Microspheres are widely utilized as a sustained-release drug delivery system, with several successful commercial products developed for the treatment of diseases such as diabetes, mellitus prostate cancer, periodontitis [1]. Compared to traditional dosage forms, microspheres offer distinct advantages, including enhanced therapeutic efficacy, reduced toxicity, and improved patient compliance. Poly (lactic-co-glycolic acid) (PLGA), a polymer approved by both the Food and Drug Administration and European Medicines Agency, is frequently employed in the development of long-acting injectable formulations due to its reliability and ability to facilitate sustained release over extended periods [[2], [3], [4]]. By fabricating microspheres with PLGA, drug release can be controlled over weeks to months [5]. Previous studies have demonstrated that the degradation rate can be modulated to accelerate the release of loaded actives from PLGA microspheres [3,6]. The release profile can be tailored by adjusting the lactic acid/glycolic acid ratio (L/G ratio), molecular weight, as well as the morphology and size of the microspheres [6,7]. Additionally, terminal groups of PLGA also contribute to the degradation behavior. Wang et al. reported that commercial acid-terminated PLGA exhibited higher encapsulation efficiency and faster release compared to ester-terminated PLGA [8]. Despite these findings, there remains a gap on the analysis of terminal groups, and the literature impacts of variations in terminal groups and on the physicochemical properties, degradation rate, and drug release characteristics of PLGA microspheres. Further development of methods for terminal group analysis is essential to explore how variations in these groups affect the release mechanisms of active ingredients encapsulated in PLGA microspheres. To enhance the clinical applicability of PLGA microspheres, it is essential to achieve precise control over the drug release period. Additionally, minor changes in the physicochemical properties of PLGA, including those influenced by terminal group modifications, can significantly impact the release profile of encapsulated drugs [9]. While PLGA shows substantial promise for both research and clinical applications, the difficulty in controlling its properties and the absence of standardized characterization methods present major challenges in the development of PLGA microsphere-based drug products [[10], [11], [12]]. Thus, the advancement of highly reproducible and precisely controllable PLGA modification techniques, coupled with a comprehensive understanding of PLGA degradation mechanisms and drug release mechanisms, is essential for the continued development of PLGA microspheres [9].

Cyproterone acetate (CYA), an active ingredient on widely used oral contraceptives, exhibits antiandrogenic effects, distinguishing it from traditional androgenic substances. This characteristic not only makes CYA an effective contraceptive but also beneficial in treating conditions, such as seborrhoea, acne, hirsutism and androgenic alopecia in a significant proportion of patients. CYA is generally well tolerated, with no clinically significant effects on metabolic functions, liver health, or body weight [13]. Over recent decades, long-acting contraceptives methods, such as injections, intrauterine devices and subdermal implants, have gained attention due to their high efficacy, long-term cost-effectiveness, and reversibility for future fertility planning [14]. Among these, long-acting injectable contraceptives, in particular, are user-friendly, as they do not require removal. Currently, medroxyprogesterone acetate is the only injectable contraceptive available in the United States [15,16]. However, its acceptability is limited by frequent side effects and a prolonged recovery period for fertility after discontinuation, primarily due to the active pharmaceutical ingredient and the microcrystalline suspension formulation [17]. Thus, there is a growing need for alternative progestins and formulations for long-acting injectables that reduce side effects and improve patient adherence.

In this study, glycolic acid, n-hexanol, dodecanol, and hexadecanol were employed to synthesize four distinct PLGA with different terminal groups through a ring-opening polymerization. To isolate the effects of terminal groups on PLGA degradation, the molecular weight, L/G ratio, and viscosity were controlled to remain consistent. A method for terminal group analyzing was developed to identify and verify the terminal groups in PLGAs. This method was also used to compare these terminal groups with those in common commercially available products to ensure integrity of our product verification process. Blank PLGA microspheres with similar morphology and size were prepared using an emulsification method. Given the lack of a standardized in vitro degradation method for microspheres, we employed the same conditions used for in vitro release assays to ensure reproducibility of the degradation process. Our findings demonstrated that varying in the terminal groups of PLGA significantly influence its degradation rates, with the degradation mechanism involving chain cleavage in phosphate-buffered saline (PBS) (0.1 M, pH 7.4). We then encapsulated CYA in PLGA microspheres via emulsification and investigated the relationship between the degradation of PLGA and the release of CYA from the microspheres. The goal was to modulate the terminal groups of PLGA to produce different release profiles of the encapsulated CYA. Ester-terminated PLGAs demonstrated slower degradation rates compared to acid-terminated variants, with longer terminal groups further delaying degradation. Ultimately, this work paves the way for the further optimization and application of PLGA-based drug delivery systems in clinical settings.