Search Results (299)

In situ-forming implants (ISFIs) based on poly(lactic-co-glycolic acid) (PLGA) offer a promising platform for long-acting parenteral drug delivery, enabling minimally invasive administration without surgical implantation. However, the development and clinical translation of PLGA-based ISFIs are hindered by formulation complexity, sensitivity to aterial variability, and limited predictability of drug release, particularly during early implant formation. Although previous reviews have described formulation components and release mechanisms, a comprehensive integration of Quality by Design (QbD) principles with a focus on risk prioritization remains absent. This review examines the application of QbD to solvent-exchange PLGA-based ISFIs, with an emphasis on identifying critical material attributes (CMAs) governing implant formation, burst release, and long-term release performance. Risk-based prioritization of CMAs and the role of design of experiments are systematically discussed. Special attention is given to burst release as a major CMA affecting safety, efficacy, and translational robustness. The evidence indicates that formulation-driven CMAs, such as polymer physicochemical properties, drug characteristics, and solvent selection, exert a greater influence on ISFI performance than process-related parameters. This review provides a structured perspective to support rational formulation design, improved reproducibility, and enhanced clinical translation of PLGA-based ISFI systems. Full article

Background/Objectives: Clonazepam (CLZ), a BCS Class II drug, presents significant oral delivery challenges due to its low aqueous solubility. This study explores the systematic development of solid self-emulsifying drug delivery systems (S-SEDDS) using Quality by Design (QbD). The primary objective was to evaluate and compare advanced mathematical optimization frameworks, specifically Derringer’s Desirability Function (D) and Weighted Goal Programming (WGP), to identify a robust formulation that enhances drug solubilization while ensuring superior processability and flowability. Methods: Liquid SEDDS were solidified by adsorption onto a porous matrix (Aerosil^® 200/Lactose). A multi-objective optimization was conducted to define a robust Design Space (DS), comparing D against WGP. The trade-offs between competing Critical Quality Attributes (CQAs), specifically powder flowability (angle of repose, AR), blending efficiency (BE), and CLZ recovery (CR), were evaluated. Characterization included morphology from Environmental Scanning Electron Microscopy (ESEM), droplet size analysis, and pH-dependent dissolution studies. Results: D provided a highly robust baseline, yielding constant optimal coordinates (F2, F3 = +1; F4 = 0) across all sensitivity levels, with a predicted AR of 40.46°, BE of 0.12 and CR of 90.0%. However, WGP successfully refined this solution by allowing a more flexible weighting of goals, achieving a more favorable compromise with an AR of 38.96°, a BE of 0.11, and a CR of 90.23%. The optimized system maintained nanometric droplet sizes (<200 nm) and showed a controlled, pH-independent release profile, reaching 80% drug solubilization at 6 h. Conclusions: Integrating WGP into the QbD framework offers a more versatile and precise optimization than the traditional D for complex pharmaceutical systems. This approach ensures the production of high-quality S-SEDDS, bridging the gap between mathematical modeling and the stringent requirements of industrial solid dosage manufacturing. Full article

The majority of approved drug products comprise formulations of either chemically synthesized small molecules or large molecular entities derived from living cells, commonly referred to as biologics. Over the past two decades, there has been remarkable growth in the approval of biologics for a variety of disorders, including respiratory diseases. The preference for biologics stems from their high target specificity, strong binding affinity, and favorable safety profiles. Most approved biologics are peptides or proteins, which are unsuitable for oral administration due to negligible bioavailability, resulting from their large molecular size, polarity, and susceptibility to enzymatic degradation in the gastrointestinal tract. Consequently, the majority of biologics are administered parenterally, delivering the drug systemically to reach target sites. However, achieving therapeutic concentrations of locally acting respiratory drugs in the lungs via systemic delivery often requires high doses, which increases the risk of adverse effects. For respiratory disorders, nasal and pulmonary drug deliveries are the preferred noninvasive routes. These routes bypass gastrointestinal and first-pass metabolism and deliver therapeutic agents directly to their local site of action. This approach enables a faster onset of action, reduces the required dose by orders of magnitude, and significantly lowers the risk of systemic adverse effects. These advantages have driven the successful development of inhaled formulations for certain rescue and maintenance medications that were originally administered orally or parenterally. Despite this, treatment options for respiratory diseases remain largely limited to small molecules, with only a single inhaled biologic approved in 1993, even though several parenterally administered biologics have since been approved for pulmonary disorders. The scarcity of inhaled biologics is primarily due to the inherent complexity of these drug substances, which impacts all stages of product development, including manufacturing, characterization, purification, stability, formulation design, delivery, and preclinical and clinical evaluations of safety and efficacy. Additionally, sponsors’ interest in developing inhaled biologics may be tempered by the lack of regulatory guidance addressing the multidisciplinary and intricate nature of their development. This article, together with the accompanying review, addresses both regulatory considerations and scientific challenges in the development of inhaled biologics. To the authors’ knowledge, these works represent seminal efforts to examine available regulatory guidance and the applicable literature across various phases of product development beyond safety and efficacy evaluations. We examined the formal regulatory expectations and summarized the requirements as they apply to inhaled products and inhaled biologic protein therapeutics. In parallel, we explored scientifically relevant considerations in the development of inhalation-specific protein therapeutics for which regulatory guidance remains limited, evolving, or absent. While they should not be considered definitive, it is hoped that these contributions will stimulate scientific and regulatory interest, ultimately promoting the identification and resolution of gaps to advance the development of locally acting biologics and address unmet patient needs. Full article

The rapid advancement of respiratory syncytial virus (RSV) mRNA vaccines has created an urgent need for robust, standardized, and predictive potency evaluation systems. Currently, this field relies on diverse, non-standardized in vitro methods that lack quantitative correlations with in vivo immune protection. This poses significant challenges for vaccine process optimization, quality control, and regulatory review. This paper systematically analyzes the strengths and limitations of existing in vitro and in vivo assessment strategies, identifying a bottleneck in the current framework due to the absence of quantitative links between in vitro indicators and in vivo outcomes. It proposes that addressing these challenges hinges on establishing predictive in vitro–in vivo correlation (IVIVC). Furthermore, it outlines a feasible pathway for constructing such predictive models through the design of systematic experimental protocols and multivariate statistical analysis. Alignment with Quality by Design (QbD) principles, this strategy aims to transition potency evaluation from empirical exploration to a predictive, standardized framework, ultimately streamlining the lifecycle management of RSV mRNA vaccines. Full article

Background/Objectives: We conducted this study to develop a generic amiodarone tablet pharmaceutically equivalent to the reference drug. This development is crucial for securing a stable supply chain for this orphan drug, which currently faces domestic market instability. Amiodarone, a national essential medicine, often experiences unstable supply due to its limited profitability. Methods: To secure this stable supply chain, we employed a factorial design, utilizing a Quality by Design (QbD) approach, to create the most suitable formulation. Initially, we observed a limitation where the formulation exhibited a flowability of 25% based on the Carr’s Index, which exceeded the target of 20%. To address this challenge, we incorporated lactose monohydrate during the pre-mixing stage rather than the post-mixing stage. Subsequently, we identified the binder content and the amount of granulation solvent as Critical Material Attributes (CMAs), and we performed a Design of Experiments (DoE). Result: Based on these investigations, we determined that the optimal prescription utilizes 5.71% povidone K25 and 40 mg/T of purified water. The final formulation successfully achieved an excellent flowability of 15.8%. Furthermore, this formulation showed a dissolution and bioequivalence PK profile equivalent to the reference drug in pH 1.2, 4.0, and 6.8 buffer solutions, each containing 1% Tween 80. Conclusions: Ultimately, the developed formulation is anticipated to establish a stable domestic supply chain and concurrently reduce national healthcare costs. These research findings also establish the groundwork for future continuous manufacturing implementation. Full article

Background/Objectives: Carrier-based dry powder inhaler (DPI) formulations remain the predominant platform for respiratory drug delivery. However, integrated development frameworks that align upstream particle engineering with downstream manufacturing are underdeveloped. This study aimed to develop a comprehensive Quality-by-Design (QbD) strategy that systematically connects jet milling, formulation design, and blending scale-up for carrier-based DPI products containing micronized crystalline active pharmaceutical ingredient (API). Methods: Phenytoin was selected as a model API to investigate process–formulation–performance relationships. Jet milling parameters were optimized to generate three distinct API particle size distributions while monitoring solid-state integrity. A design of experiments (DoE) evaluated the impact of API particle size and lactose fines level on aerodynamic performance (fine particle fraction, FPF) and powder processability (flowability, compressibility). High-shear and low-shear blending techniques were compared, and a novel V-shell blending scale-up methodology was developed based on maintaining particle fall velocity and total strain across multiple scales (one-, two-, and eight-quart). Results: Optimized jet milling produced inhalation grade API particles with controlled amorphous content localized to high-energy processes. DoE analysis identified a design space in which API Dv90 of 2.9–4.5 µm and coarse lactose <96% maximized both aerosolization and blend flowability. Low-shear blending achieved superior lung delivery (FPF 62.6 ± 1.7%) compared with high-shear micing (50.1 ± 1.5%). The particle-velocity-based scale up strategy produced statistically equivalent FPF and ED across all scales (p < 0.01), with content uniformity (RSD ≤ 5%) and variability comparable to commercial DPIs. Conclusions: This integrated QbD framework demonstrates that the co-optimization of particle size engineering, formulation composition, and blending dynamics is essential for achieving robust and scalable DPI products. The approach offers a material-sparing, efficient pathway from API characterization through commercial scale manufacturing and is broadly applicable to respiratory drug development. Full article

Zeolites are microporous aluminosilicate minerals widely recognized for their adsorption and ion-exchange properties. Their capacity to capture toxic heavy metals has prompted growing interest in their use as anti-pollution agents in skin care formulations. This study investigates zeolite-based creams through an in vitro permeation test using Franz diffusion cells within a Quality by Design (QbD) framework. A 2 × 2 × 2 full factorial design was applied to evaluate the effects of three critical factors: membrane type (Strat-M^® vs. silicone), dosage (10 vs. 20 mg), and dosage regimen. The adsorption and retention of five heavy metals, cadmium (Cd), cobalt (Co), chromium (Cr), lead (Pb), and nickel (Ni), were assessed over 12 h using an in vitro membrane model. The cream containing Zeolite demonstrated significantly higher adsorption of Cr, Co, and Cd compared to placebo and membrane controls, while Ni and Pb exhibited less consistent patterns. No sampling of the receptor compartment was performed; therefore, the analysis focused on metal residues in the donor and membrane compartments. Statistical analyses confirmed the significance of these findings, and graphical trends further supported zeolite’s selective adsorption behavior. Overall, the results provide mechanistic and statistical evidence supporting zeolite as a promising active ingredient for the development of anti-pollution skin care formulations and offer a methodological framework for assessing metal adsorption in topical products. Full article

Background/Objectives: Manual preparation of semisolid formulations (creams, ointments, gels) is prone to variability in mixing energy and time, which may compromise uniform API distribution. This study aimed to evaluate an Electronic Mortar and Pestle (EMP; Unguator™) as a standardized compounding tool, with objectives to: (i) validate stability-indicating UHPLC methods; (ii) assess content uniformity across jar strata; (iii) quantify the impact of mixing time and rotation speed via design of experiments (DOE); and (iv) verify cleaning effectiveness and cross-contamination risk. Methods: Five representative formulations were compounded: urea 40%, clobetasol 0.05%, diclofenac 2.5% in hyaluronic acid 3% gel, urea 10% + salicylic acid 1%, and hydroquinone 5%. UHPLC methods were validated per ICH Q2(R2) and stress-tested under acid, base, oxidative, thermal, and UV conditions. Homogeneity was assessed by stratified sampling (top/middle/bottom). A 3² factorial DOE (time: 2/6/10 min; speed: 600/1500/2400 rpm) modeled effects on % label claim and RSD. Cleaning validation employed hydroquinone as a tracer, with swab sampling pre-/post-use and post-sanitization analyzed by HPLC. Results: All UHPLC methods met specificity, linearity, precision, accuracy, and sensitivity criteria and were stability-indicating (Rs ≥ 1.5). Formulations achieved 90–110% label claim with strata CV ≤ 5%. DOE revealed speed as the dominant factor for clobetasol, urea, and diclofenac, while time was more influential for salicylic acid; gels exhibited curvature, indicating diminishing returns at high rpm. Model-predicted optima were implementable on the Unguator™ with minor rounding of rpm/time. Cleaning validation confirmed post-sanitization residues below LOQ and <10 ppm acceptance. Conclusions: The Unguator™ provides a practical, parameter-controlled route for compounding pharmacies to standardize semisolid preparations, achieving reproducible layer-to-layer content uniformity within predefined criteria under the evaluated conditions through programmable set-points and validated cycles. DOE-derived rpm–time relationships define an operational design space within the studied ranges and support selection of implementable device settings and set-points. Importantly, the DOE-derived “optima” in this study are optimized for assay-based content uniformity (mean % label claim and strata variability). Cleaning validation supports a closed, low-cross-contamination workflow, facilitating consistent routines for both routine and complex formulations. Overall, the work implements selected QbD elements (QTPP—Quality Target Product Profile; CQA—Critical Quality Attribute definition; CPP—Critical Process Parameter identification; operational design space; and a proposed control strategy) and should be viewed as a step toward broader lifecycle QbD implementation in compounding. Full article

