Purpose: As an orally precendented excipient, hydrogenated castor oil (HCO) was evaluated as an alternative matrix for controlled release lipid multiparticulates (LMPs). LMPs are a technology platform capable of tunable release of crystalline drugs, for which an HCO formulation space was tested to improve the overall product stability and processability of a model product.
A formulation space using HCO was defined looking at multiple levels for factors of drug loading and permeability enhancing agent content. Formulations were screened using a material sparing, risk-based approach to enable rapid development timelines. Drug dissolution was the primary output for the product with the goal of bracketing two differentiated release rates for the model compound acetazolamide. Product stability was tested for two formulation concepts showing the impact on product attributes for assay, impurities, and dissolution at multiple storage conditions. Processability was assessed through the annealing time required to achieve stable drug dissolution.
Methods: The design space consisted of five formulations, with 10, 25, or 40% drug load and a P/(P+C) ratio (P, pore former poloxamer: C, carrier HCO) of 8, 10, or 12%. All formulations utilized micronized drug with a particle size d90 of less than 20 µm. These were manufactured as 25 gram batches on custom-built melt-spray-congeal equipment operated to achieve a target multiparticulate particle size d50 of 230 µm. HCO-based LMPs were annealed at 50°C/75%RH for an initial time of 7 days with additional annealing totaling 14 day to assess processability. Dissolution performance was tested using a reduced volume USP 2 dissolution with in situ UV fiber optic probe and assay-purity was tested by HPLC using a symmetry C-18 column. Two lead formulations were selected for accelerated stability testing at 25°C/60%RH and 40°C/75%RH in an open configuration for up to three time points.
Results: Comparing the initial dissolution rates, it was determined that there was a greater effect on the dissolution release rate by increasing the poloxamer content than increasing the drug loading. Lead formulations were chosen to be HCO-2 with 10% drug load and HCO-5 with 25% drug load, both having a P/(P+C) ratio of 12%. HCO-2 showed the highest dissolution release rate with 15 ± 2.3%/hr. HCO-5 was chosen as the second lead formulation due to its P/(P+C) ratio. This was to minimize variables and help determine drug solubility effects on this matrix. HCO-5 also bracketed the formulation space release rate profile with a 3.4 ±0.1%/hr rate.
Additional annealing was performed on the two lead formulations totaling 14 days at 50°C/75%RH. HCO-2 showed consistent release rates to the initial with 16.2 ±2.6%/hr whereas HCO-5 had an increase to 6.4 ±0.1%/hr. Samples after 4 week stability showed consistent release profiles to the 14 day annealed samples with complete release upon assay testing and no additional peaks seen above LOQ on purity.
Conclusion: Hydrogenated castor oil as the carrier excipient in a lipid multiparticulate was determined to have good processability with annealing times of 7 days or less. Two differentiated release rates of 15 and 3.4 %/hr were bracketed using a material sparing, risk-based approach with rapid timelines. These formulations were stable for 1 month when tested for dissolution, assay, and purity.
Daniel Kuntz– Lonza Pharma and Biotech, Bend, Oregon
Kathryn Pugh– Lonza Pharma and Biotech, Bend, Oregon
Michael Venters– Engineer, Lonza Pharma and Biotech, Bend, Oregon
Edward LaChapelle– Sr. Scientist Product Development, Lonza Pharma and Biotech, Bend, Oregon
Jaspreet Arora– Senior Engineer, Product Development, Lonza, Bend, Oregon
Matthew Shaffer– Manager Multiparticulate Product Development, Lonza Pharma and Biotech, Bend