(M1230-01-03) Characterization of Drug Release from a Blended Biodegradable Polymeric Film Using a Central Composite Design

Purpose: Drug delivery from polymer films provides a unique approach for controlling drug release with applications across transdermal and intra-oral therapeutic systems. It is key to the success of these polymeric platforms that drug release rates be quantitatively characterized. An understanding of factors influencing release rate will facilitate the design of customized polymeric delivery systems that can be programmed to release drug at a predetermined rate. The rate of release can be tailored to account for the specific physico-chemical properties of the drug that it is delivering. This program set out to develop films of two blended biodegradable polymers in order to quantitatively assess their individual contributions to release of a drug through development of a regression equation that could characterize drug release kinetics. While all films contained a blend of different concentrations of each polymer, statistical analyses can be used to solve for the individual polymer contribution to controlling release.

Methods: Polycaprolactone (PCL) and Poly-Lactic-co-glycolic-Acid (PLGA) were selected due to their unique physical and mechanical properties. When blended in different ratios, these polymers can be used to optimize drug release rates. The Central Composite Face-Centered (CCD) design is a statistical approach to efficiently test different combinations of polymer blends to understand the relationship between the composition and release rate. Polymeric films were prepared by solution casting and drug release was assessed by dissolution testing with spectrophotometric analysis of a model drug, methylene blue. The films were further characterized through tensile strength testing to understand their mechanical properties in an effort to facilitate routine preparation. Also, Scanning Electron Microscopy (SEM) of pre- and post-dissolution films was employed to help understand both the factors that influence release kinetics and the mechanistic basis for drug release.

Results: All developed films demonstrated controlled delivery over 48 hours. Higuchi analyses confirmed that films released drug through a diffusion mechanism and the slopes of the Higuchi analysis were assigned as a Response Variable for the Minitab analysis of the CCD. The regression equation that was derived was: Drug Release Rate = 9.74 - 19.5 PCL + 0.6 PLGA + 17.0 PCL*PCL - 1.7 PLGA*PLGA - 1.2 PCL*PLGA This regression equation and corresponding response surface plots demonstrated primarily that PCL was notably more effective than PLGA at slowing drug release. The Center Point Sample (50:50 ratio of PCL and PLGA) was replicated 5 times and demonstrated statistical reproducibility. SEM confirmed that drug release occurs by diffusion through pores in the polymeric films. These pores were reduced in diameter over time as the polymers swelled in solution. Tensile strength testing allowed determination of Young's modulus from the slope of the stress-strain curves. This mechanical testing showed the films to be of sufficient strength and Young’s Moduli were 0.008 kN/m² or higher, indicating a pronounced elastic nature.

Conclusion: CCD is an efficient statistical optimization technique to determine the contribution of different polymeric contributors in complex systems. In this polymeric system, PCL was more effective than PLGA in slowing drug release. In addition, self-interactions between PCL molecules had an influence on drug release. With this information, polymeric blends can be developed to customize drug release rates. CCD allowed for derivation of a quantitative regression analysis that facilitated a mechanistic understanding of the individual contributions of blended polymeric systems.

References: Aksu, B. et al. (2019) Int J Pharm Res, 11: 1094–1101; Karki, S. et al. (2016) J Pharm Sci, 11(5): 559-574; Pamlényi, K. et al. (2021) Pharmaceutics,13: 619

Acknowledgements: The authors gratefully acknowledge the advice of Dr. Mark Licurse (Director of Education & Outreach) and the use of facilities and instrumentation (Scanning Electron Microscopy and Tensile Strength Testing) supported by NSF through the University of Pennsylvania Materials Research Science and Engineering Center (MRSEC), DMR-1720530.