Background/Objectives: Topical treatment of cutaneous tuberculosis (CTB) requires reliable models to evaluate dermal drug release and diffusion, particularly for fixed-dose combinations (FDCs) with contrasting physicochemical properties. Human skin remains the reference standard but poses ethical, logistical, and reproducibility challenges. This study investigated the suitability of Strat-M^® synthetic membranes as an alternative to human skin for assessing the simultaneous release and diffusion of clofazimine (CFZ) and pyrazinamide (PZA) from a topical FDC, and aimed to develop an optimized dermal emulsion using a Quality-by-Design (QbD)-informed formulation development tool. Methods: Self-emulsifying dermal emulsions containing CFZ and PZA were developed following QbD principles. Preformulation studies included drug solubility screening, oil phase selection, and pseudoternary phase diagram construction to identify stable emulsion regions. Formulations were characterized for droplet size, polydispersity index, zeta potential, viscosity, self-emulsification efficiency, and thermodynamic stability. Eight stable emulsions were identified, of which four were selected for in vitro drug release studies. The peppermint oil-based emulsion (PPO415) was further evaluated in comparative diffusion studies using Strat-M^® membranes and ex vivo human skin (Caucasian and African). Results: PPO415 demonstrated favorable physicochemical properties, including high CFZ solubility, uniform droplet distribution, and suitability for dermal application. Comparative diffusion studies showed that Strat-M^® underestimated the partitioning of lipophilic CFZ while overestimating the diffusion of hydrophilic PZA relative to human skin. These differences were attributed to compositional and structural disparities between synthetic membranes and biological skin. Conclusions: Strat-M^® membranes show potential as a reproducible and ethical in vitro screening tool during early-stage formulation development for topical FDCs. However, ex vivo human skin remains essential for accurately predicting dermal drug distribution and therapeutic performance. Full article

The application of blockchain technology in large-scale sustainable scenarios requires advancement. Therefore, high-performance cross-chain infrastructure is essential for domains like green supply chain management and peer-to-peer renewable energy trading. This study proposes an integrated modeling framework, whose core innovation is the combination of Phase-Type (PH) distribution, the $GI/PH/1$ queuing model, and quasi-birth-and-death (QBD) process theory to systematically describe the multi-stage service and dynamic interactions in a notary-based cross-chain system. This framework overcomes the limitations of traditional models that rely on oversimplified service assumptions. By utilizing matrix-analytic methods, it enables the precise quantification of key performance metrics, such as system throughput, response time, and rejection rate. This research provides a unified, scalable theoretical tool for cross-chain performance evaluation and establishes a methodological foundation for optimizing system resource allocation and sustainable infrastructure design. Full article

