Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder that is marked by hepatic lipid accumulation, insulin resistance, and progressive liver injury. Despite its increasing global burden, effective pharmacological therapies remain limited. Long-acting peptide-based agents are a potential strategy to address this unmet clinical need. In this context, we investigated PGLa-ABD-AFF, a modified long-acting construct derived from the amphibian peptide (peptide-glycine-leucine-amide-AM1 (PGLa)), which was engineered to enhance systemic exposure and therapeutic efficacy. PGLa-ABD-AFF was designed by fusing PGLa with an albumin-binding domain (ABD) and an FcRn-targeting affibody (AFF) to extend its circulatory half-life. The fusion protein was expressed, purified, and evaluated for purity and in vitro safety. Moreover, the pharmacokinetic properties were evaluated in mice, including plasma half-life and tissue biodistribution. The metabolic and hepatic effects of PGLa-ABD-AFF were examined in vivo by assessing glycemic control, body weight, food intake, liver steatosis, and pancreatic islet morphology. PGLa-ABD-AFF was successfully produced with high purity and demonstrated a favorable in vitro safety profile. Pharmacokinetic analysis revealed a substantially prolonged plasma half-life of approximately 47 h. Biodistribution studies showed predominant accumulation in the liver and kidneys. In vivo treatment with PGLa-ABD-AFF significantly improved glucose homeostasis, reduced body weight and caloric intake, and markedly attenuated hepatic steatosis. Furthermore, PGLa-ABD-AFF preserved pancreatic islet architecture by alleviating metabolic stress-induced hypertrophy. These findings indicate that PGLa-ABD-AFF is a potent long-acting peptide therapeutic with beneficial metabolic and hepatoprotective effects. The prolonged systemic exposure and multi-organ efficacy support its potential as a promising candidate for the treatment of obesity-associated metabolic dysfunction and hepatic steatosis.
Protein‑based therapeutics represent a substantial fraction of FDA‑approved biologics, and the continued expansion of protein modalities has increased the demand for effective stabilization strategies. Although solid‑state protein formulations generally offer superior storage stability compared to liquid formulations, drying processes such as lyophilization, spray drying, and spray freeze‑drying can introduce significant physical and chemical stresses that compromise protein stability. This review focuses on the role of high‑molecular‑weight polymeric excipients in the solid‑state stabilization of protein‑based injectable formulations. It discusses common sources of instability introduced during drying and long‑term storage, while summarizing and highlighting the growing interest in polymeric excipients as stabilizers. Mechanisms by which polymeric excipients enhance protein stability including amorphous matrix formation, reduced molecular mobility, and surface‑active protection against interfacial stresses are discussed. The regulatory status of polymeric excipients currently used in FDA‑approved injectables versus investigational materials is also considered. Polymeric excipients offer unique advantages for solid-state protein stabilization and may complement or surpass traditional low-molecular-weight stabilizers when rationally selected. However, broader adoption will require improved mechanistic understanding, careful consideration of excipient–protein interactions, and alignment with regulatory expectations. Continued development and systematic evaluation of polymeric excipients are expected to expand formulation design options and improve the stability and performance of next-generation protein therapeutics.
