Phase-separated polymer blends for controlled drug delivery by tuning morphology

Controlling drug release is crucial for improving therapeutic effectiveness and patient compliance. Many drugs have poor aqueous solubility and bioavailability, posing challenges in pharmaceutical development. Amorphous solid dispersions (ASDs) are a common approach to improve dissolution by dispersing the drug in a solid carrier matrix, often utilizing a dual-polymer system to combine different properties (e.g., hydrophobic for stability and hydrophilic for faster release). Hot melt extrusion (HME) is a preferred processing method for ASDs due to its cost-effectiveness, sustainability, and elimination of toxic residues and solvent drying steps. While phase separation has been observed in extruded dual-polymer ASDs, its use for tailored drug release has not been fully explored. This research investigates phase-separated polymer blends in solid dispersions as a means to achieve controlled drug release. The study uses hydroxypropyl methylcellulose (HPMC), a hydrophilic polymer with a swelling release mechanism, and polylactic acid (PLA), a hydrophobic polymer used in implants for extended release. Combining these polymers creates a phase-separated matrix where HPMC acts as a channeling agent within the PLA matrix, influencing the drug release profile.

Previous research extensively covers the challenges of drug delivery and the strategies employed to improve drug solubility and bioavailability, such as the use of amorphous solid dispersions (ASDs). The advantages of dual-polymer systems in ASDs are well-documented, providing opportunities for optimizing flow properties during thermal processing, which is favored over solvent-based methods for its sustainability and safety. Hot melt extrusion (HME) has gained popularity as a scalable and efficient technique for ASD production, opening avenues for personalized medicine through additive manufacturing. However, the literature lacks a comprehensive exploration of leveraging phase separation within dual-polymer ASDs to precisely control drug release profiles in oral formulations, highlighting the novelty of this study.

The study prepared melt-extruded filaments using nicotinamide (drug), HPMC, and PLA in various weight ratios (30/70, 50/50, 70/30 PLA/HPMC) with 0 and 10 wt% nicotinamide. HME was performed using a micro compounder at 180°C. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to characterize the amorphous nature and thermal properties of the ASDs. In vitro dissolution studies, using a USP paddle apparatus with phosphate buffer (pH 6.8) at 37°C, measured drug release profiles. Scanning electron microscopy (SEM) imaged the remaining polymer matrix after dissolution. Advanced imaging techniques, scanning transmission X-ray microscopy (STXM) and ptychographic X-ray computed tomography (PXCT), characterized the morphology and drug distribution in the ASDs. STXM, coupled with near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, provided chemical contrast to map the distribution of the drug, HPMC, and PLA. PXCT generated 3D images with high resolution to investigate the connectivity and thickness of the hydrophilic HPMC domains. Image analysis techniques, such as singular value decomposition for STXM and watershed segmentation for PXCT, were used to quantify the morphological features. Local thickness analysis of the HPMC-rich domains was done using ImageJ and Avizo.

DSC and XRD confirmed the amorphous nature of nicotinamide in the ASDs at 10 wt% loading; higher loading led to crystallization. Dissolution studies revealed distinct release profiles depending on the PLA/HPMC ratio. The 30/70 PLA/HPMC blend showed a rapid burst release, while 50/50 and 70/30 blends exhibited slower, extended release. SEM revealed the porous structure remaining after HPMC leaching, with higher HPMC content resulting in more brittle and porous structures. STXM and NEXAFS confirmed phase separation and showed that nicotinamide was present in both phases, with a tendency to favor the HPMC phase. The spatial distribution of nicotinamide was homogeneous within each phase. PXCT provided 3D visualizations, showing that the morphology (connectivity and size of HPMC domains) was altered by polymer fraction and the presence of the drug. Increasing the PLA fraction resulted in a narrower, less connected HPMC network, leading to slower release. The addition of nicotinamide increased the size and connectivity of HPMC domains. Local thickness analysis quantified the size and distribution of HPMC domains, showing that higher HPMC fractions led to more homogenous domain thickness and faster dissolution. A comparison of the pristine and leached morphologies showed that the swelling of HPMC during dissolution leads to a fractured PLA matrix and increases the exposed surface area of PLA, enhancing drug release from the PLA-rich phase.

The findings directly address the research question by demonstrating a clear correlation between the morphology of phase-separated polymer blends and the drug release rate in ASDs. The ability to tune drug release by simply adjusting the polymer ratio during HME is a significant contribution. The observed release mechanism is primarily governed by the diffusion of the drug through the wetted HPMC phase. The use of advanced imaging techniques like STXM and PXCT provided crucial insights into the intricate relationships between morphology and drug release, far beyond what could be obtained with conventional techniques. The results have implications for the design and optimization of controlled-release oral drug formulations, offering a facile strategy for tailoring drug delivery to meet specific therapeutic needs.

This study successfully demonstrates the use of phase-separated polymer blends produced by HME to control the drug release rate in ASDs. The morphology of the resulting matrix, tunable by adjusting the polymer ratio, dictates the release profile. Higher HPMC content leads to faster release, while increased PLA results in slower, extended release. This method offers a promising and easily scalable approach for designing tailored drug delivery systems, paving the way for more effective and personalized therapies. Future studies could explore other drug-polymer combinations and investigate the impact of different processing parameters on morphology and release kinetics.

The study focused on a single drug, nicotinamide, and two polymers, HPMC and PLA. The results might not be directly generalizable to other drug-polymer systems. While advanced imaging techniques provided high-resolution morphological data, some limitations in quantitative analysis of drug partitioning between phases existed due to limitations in resolution and spectral interpretation. The in vitro dissolution studies, although important, do not fully capture the complexities of in vivo drug release.