Following the discovery of therapeutic molecules and the identification of specific biological targets, preparation of regulatory dossiers entails extensive product development and characterization to support their safety, efficacy, and stability. We have examined the drug development and relevant regulatory considerations related to inhaled biological proteins in the accompanying article. This review focuses on the characterization of locally acting inhaled biological proteins. Drug product characterization is a regulatory requirement, and it ensures drug product safety, efficacy, stability, and usability by the target populations. Together, these two articles provide a comprehensive discussion based on our review and analysis of the available open literature. We have attempted to fill gaps and simulate discussion of challenges following sound scientific pathways. This approach has the prospect of addressing regulatory expectations leading to rapid solutions to unmet medical needs. The robustness of characterization strategies and the development of analytical methods used in the in vitro testing for the evaluation of drug product attributes is assured through application of the Design-of-Experiment (DOE) and Quality-by-Design (QBD) approaches. Drug product characterization entails a variety of in vitro studies evaluating drug products for purity and contamination, and determination of drug delivery by the intended route of administration. Measurement of the proportion of the labeled amount per dose and the form suitable for delivery to the intended target sites is central to this assessment. For respiratory Drug–Device combination products, the testing may vary with the product designs. However, determination of the single-dose content, delivered-dose uniformity, aerodynamic particle size distribution, and device robustness when used by the target populations is common to all combination products. Characterization of aerosol plumes is limited to inhalation aerosols that produce specific aerosol clouds upon actuation. The flow rate dependency of devices is also examined. Product characterization also includes safety-related product attributes such as degradation products and leachables. For inhaled biological proteins, safety-related in vitro testing includes additional testing to assure maintenance of the three-dimensional structural integrity and the sustained biological activity of the drug substance in the formulation, during aerosolization and upon deposition. This article discusses various tests employed for regulatory-compliant product characterization. In addition, the stability testing and handling of possible changes during product development and post-approval are discussed. Full article

Background: Solid organ transplantation (SOT) is a life-saving treatment for patients with end-stage diseases and/or organ failure. However, access to healthy organs is often limited by challenges in organ preservation. Furthermore, upon transplantation, ischemia–reperfusion injury (IRI) can lead to increased organ rejection or graft failures. The work presented aims to address both challenges using an innovative nanomedicine platform for simultaneous drug and oxygen delivery. In recent studies, resveratrol (RSV), a natural antioxidant, anti-inflammatory, and reactive oxygen species (ROS) scavenging agent, has been reported to protect against IRI by inhibiting ferroptosis. Here, we report the design, development, and scalable manufacturing of the first-in-class dual-function perfluorocarbon-nanoemulsion (PFC-NE) perfusate for simultaneous oxygen and antioxidant delivery, equipped with a near-infrared fluorescence (NIRF) reporter, longitudinal, non-invasive NIRF imaging of perfusate flow through organs/tissues during machine perfusion. Methods: A Quality-by-Design (QbD)-guided optimization was used to formulate a triphasic PFC-NE with 30% w/v perfluorooctyl bromide (PFOB). Drug-free perfluorocarbon nanoemulsions (DF-NEs) and RSV-loaded nanoemulsions (RSV-NEs) were produced at 250–1000 mL scales using M110S, LM20, and M110P microfluidizers. Colloidal attributes, fluorescence stability, drug loading, and RSV release were evaluated using DLS, NIRF imaging, and HPLC, respectively. PFC-NE oxygen loading and release kinetics were evaluated during perfusion through the BMI OrganBank^® machine with the MEDOS HILITE^® oxygenator and by controlled flow of oxygen. The in vitro antioxidant activity of RSV-NE was measured using the oxygen radical scavenging antioxidant capacity (ORAC) assay. The cytotoxicity and ferroptosis inhibition of RSV-NE were evaluated in RAW 264.7 macrophages. Results: PFC-NE batches maintained a consistent droplet size (90–110 nm) and low polydispersity index (<0.3) across all scales, with high reproducibility and >80% PFOB loading. Both DF-NE and RSV-NE maintained colloidal and fluorescence stability under centrifugation, serum exposure at body temperature, filtration, 3-month storage, and oxygenation. Furthermore, RSV-NE showed high drug loading and sustained release (63.37 ± 2.48% at day 5) compared with the rapid release observed in free RSV solution. In perfusion studies, the oxygenation capacity of PFC-NE consistently exceeded that of University of Wisconsin (UW) solution and demonstrated stable, linear gas responsiveness across flow rates and FiO₂ (fraction of inspired oxygen) inputs. RSV-NE displayed strong antioxidant activity and concentration-dependent inhibition of free radicals. RSV-NE maintained higher cell viability and prevented RAS-selective lethal compound 3 (RSL3)-induced ferroptosis in murine macrophages (macrophage cell line RAW 264.7), compared to the free RSV solution. Morphological and functional protection against RSL3-induced ferroptosis was confirmed microscopically. Conclusions: This study establishes a robust and scalable PFC-NE platform integrating antioxidant and oxygen delivery, along with NIRF-based non-invasive live monitoring of organ perfusion during machine-supported preservation. These combined features position PFC-NE as a promising next-generation acellular perfusate for preventing IRI and improving graft viability during ex vivo machine perfusion. Full article