Nanocrystal technology is a practical and clinically validated strategy for improving the solubility, dissolution, and bioavailability of poorly water-soluble drugs. Nanocrystals reduce drug substances to the nanoscale and stabilize their high surface energies using small amounts of polymers or surfactants. This enables high drug loading and applicability across various administration routes. Considering that nanocrystal quality depends on the interactions between the formulation variables and process parameters, understanding these relationships is essential for systematic development. This review summarizes the fundamental principles, physical instabilities, and performance mechanisms of nanocrystals. This includes their effects on dissolution, apparent saturation solubility, and bioavailability. Specifically, top-down, bottom-up, and hybrid preparation methods are discussed with an emphasis on their mechanisms, advantages, limitations, and process-specific parameters affecting critical quality attributes (CQAs). Moreover, stabilization mechanisms and commonly used stabilizers are reviewed from a quality by design (QbD) perspective. In particular, stabilizer type, concentration, and physicochemical properties are considered as potential critical material attributes (CMAs). Furthermore, the review discusses the application of QbD to wet media milling-based nanocrystal development. This includes defining the quality target product profile (QTPP) and CQAs, risk-based identification of CMAs and critical process parameters, risk assessment, design of experiments, design space, and control strategies. The QbD considerations are further extended to solidification and scale-up. Nanocrystal development should be viewed as an integrated process in which the particle properties, stabilization mechanisms, preparation methods, solidification, and scale-up are closely interconnected. Moreover, QbD will support a systematic understanding of the relationship between formulation variables, process parameters, and the quality attributes of nanocrystals. Ultimately, QbD-based predictive development and quality control strategies will improve developmental efficiency and facilitate industrial and clinical translation of nanocrystals.
Particle engineering critically affects the physicochemical properties, dissolution rate, and bioavailability of pharmaceutical products. Conventional supercritical fluid (SCF)-based particle formation processes offer distinct advantages but have limited industrial application, particularly because they require large-volume and high-pressure vessels. Supercritical CO₂ (scCO₂)-assisted spray particle formation technologies—including supercritical-assisted atomization (SAA), supercritical enhanced atomization (SEA), and scCO₂-assisted spray drying (SASD)—have emerged as scalable alternatives that combine the mechanical atomization of conventional spray drying with the thermodynamic advantages of scCO₂ expansion. This review consolidates historically-fragmented scCO₂-assisted spray particle formation variants within a single mechanistic framework. It examines fundamental process principles, including scCO₂-assisted atomization mechanisms and droplet-to-particle solidification pathways, and surveys pharmaceutical applications ranging from dissolution enhancement and polymorphic/solid-state control to inhalable dry powder formulations, controlled release, and emerging therapeutic applications for thermolabile biologics and natural bioactives. Current limitations and the path toward commercial implementation, including continuous manufacturing, quality-by-design (QbD), and computational fluid dynamics (CFD) modeling are critically discussed. The distinguishing strength of these technologies lies less in surpassing the absolute performance of conventional spray drying than in enabling the single-step, co-processing of thermolabile actives with functional excipients under mild conditions. Of these variants, SASD offers the most practical industrial route due to its retrofit compatibility with existing spray dryers. Realizing this potential now depends on validated scale-up, sterile continuous processing, QbD/CFD-guided design, and standardized cross-platform benchmarking, rather than further proof-of-concept demonstrations.
Bojungikgitang (BJIGT), Ijintang (IJT), and Cheongsanggyeontongtang (CSGTT) are traditional herbal formulations with a long history of use in East Asian traditional medicine for the symptomatic management of cardiovascular and cerebrovascular diseases. Although these formulations are frequently coadministered with anticoagulants, clinical evidence on their interactions with direct oral anticoagulants (DOAC) remains scarce. This study aimed to evaluate the effects of BJIGT, IJT, and CSGTT on the pharmacokinetics and pharmacodynamics of edoxaban, a widely used DOAC. In a fixed-sequence, two-period clinical study, healthy volunteers received 60 mg edoxaban alone and after repeated dosing with BJIGT, IJT, or CSGTT. Plasma concentrations of edoxaban and its active metabolite M4 were quantified by liquid chromatography coupled with tandem mass spectrometry. Pharmacokinetic parameters were compared using linear mixed-effects models. Pharmacodynamic effects were assessed with prothrombin time and activated partial thromboplastin time. The CYP3A4 inhibitory potential of BJIGT, IJT, and CSGTT was evaluated in vitro. BJIGT significantly increased edoxaban exposure, approximately doubling systemic levels, whereas IJT exerted minimal effects and CSGTT reduced exposure by approximately 40
