L-carnosine as a biocompatible dipeptide carrier for oral delivery of amorphous bosentan: the binary systems.

In this research, the functionality of a multifunctional and biocompatible dipeptide, L-carnosine was investigated for the first time for the manufacturing of enabling formulations. Considering the thermal lability and limited solubility of the dipeptide in organic solvents, we established the protocol of its mechanical activation under ambient conditions to prepare amorphous L-carnosine and describe its properties. Then, binary solid dispersions loaded with a poorly soluble bosentan hydrate model drug and L-carnosine in three ratios 46:54 wt%, 72:28 wt% and 88:12 wt% were prepared by high energy ball milling. The combination of XRPD, DSC and Raman spectroscopy enabled us to discover that water released from mechanically disordered bosentan crystals made L-carnosine amorphization impossible and a single phase co-amorphous system could only be formed when the crystalline drug was comilled with amorphous L-carnosine in a similar wt. ratio (46:54). When the load of the crystalline drug prevailed (72 wt%) over the amorphous dipeptide (28 wt%), the nanocrystals of L-carnosine were dispersed in the amorphous bosentan matrix. A further increase in the drug load (88 wt%) led to a system in which microcrystals of L-carnosine were dispersed in the amorphous bosentan. The outcomes of two stage biorelevant dissolution showed that both single- and two-phase solid dispersions created supersaturated solutions, but the supersaturation level of the single phase coamorphous formulation exceeded the others with no drug precipitation at the intestinal stage. These findings were further supported by the results of in vitro permeability studies in Caco-2 cell monolayers where the apparent permeability of bosentan from the single phase co-amorphous system loaded with L-carnosine was of 60 % higher than that of the drug alone.