift of almost five units (from 1.2 to 6.2) in the presence of CB[7] . Likewise, a CB[7]‐induced p K a shift was demonstrated with the epidermal growth factor receptor inhibitor gefitinib; the complexation of gefitinib with CB[7] decreased the acidity of the protonated drug, resulting in an upward p K a shift moderately by 0.6–1.3 units .…”

“…Drug molecules encapsulated by CB[7] often exhibit enhanced chemical and thermal stability owing to a protective pocket provided by the cavity of CB[7] to included guests. For instance, CB[7] can stabilize camptothecin (CPT), an anticancer drug, by slowing down the hydrolysis reaction and minimizing the adverse effects caused by the hydrolyzed carboxylate form of CPT . In particular, high‐performance liquid chromatography (HPLC) analysis has shown that 60% of CB[7]–CPT complexes remained in the lactone form, but only 36% of free CPT remained in the lactone form after 5 hours .…”

“…For instance, CB[7] can stabilize camptothecin (CPT), an anticancer drug, by slowing down the hydrolysis reaction and minimizing the adverse effects caused by the hydrolyzed carboxylate form of CPT . In particular, high‐performance liquid chromatography (HPLC) analysis has shown that 60% of CB[7]–CPT complexes remained in the lactone form, but only 36% of free CPT remained in the lactone form after 5 hours . Similarly, thermal analysis of triamterene, a mild potassium‐sparing diuretic drug with poor solubility and oral bioavailability, revealed that the thermal stability of this drug was enhanced when it became encapsulated within the hydrophobic cavity of CB[7], with the initial decomposition temperature of triamterene increasing from 281 to 356 °C after the formation of a CB[7]–triamterene complex .…”

“…27 In particular, high-performance liquid chromatography (HPLC) analysis has shown that 60% of CB[7]-CPT complexes remained in the lactone form, but only 36% of free CPT remained in the lactone form after 5 hours. 27 Similarly, thermal analysis of triamterene, a mild potassium-sparing diuretic drug with poor solubility and oral bioavailability, revealed that the thermal stability of this drug was enhanced when it became encapsulated within the hydrophobic cavity of CB [7], with the initial decomposition temperature of triamterene increasing from 281 to 356°C after the formation of a CB[7]-triamterene complex. 28 Meanwhile, differential-scanning calori-metry characterization of CB[7]-albendazole (ABZ) complexes successfully demonstrated that CB [7] enhanced the thermal stability of ABZ in the solid state.…”