Cetirizine release from cyclodextrin formulated compressed chewing gum.

Beside the efficient effect on masking cetirizine bitter taste, the cyclodextrins (CDs) as well could have influence on the release from the formulation. In vitro release profiles of cetirizine from compressed chewing gums containing α-, ß- and γ-CD were investigated using a three cell chewing apparatus. Different cetirizine/CD formulations were produced and analysed with respect to type of CD (α-, ß- and γ-CD), the molar ratio between cetirizine and CD and the formulation of cetirizine (complex or physical mixture). Release experiments from all compressed chewing gum formulations gave similar release patterns, but with variations in the total amount released. Chewing gum formulated with cetirizine alone, demonstrated a release of 75% after 8 min of chewing. The presence of CDs resulted in increased cetirizine release. The analysis of variance (ANOVA) demonstrated that parameters with the most important influence on the release were the molar ratio of cetirizine/CD (P < 0.05) and the formulation of cetirizine/CD (complex or physical mixture) (P < 0.05). The compressed chewing gum formulations with 1:5 molar ratio of cetirizine/CD in complexed form demonstrated the highest release. Even though the statistical analysis (ANOVA) demonstrated significance in the release (P < 0.05) for the complex/physical mixture factor, this difference was negligible compared to the release from chewing gums containing cetirizine without CD. This makes physical mixtures suitable for use in cetirizine/CD formulations instead the complexes with respect to release yield. Thus unnecessary expenses for the complex preformulation may be avoided.

Cyclodextrins: Efficient biocompatible solubilizing excipients for bromhexine liquid and semi-solid drug delivery systems.

Bromhexine hydrochloride (bromhexine) is a mucolytic agent with very low aqueous solubility. However, with addition of cyclodextrins (CD) to the formulation, this disadvantage may be limited and therapeutic doses of bromhexine in solution can be achieved. The interaction of bromhexine with α-, ß-, γ- and sulfobutylether (SBE)-ß-CD, respectively, was elucidated by means of phase solubility diagrams and calorimetric analysis. The complexes were further characterized by size, and the effect of the CD concentrations used was evaluated in a viability assay. From phase solubility diagrams with α-, ß-, γ- and SBE-ß-CD and bromhexine, it was determined that the solubility of bromhexine significantly increased with addition of CDs, showing an A(L) type solubility curve for bromhexine/α- and ß-CD, and an A(N) type for bromhexine/γ- and SBE-ß-CD. The highest soluble concentrations of bromhexine were achieved with α- and SBE-ß-CD, i.e. when using a 100mM α- or SBE-ß-CD solution, 4 and 5.5 times more bromhexine was solubilized, respectively, compared to pure aqueous solubilization of bromhexine. The apparent association constants determined from the phase solubility studies showed very low values of 34, 17, 8 and 156 M(-1) for bromhexine/α-, ß-, γ- and SBE-ß-CD, respectively, as compared to the association constants determined by ITC which exhibited values of 89, 307 and 1680 M(-1) for bromhexine/α-, ß- and SBE-ß-CD, respectively. The formation of aggregates aided solubilization of bromhexine in the phase solubility studies explaining the difference in the association constants between the two methods. Due to very low signal to noise ratio, no information was extracted for bromhexine/γ-CD solutions from the ITC measurements. The effect on cellular viability of the CDs ranked ß->α->SBE-ß->γ-CD. In conclusion, the results altogether demonstrated that SBE-ß-CD is the most suitable CD for future drug delivery systems from the aspect of high amounts of solubilized bromhexine and high safety of the SBE-ß-CD.

Study of the inclusion complexes formed between cetirizine and α-, ß-, and γ-cyclodextrin and evaluation on their taste-masking properties.

Complexation properties of cetirizine dihydrochloride (cetirizine) with α-, ß-, and γ-cyclodextrin (CD) were investigated by ultra violet (UV) and nuclear magnetic resonance (NMR) spectroscopies and isothermal titration calorimetry (ITC). The use of the continuous variation method, applied on UV and NMR data, demonstrated 1:1 complex stoichiometry for cetirizine-α-CD, cetirizine-ß-CD, and cetirizine-γ-CD, respectively. NMR two-dimensional Rotational nuclear Overhauser Effect SpectroscopY experiments revealed that for α- and ß-CD, the complexation takes place by including either the phenyl or chlorophenyl ring of the cetirizine into the CD cavity, whereas in the case of γ-CD, both rings can be included simultaneously. Association constants (K(a)) determined by UV spectroscopy demonstrated that cetirizine forms more stable complex with ß-CD (K(a) = 5641 ± 358 M(-1)) than α-CD (K(a) = 1434 ± 60 M(-1)). No information could be extracted from the UV spectroscopic analysis of cetirizine-γ-CD solutions. ITC results for association constant determination were in compliance with UV results and confirmed that the highest association constant was found for the cetirizine-ß-CD complex (2540 ± 122 M(-1)). The association constants from ITC measurements for cetirizine-γ-CD and cetirizine-α-CD complexes were found to be 1200 ± 50 and 800 ± 22 M(-1) , respectively. Taste-masking studies revealed that ß-CD is the only native CD recommendable for oral pharmaceutical formulations.