Student Rowan University Pearl River, New York, United States
Introduction: In geriatric, pediatric, and psychiatric patients, significant intentional and accidental non-compliance with medication regimens is common, leading to these patients often missing their medications or not taking them on time. Beyond issues of non-compliance, much of the world faces strained access to healthcare providers/pharmacies, further complicating proper medication adherence. This work proposes the development of pulsatile drug delivery implants that operate via a fuse and reservoir system. While numerous constant-release implants have been developed and approved, limited options exist for pulsatile drug delivery, an important achievement, and necessity for many medications and treatment regimens. The proposed device can be programmed to rapidly release a drug load at predetermined intervals, significantly enhancing compliance and reducing the risk of medication abuse. This approach offers a promising solution for ensuring timely and accurate medication delivery without patient intervention. Though a proof of concept was established by this lab for a three-reservoir, once-daily device, there were still limitations and shortcomings that needed to be addressed. This work focused on reducing batch-to-batch variability as well as the diffusion or release time of a given drug load or drug model. The in vitro studies demonstrated the device's ability to provide precisely timed and high-resolution drug delivery. The development of such pulsatile drug delivery implants represents a significant advancement in the field of drug delivery, offering a versatile and effective solution to pressing healthcare challenges.
Materials and
Methods: To fabricate these devices, a positive mold was created using SU-8 photoresist. PDMS was then cast on top of that SU-8 mold to create a negative mold, and CAPP (Cellulose Acetate Phosphate + Pluronic F-127) was poured into the PDMS mold to form the final devices. The devices were cast in this dish overnight, after which the array of devices was removed and allowed to expel residual solvent for an additional 24 hours. Once the devices were cut from the array, the drug model could be loaded. For higher resolution in vitro studies, the devices were loaded with either rhodamine b or fluorescein (FITC) as fluorescently quantifiable drug models. Varying polymer ratios were produced by dissolving specified weights of CAP and Pluronic F-127 (P) in acetone. Specifically for comparing behavior across varying polymer ratios, those solutions were mixed with small volumes of rhodamine b and cast in glass dishes. The resulting films were then dissolved in phosphate-buffered saline (PBS), and both thickness and mass were measured over time. Additives were explored as a means of reducing drug release time. Mannose, table salt, and ethylenediaminetetraacetic acid were introduced to FITC at varying weight ratios. Packed devices were then encapsulated in polycaprolactone and cut on one end to expose one surface of the CAPP bodies. In one study, devices were suspended in a stagnant solution of PBS; in an alternate study, vials were kept in an incubated shaker. Fluorescent measurements of the PBS bath were taken using a standard plate reader.
Results, Conclusions, and Discussions: The study demonstrated the successful implementation of a pulsed drug delivery system capable of achieving rapid and precisely timed drug release. When conducting degradation studies on uniformly cast CAPP films, it was observed that the height of the 70:30 (CAP:P ratio) weight percent CAPP films exhibited 30% swelling, whereas the 90:10 CAPP films exhibited linear degradation without swelling. Switching to 90:10 CAPP films significantly reduced the diffusion time of the drug model compared to 70:30 CAPP films. While previous studies showed distinct peaks corresponding to FITC release from three different reservoirs, the release period was over 16 hours and the peaks did not return to baseline. Studies on additives such as salt and mannose showed increased release rates when the reservoirs were fully exposed to PBS. However, when a thin layer of CAPP was left to degrade before the reservoirs were exposed, no significant difference in release rates was observed. This suggests that when a small hole is first exposed, the solution enters the reservoir faster than the drug model can diffuse out, leading to clumping and re-wetting issues. Introducing kinetics via an orbital shaker effectively reduced the drug release time from 16 hours to 30 minutes, suggesting conditions more aligned with the human body, where small laminar flows and body movements create kinetic conditions, unlike the initial stagnant vial studies. The absence of the need for additives in the later kinetic studies implies that more drugs can be loaded into the system, opening the door to new drug classes. Future plans include extending the device to hold a month's worth of doses and support more than three releases. Additional goals are to release multiple drugs and vary the time between doses, aiming to improve medication adherence and healthcare outcomes. This advancement addresses the limitations of previous designs, underscoring the potential of pulsatile drug delivery implants to enhance medication adherence and reduce the risk of medication abuse. Rapid-release mechanisms ensure timely administration of therapeutic agents, which is crucial for improving patient compliance, especially among geriatric, pediatric, and psychiatric patients who often struggle with consistent medication intake.
Acknowledgements (Optional): Thank you to Lilly Ates, Parker Brewster, Dr. Werfel, Dr. Walker, Dr. Reinemann, and the rest of Dr. Werfel’s Lab.
This project is funded by both NSF 2148764, REU funding, and NIH R21 EB031454-01A1.
