(M1430-03-20) Enhancing Oral Bioavailability in Preclinical Dog PK Studies Using Ball Milling Technology

Purpose: In preclinical pharmacokinetic (PK) studies, particle size reduction is a common strategy to enhance the oral bioavailability of compounds^[1]. Ball milling technology employs high-energy mechanical forces to reduce drug particles to micron or nanometer levels, enhancing the dissolution rate and solubility of poorly soluble drugs. This method is suitable for laboratory-scale operations and improves oral bioavailability in PK studies^[2]. Key factors in the ball milling process include solvent viscosity, bead size, milling speed, duration, and temperature control^>[3,4]. Our investigation focuses on these factors to establish an efficient process for enhancing oral bioavailability in dog PK studies.

Methods: Materials - Compound: Aprepitant powder (Sigma-Aldrich, BCS Class II, solubility < 5 μg/mL). Equipment: Ball mill (Retsch PM100), Zirconia milling beads (1 mm, 3 mm), Polarized Light, Microscope (PLM), Particle Size Analyzer (PSD). Dispersants: Hydroxypropyl cellulose (HPC), Sodium lauryl sulfate (SLS). Study

Design: Preparation of formulations：The raw drug was suspended in 0.5% HPC/0.2% SLS at a concentration of 0.4 mg/mL. The nanometer suspension was prepared using a ball milling process at a concentration of 50 mg/mL first and diluted to 0.4 mg/mL with 0.5% HPC/0.2% SLS. Animal Study: Conducted oral administration tests in 10 male Beagle dogs (n=5 per group) to compare the PK of the raw drug with the nanometer suspension.

Results: Using 1 mm beads at speed 450 rpm, 0.5% HPC + 0.2% SLS was used as dispersant, we achieved a uniform nanometer suspension after overnight milling by planetary ball mill. The particle size of nanometer suspension was 258 nm compared to raw drug suspended in 0.5% HPC/ 0.2% SLS that has a particle size of 4.56 μm. PK results of the nanometer suspension group in Beagle dogs showed a 2.31-fold increase in C_max and a 1.85-fold increase in AUC compared to the raw drug group.

Conclusion: Ball milling technology has the potential to enhance the oral bioavailability of poorly soluble drugs by reducing particle size, which can lead to improved systemic exposure in vivo. For heat-sensitive drugs, it is important to use intermittent milling and controlled speed to prevent degradation. we have evaluated a series of dispersants to ensure stability and proper particle size for nanometer suspension. Selecting the appropriate stabilizer and carefully considering critical instrument parameters are crucial steps in preparing effective nanometer suspensions. In summary, the careful selection of dispersants and the optimization of milling parameters are essential for preparing high-performance nanometer suspensions. These strategies offer promising options for improving drug oral bioavailability.

References: [1] Bhalani DV, Nutan B, Kumar A. Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics. Biomedicines. 2022 Aug 23;10(9)
[2] Alshora D, Ibrahim M, Elzayat E, Almeanazel OT, Alanazi F. Defining the process parameters affecting the fabrication of rosuvastatin calcium nanoparticles by planetary ball mill. Int J Nanomedicine. 2019;14:4625-4636.
[3] 曾素梅,蔡文坚,曾少群等.湿法介质研磨技术制备注射用纳米混悬剂及其质量评价研究进展[J].中国医药工业杂志,2022,53(09):1251-1261.
[4] Burmeister CF, Kwade A. Process engineering with planetary ball mills. Chem Soc Rev. 2013 Sep 21;42(18):7660-7.