Journal of pharmaceutical sciences最新文献

Photostability is a critical factor influencing the quality and safety of drug products. This study presents a novel method to assess the photostability of drug products under indoor LED lighting, complementing certain aspects of but also challenging the limitations within the existing ICH guideline. In particular, the focus on actual indoor lighting is emphasized, contrasting with the guideline's use of only daylight (UV + visible), and the inappropriate use of the illuminance unit lux is critically analysed. Instead, an LED-array-based tool is presented, which provides a deeper understanding of the photostability by determining both its wavelength dependency and threshold. For the specific GLP-1 analogue test drug product used in this study, wavelengths above 590 nm (yellow-red) are safe, while exposure to shorter wavelengths (blue-green) can lead to photodegradation. Finally, practical solutions and pathways are discussed for minimizing photodegradation, including the optimization of lighting conditions and packaging designs, ultimately ensuring the development of safer drug product.

The National Institute for Health and Care Excellence recommend the routine use of topically applied chlorhexidine digluconate (CHX) formulations to eliminate skin microorganisms prior to incision to prevent surgical site infections (SSI). However, CHX exhibits poor permeation through the stratum corneum and consequently is not effective in eliminating all skin microbes, resulting in an increased chance of patients acquiring infection. This study validates an in vitro porcine permeation model (Franz-type diffusion cell) by comparing CHX permeation through the porcine stratum corneum to in vivo human stratum corneum. Tape strips were sampled from the epidermis of both models and CHX distribution and abundance was analysed using time-of-flight secondary ion mass spectrometry (ToF-SIMS) and high performance liquid chromatography (HPLC). