A Scalable Platform for Fabricating Biodegradable Microparticles with Pulsatile Drug Release

Abstract

Despite the success of therapeutics and prophylactics in prolonging life and improving quality of life, these benefits are limited by poor patient adherence, which can be as low as 50% in patients with chronic conditions. [3][4][5] This lack of patient adherence contributes to negative outcomes, including death, and results in an additional $289 billion in healthcare costs each year in the United States alone. [6][7][8] Reducing drug dosing frequency has been identified as one of the most effective means to increase patient adherence. [9,10] However, many diseases including diabetes, cancer, human immunodeficiency virus infection, depression, and autoimmune disorders, are typically treated with frequent, repeated, and longterm administration of therapeutics, often as frequently as multiple times a day, to maintain drug levels that are both safe and effective. Controlled drug delivery systems represent a promising solution to mitigate compliance issues. By releasing drugs over an extended period of time, these systems can be administered less frequently, thereby improving adherence and patient outcomes. For example, the FDA-approved Lupron Depot, composed of drug-loaded biodegradable microspheres, has been shown to improve patient adherence and convenience by reducing administration frequency from a once-daily injection to one injection every one to six months. [11,12] Oral delivery systems are convenient, but their rapid passage through the gastrointestinal tract limits their duration of action, often requiring frequent re-dosing that can lead to lower levels of patient adherence compared to less frequent parenteral injection(s). [13] Unfortunately, most injectable controlled-release systems generate an initial burst release followed by first-order release kinetics in which drug is released at a perpetually lower rate over time. [14,15] Although these devices extend the duration of drug activity, their front-loaded and slowing rate of release limits their ability to maintain therapeutic efficacy over a long period of time, especially when the biological half-life of the drug is short or the therapeutic window is small. Increasing initial drug loading can extend the duration of release in these Pulsatile drug delivery systems have the potential to improve patient adherence and therapeutic efficacy by providing a sequence of doses in a single injection. Herein, a novel platform, termed Particles Uniformly Liquified and Sealed to Encapsulate Drugs (PULSED) is developed, which enables the high-throughput fabrication of microparticles exhibiting pulsatile release. In PULSED, biodegradable polymeric microstructures with an open cavity are formed using high-resolution 3D printing and soft lithography, filled with drug, and sealed using a contactless heating step in which the polymer flows over the orifice to form a complete shell around a drug-loaded core. Poly(lactic-co-glycolic acid) particles with this structure can rapidly release encapsulated material after delays of 10 ± 1, 15 ± 1, 17 ± 2, or 36 ± 1 days in vivo, ...

Fabrication of Pulsatile Polymeric Microparticles Encapsulating Rabies Antigen

“…Procurement of a piezoelectric dispensing robot requires a significant initial upfront investment, often in the range of $80,000 to $200,000, depending on the brand, throughput, and capabilities. Although several other filling methods are potential alternatives, these methods have not been validated using the RABV antigen 12 .…”

“…Micromolding is used to generate particles that are filled with a liquid payload and heated to allow the polymer to reflow and fully encapsulate the central depot of cargo within a contiguous layer of the biodegradable polymer. This microstructure results in the pulsatile release of the payload, after a duration that is dependent on the degradation rate of the polymeric shell 12 . This manuscript demonstrates the encapsulation of inactivated RABV within microparticles composed of poly(lactic-co-glycolic acid) (PLGA), a biodegradable polymer used in many FDA-approved formulations 13 , using the PULSED fabrication method to encapsulate stable RABV antigen as evaluated by an enzyme-linked immunosorbent assay (ELISA).…”

Fundamentals Applications of Controlled Release Drug Delivery

“…One notable benefit of these degradable polymers is in their ability to undergo degradation into biologically acceptable compounds, which can subsequently be metabolized and eliminated from the body by regular metabolic processes. Nevertheless, it is important to acknowledge that biodegradable materials do generate breakdown by-products, which must be accepted within the biological environment without causing significant negative reactions [51].…”

Injectable controlled‐release systems for the prevention and treatment of infectious diseases

“…Significant loss of antigen can occur during encapsulation and release from polymers such as PLGA, for reasons such as its degradation products altering the environment inside the system and exposure to solvents during fabrication 113,114 . Though stabilization strategies have been reported, such as the use of basic excipients to control pH, 115 stabilization still remains a large challenge to overcome with many such systems.…”