(T1230-01-03) A High Oral Bioavailable Berberine-Lornoxicam Cocrystal with Improved Caco-2 Permeability, Tunable Dissolution, and Improved Taste

Purpose: Berberine hydrochloride (BER), a promising candidate in treating tumors and diabetes and managing pain, has a relatively low oral absorption and bioavailability due to its low intestinal permeability. Besides, bitter taste also hinders the commercialization of BER oral disintegration formulations because of a lack of patient acceptability and compliance. To address these challenges, we developed a BER and lornoxicam cocrystal (BLCC) by a solvent evaporation method.

Methods: BER and lornoxicam (1:1 M ratio) were dissolved into a mixed solvent of ethanol and chloroform (9:1 v/v) with a concentration of 20 mM. Subsequently, it was set in a fume hood at 25 °C to evaporate until yellow crystals precipitated and then the precipitates were vacuum dried at 30 °C for 12 h. The sample was characterized using X-ray powder diffraction (XRPD, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and single crystal X-ray diffraction (SCXRD). In-vitro dissolution of BLCC was investigated in physiologically relevant pH media (pH1.0 HCl, pH 6.8 PBS and water). Its intestinal permeability was evaluated by using a Caco-2 monolayer model, where pure BER was used as a reference. In-vivo oral bioavailability and taste assessment in rats were carried out to assess the potential of BLCC in developing BER oral dosages.

Results: BLCC was successfully prepared by solvent evaporation. PXRD patterns displayed that the characteristic diffraction peaks of BLCC powder exhibited at 6.3^◦, 6.9^◦, 8.7^◦, 11.2^◦, 12.7^◦, 14.3^◦, 18.0^◦, 18.5^◦, 20.9^◦ and 25.2^◦ 2θ but they were different from pure BER or lornoxicam (LOR). DSC thermogram of BLCC exhibited one endothermic peak at 223.8 °C followed by an exothermic peak at 227.6 °C. This could be attributed to the fusion of the cocrystal followed by degradation or evaporation at higher temperatures. To further confirm the formation of BER and LOR cocrystal, the single crystal structure of BLCC was solved. In the BLCC cells, each BER connects with the LOR molecule via π…π forces and C-H…O non-covalent complex interactions. Compared with BER, BLCC exhibited a faster dissolution in pH 1.0 HCl and a sustained release up to 24 hours in 6.8 PBS and water. BLCC significantly increased the Caco-2 permeability of BER from P_app 6.73 × 10^-7 cm/s to 50.3 × 10^-7 cm/s. Furthermore, BLCC demonstrated a relative bioavailability of 4560% in comparison to the original BER, due to notably enhanced intestinal permeability of BLCC and sustained dissolution in simulated intestinal fluid. Meanwhile, BLCC effectively masked the bitter taste of commercial BER.

Conclusion: PXRD, DSC and SCXRD results of BLCC demonstrated the cocrystal formation between BER and LOR. BLCC significantly increased the Caco-2 permeability and delayed the dissolution of BER in 6.8 PBS, which resulted in a 45.6-fold increase in the relative oral bioavailability of BER. This work demonstrates the great potential of cocrystallization as an effective approach to improving oral bioavailability by tailoring permeability and dissolution of low-permeable drugs. Furthermore, BLCC effectively masked the bitterness of commercial BER, providing a promising candidate for developing BER oral preparations.