In situ forming implants with high drug loading via microcrystal compaction for long-term release

In situ forming implants (ISFIs) offer a promising alternative to conventional surgical implants, as they can be subcutaneously injected in a liquid state, avoiding invasive surgery. ISFIs consist of a drug and water-insoluble biodegradable polymers in organic solvents, which solidify upon injection due to solvent diffusion and phase separation, forming a drug depot with tailored release over various timeframes. ISFIs present numerous advantages, such as compatibility with various pharmaceutical compounds, enabling co-formulation of multiple drugs, and simple manufacturing processes. However, limitations in drug loading capacity hinder long-term delivery via ISFIs. Constraints arise from factors like drug-polymer compatibility and the high polymer proportion needed for depot mechanical integrity. Additionally, burst release occurs due to rapid solvent exchange upon injection, leading to potential overdosing or unpredictable release profiles.

To tackle these challenges, we propose a novel ISFI formulation approach for long-term delivery of hydrophobic drugs, which comprise a significant portion of small molecule therapeutics in the pharmaceutical industry. Our hypothesis is that the spontaneous, formulation-driven compaction of drug microcrystals in situ upon injection will reduce their surface area, thereby extending and regulating drug release. Furthermore, we anticipate that jamming between drug microcrystals will enable solid depot formation with the required mechanical properties for a long-term implant, minimizing polymer excipient usage. This approach should significantly increase drug loading compared to previous ISFI systems. We aim to investigate compaction mechanisms and drug microcrystal behavior to optimize drug loading capacity and achieve desired release kinetics, ultimately enhancing system performance.

To investigate the proposed ISFI formulation, we designed a comprehensive study combining in vitro characterization, in vivo animal experiments, and in vitro and in vivo correlation (IVIC) analysis. This approach aims to understand the compaction mechanism during our depot formation process, using Levonorgestrel (LNG) as a model hydrophobic drug. We created an ISFI formulation consisting primarily of a suspension of LNG microcrystals in a biocompatible solvent. Solvents with varying degrees of miscibility with water, as well as different concentrations of an optional polymer excipient, were varied to understand how different formulation parameters impact the microcrystal compaction process.

In Vitro Characterization: The compaction of LNG microcrystals was studied in vitro using microscopy to observe drug depot formation in real time. In vitro drug release rates and rheological properties were also measured.

In Vivo Animal Studies: Rat and pig models were used to evaluate the efficacy of the ISFI system. Ultrasound imaging data was collected to assess particle compaction and the resulting properties, pharmacokinetics, and mechanical integrity of the depot in the in vivo environment.

In Vitro and In Vivo Correlation (IVIC) Analysis: To understand the impact of the in vivo environment on the compaction mechanism, we established correlations between in vitro and in vivo observations. This analysis guided improvements in the formulation and helped develop an optimal ISFI system.

To investigate the proposed ISFI formulation, we designed a comprehensive study combining in vitro characterization, in vivo animal experiments, and in vitro and in vivo correlation (IVIC) analysis. This approach aims to understand the compaction mechanism during our depot formation process, using Levonorgestrel (LNG) as a model hydrophobic drug. We created an ISFI formulation consisting primarily of a suspension of LNG microcrystals in a biocompatible solvent. Solvents with varying degrees of miscibility with water, as well as different concentrations of an optional polymer excipient, were varied to understand how different formulation parameters impact the microcrystal compaction process.

In Vitro Characterization: The compaction of LNG microcrystals was studied in vitro using microscopy to observe drug depot formation in real time. In vitro drug release rates and rheological properties were also measured.

In Vivo Animal Studies: Rat and pig models were used to evaluate the efficacy of the ISFI system. Ultrasound imaging data was collected to assess particle compaction and the resulting properties, pharmacokinetics, and mechanical integrity of the depot in the in vivo environment.

In Vitro and In Vivo Correlation (IVIC) Analysis: To understand the impact of the in vivo environment on the compaction mechanism, we established correlations between in vitro and in vivo observations. This analysis guided improvements in the formulation and helped develop an optimal ISFI system.