Methoxy radicals (CH₃O•), formed as intermediates during methane oxidation, may play an underexplored but locally significant role in the atmospheric oxidation of dimethyl sulfide (DMS), a key sulfur-containing compound emitted primarily by marine phytoplankton. This study presents a comprehensive computational investigation of the reaction mechanisms and kinetics of DMS oxidation initiated by CH₃O•, using density functional theory B3LYP-D3(BJ)/6-311++G(3df,3pd), CCSD(T)/6-311++G(3df,3pd), and UCBS-QB3 methods. Our calculations show that DMS reacts with CH₃O• via hydrogen atom abstraction to form the methyl-thiomethylene radical (CH₃SCH₂•), with a rate constant of 3.05 × 10⁻¹⁶ cm³/molecule/s and a Gibbs free energy barrier of 14.2 kcal/mol, which is higher than the corresponding barrier for reaction with hydroxyl radicals (9.1 kcal/mol). Although less favorable kinetically, the presence of CH₃O• in localized, methane-rich environments may still allow it to contribute meaningfully to DMS oxidation under specific atmospheric conditions. While the short atmospheric lifetime of CH₃O• limits its global impact on large-scale atmospheric sulfur cycling, in marine layers where methane and DMS emissions overlap, CH₃O• may play a meaningful role in forming sulfur dioxide and downstream sulfate aerosols. These secondary organic aerosols lead to cloud condensation nuclei (CCN) formation, subsequent changes in cloud properties, and can thereby influence local radiative forcing. The study’s findings underscore the importance of incorporating CH₃O• driven oxidation pathways into atmospheric models to enhance our understanding of regional sulfur cycling and its impacts on local air quality, cloud properties and radiative forcing. These findings provide mechanistic insights that improve data interpretation for atmospheric models and extend predictions of localized variations in sulfur oxidation, aerosol formation, and radiative forcing in methane-rich environments. Full article

Cosmeceuticals are cosmetic formulations that are intended to alleviate skin conditions that affect its appearance and functionality. They are not considered medications but contain molecules that exert biological action on the skin beyond traditional cosmetic actions. Sometimes, the bioactives used have limitations for transdermal passage, and it has been suggested that the use of nanocarriers can increase the effectiveness of cosmeceutical products. The degree of sophistication of nanocosmeceuticals requires that safety and efficacy aspects be verified before going on the market. In this regard, the application of the Quality by Design (QbD) approach during product development ensures that products meet the consumer needs in full. This review analyzes the implementation of QbD in the development of nanocosmeceuticals, considering the main characteristics of the most used bioactive groups and nanocarriers that have proven to be ideal vehicles for topical and transdermal applications. Full article

Introduction: In this study, we aimed to optimize the microfluidizer-based preparation of poly(lactic-co-glycolic acid) nano-micelles (PLGANM), increasingly used for parenteral delivery of poorly water-soluble drugs but typically exhibiting poor physical stability when produced by conventional methods. Method: By systematically tuning microfluidization (MFZ) parameters, we demonstrate an efficient strategy to enhance PLGANM stability and ensure robust, scalable manufacturing, relevant for long-term storage and clinical translation applications. The influence of several key factors designed by Central Composite Design (CCD), including the amount of PLGA and Tween 80, homogenization pressure, and number of passes of MFZ on the size, polydispersity (measured by DLS), and hence stability of the PLGANM, was analyzed for 60 days. 60 PLGANMs produced by the MFZ method (PMFZ) were compared with the PLGANM consisting of equivalent amounts of PLGA and T80 produced using the traditional oil-in-water method (POW). Desired limits were set to minimize standard deviations for Z-average, Zeta Potential, and PDI. Results: Coded variables for optimized PMFZ (OPMFZ) were found to be 82.96 mg PLGA, 6.78 mL 5% T80, 11,000 psi pressure, and 1 pass. Conclusions: This study demonstrates that microfluidization, when guided by a QbD framework, offers precise control over particle attributes and enables reproducible production of stable PLGANM. Full article