Purpose: Lipid multiparticulates (LMPs) are a commercially viable dosage form that can be used in all phases of clinical development. LMPs are a single dosage form technology that have tunable release characteristics, are amenable to high doses, have a high degree of dose flexibility, and are appropriate for pediatric patients. Here we present a case study of a controlled release (CR) lipid multiparticulate developed using a rapid, materials-sparing platform formulation approach. LMP prototypes were manufactured using a melt-spray-congeal (MSC) process and were characterized for performance and stability at standard and accelerated stability conditions. Bio-modeling was performed to predict in vivo clinical outcomes of the lead formulations determined by the in vitro performance and stability data of the formulation space studied. This rapid development case study was performed in 3 months with less than 50 g API, delivering a process, formulation space and predicted pharmacokinetic data to design and manufacture early clinical phase supplies.
Methods: Five formulations with different dissolution rates and drug loadings were manufactured using acetazolamide as the model drug. The formulation platform used poloxamer 407 as pore former (P) and Compritol 888 as carrier (C): the release rate was altered by controlling the P/(P+C) ratio. The formulations bracketed the target release rate, allowing for interpolation to achieve the target product profile in subsequent iterations. Melt screening techniques were used to assess manufacturability and determine the MSC process parameters. MSC manufacturing process includes incorporating crystalline API into the molten pore former/carrier matrix, atomizing the melt into droplets, and congealing the LMP product. The LMPs were manufactured on a customized MSC processor that enables batch sizes as small as 10 g. The design of the development MSC unit minimizes tech transfer and scale up risk because the atomization physics are identical to the clinical scale unit. The CR LMPs were annealed to stabilize the release rate. Fit for purpose dissolution and potency methods were designed to minimize sample usage while using standard equipment and meeting industry standards. Biomodeling was performed using GastroPlus software.
Results: A clinical trial manufacture (CTM) ready formulation space and process was achieved in 3 months using less than 50 g API. Multiple release rates were demonstrated using an uncoated matrix system and a single formulation concept. The formulations were chemically stable for at least one month at 40°C/75%RH and 25°C/60%RH. Physiologically based pharmacokinetic modeling was used to predict the in-vivo response and identify potential clinical candidates. The lead formulations with different in vitro release rates were predicted to have distinct in vivo performance.
Conclusion: We demonstrated a rapid, material-sparing platform approach for development of controlled release LMPs. The drug release of the prototypes bracketed a range of release profiles, which demonstrates how the formulation can be modified to tune release rate. The technology platform’s versatility also allows for the development of a complimentary immediate release product for clinical studies. Biomodeling enables tuning/iteration of the release profile based on PK data without additional development, facilitating faster progression to later clinical stage studies.
Michael Venters– Engineer, Lonza Pharma and Biotech, Bend, Oregon
Samantha Saville– Lonza Pharma and Biotech, Bend, Oregon
Amanda Pluntze– Lonza Pharma and Biotech, Oregon
Cody Prather– Lonza Pharma and Biotech
Aaron Stewart– Lonza Pharma & Biotech
Daniel Kuntz– Lonza Pharma and Biotech, Bend, Oregon
Edward Lachappelle– Lonza Pharma and Biotech
Martin Markovich– Sr. Engineering Technician Product Development, Lonza Pharma and Biotech
Matthew Shaffer– Manager Multiparticulate Product Development, Lonza Pharma and Biotech, Bend