Category: Formulation and Quality
Purpose: Cyclodextrins (CDs) can enhance solubility of drugs through formation of water-soluble complex. Drug/CD complexes, especially those of the natural CDs are known to self-assemble to form nanosized aggregates in aqueous medium. In aqueous CD solutions the size of the aggregates increases with increasing CD concentration until they precipitate. Heating is used to prepare drug/CD complexes both on laboratory scale and in industry. However, this method is applicable only for heat stable guests. Cediranib maleate, a protein kinase inhibitor (KI), is slightly soluble in aqueous media. Its solubility can be enhanced by employing drug/CD complexation technique. Although an official report confirmed that this active substance is not sensitive to moisture and heat, the entrapment of drug in CD can alter its physiochemical properties. In general, CDs are used to protect compounds against light, heat, and oxygen. However, CD at higher concentration has tendency to form larger aggregates that probably induces an adversary effect instead. Thus, preparation of CD nanoparticle suspension by heating may require the use of thermal stabilizer. This present study was aimed to enhance thermal stability of cediranib maleate/gamma cyclodextrin (γCD) complex by stabilizer in aqueous suspension.
Methods: The solubility of cediranib maleate was studied at pH 1-11 by dropwise titration of the aqueous media with sodium hydroxide or hydrochloric acid. Thermal stability of drug was investigated in presence of γCD and various stabilizers. The saturated solution underwent an autoclaving process at 121o C for 20 min. Phase-solubility profiles of binary cediranib maleate/γCD complexes and ternary cediranib maleate/γCD/stabilizer complexes were determined in pure water. These complexes were prepared by a heating method. The excess amount of cediranib maleate was added in aqueous γCD solutions of different concentrations. These mixtures were heated in an autoclave as described previously, then equilibrated at room temperature under constant agitation for 7 days. Their centrifuged supernatant was collected for drug analysis. Aqueous cediranib maleate/γCD suspensions were formulated by including selected stabilizer and other excipients in order to reduce thermal drug degradation during heating process. The physicochemical properties of such complexes and optimal formulation were evaluated.
Results: The aqueous solubility of cediranib maleate was pH-dependent. As the drug is weak basic, it was more soluble in acidic media. Thermal stability studies revealed that cediranib maleate was slightly sensitive to heat (about 5% drug loss during autoclaving), but stable in presence of 5% (w/v) γCD. However, at higher γCD concentrations the drug underwent thermal degradation. Riboflavin acted as a good stabilizer preventing drug loss during heating. The phase-solubility profiles showed formation of binary cediranib maleate/γCD complexes, and ternary complexes with riboflavin that have limited solubility in water (Bs type profiles). Riboflavin slightly decreased the amount of dissolved drug. The optimal γCD concentration was determined to be 15% (w/v) γCD. NMR study confirmed formation of binary and ternary complexes in aqueous solutions. Cediranib maleate was loaded (drug load up to 3%) in cyclodextrin-based nanoparticles at pH 5. Riboflavin lowered thermal degradation of the drug. To obtain high drug load, co-solubilizers/stabilizers such as polymers were also included. Stable aqueous drug/γCD complex suspensions were prepared. The zeta potential, particle size, viscosity and pH of formulations were within in acceptable criteria.
Conclusion: In the binary and ternary complexes, tested riboflavin was able to decrease thermal degradation of cediranib maleate. Suspension formulations containing riboflavin and polymers did retard or prevent the drug loss during heating process. This is ongoing project were optimal formulation will be investigated regarding shelf-life and drug release.
Thorsteinn Loftsson– Professor, University of Iceland, Reykjavik, Hofuoborgarsvaoio, Iceland