Proof-of-concept preparation and characterization of dual-drug amorphous nanoparticle complex as fixed-dose combination of poorly soluble drugs

Objectives: To carry out a proof-of-concept study on the development of dual-drug amorphous nanoparticle complex (nanoplex in short) as a potential formulation platform for fixed-dose combination (FDC) of poorly-soluble drugs. Significance: FDC has been proven effective in improving patient compliance for treatment that requires complex multidrug regimen. Currently, there is growing interest to develop FDC of poorly-soluble drugs due to the increased number of drugs exhibiting poor solubility thus low bioavailability. Methods: The dual-drug nanoplex was prepared by electrostatically-driven co-complexation of drug molecules with oppositely charged dextran sulfate, using ciprofloxacin (CIP) and itraconazole (ITZ) as the model poorly-soluble drugs. Results: We first verified that the co-complexation products were dual-drug CIP-ITZ nanoplex, and not binary mixtures of the single-drug CIP and ITZ nanoplexes, by demonstrating their distinct thermal behaviors and dissolution characteristics. Depending on the preparation condition, the dual-drug nanoplex exhibited size and zeta potential of 160-410nm and -35-50 mV, respectively. The individual drug pay-loads were readily manipulated by varying the CIP/ITZ mass ratio in the feed, resulting in CIP and ITZ pay-loads in the range of 60-30% and 15-45%, respectively. The CIP-ITZ nanoplex, however, exhibited diminished CIP supersaturation generation, thus lower CIP solubility enhancement, compared to the single-drug CIP nanoplex. The CIP-ITZ nanoplex, nonetheless, remained capable of generating high ITZ supersaturation level. Conclusion: Dual-drug nanoplex was successfully prepared with a high degree of control over its physical characteristics. Nevertheless, whether dual-drug nanoplex always exhibits diminished solubility enhancement compared to its single-drug counterparts needs to be investigated using different poorly-soluble drugs.