Preparation of nanosuspensions of a 1,4-dihydropyridine-based mixed L-/T-type calcium channel blocker by combined precipitation and ultrasonication methods

• Published in: Journal of drug delivery science and technology 2023-09, Vol.87, p.104772, Article 104772
• Main Authors: Pezik, Esra, Gulsun, Tuğba, Gündüz, Miyase Gözde, Sahin, Selma, Öztürk, Naile, Vural, İmran
• Format: Article
• Language: English
• Subjects: Equilibrium solubility; Hexahydroquinoline; Hypertension; Nanocrystals; Nanosuspension; Permeability
• ISSN: 1773-2247
• DOI: 10.1016/j.jddst.2023.104772

M3, a condensed 1,4-dihydropyridine (DHP) derivative, targets both L- and T-type calcium channels and therefore, stands as a promising antihypertensive drug candidate. This study aims to improve the poor solubility of M3 using nanocrystal technology (a combination of precipitation and ultrasonication methods) to enhance its oral bioavailability. Pre-formulation studies were performed and M3 nanosuspensions were prepared using different stabilizers (polyvinyl pyrrolidone K30, polyvinyl alcohol, SoluPlus®) and surfactants (poloxamer 188, poloxamer 407, sodium deoxycholate, sodium lauryl sulfate) at different concentrations (0.05, 0.1, 0.5, 1.0, 2.0%, w/v). The optimum nanosuspension formulation was freeze-dried using different cryoprotectants (mannitol, trehalose, glucose, sucrose, dextran) at different ratios (1.25, 2.5, 5.0%, w/v). It was determined that the most suitable cryoprotectant and ratio was 5.0% trehalose, resulting in nanocrystals with a size of 320.2 ± 15.3 nm and a zeta potential of −27.4 ± 0.1 mV. The physicochemical properties of M3, poloxamer 188, physical mixture and freeze-dried nanocrystals were evaluated by XRD, DSC and FT-IR analyses. Characterization studies showed amorphization of M3 in the freeze-dried nanocrystals prepared with poloxamer 188. The result of equilibrium solubility and permeability studies results indicated that M3 could be a BCS class 4 compound. Cell culture studies using Caco-2 cells showed that M3 had no significant toxic effect on the cells and had a Papp value of 2.2 × 10−7 cm/s. Compared to coarse M3 powder freeze-dried M3 nanocrystals showed a 200-fold increase in solubility and a 28.6-fold increase in apparent permeability. The cytotoxic effect of M3 was also reduced by using poloxamers as stabilizers in the formulation. M3 nanosuspensions were found to be a promising candidate for the oral administration of M3 for the potential treatment of hypertension due to the increase in solubility and permeability which could enhance its oral bioavailability. [Display omitted] •Hypertension is a chronic disease that is considered as an important public health problem worldwide.•M3, a mixed L- and T-type calcium channel blocker with a condensed 1,4-dihydropyridine (DHP) scaffold, is a promising drug candidate for hypertension.•Low aqueous solubility of M3 is a significant problem during formulation development, as in commercial DHPs.•Preparation of M3 nanosuspensions may be an appropriate formulation approach to overcom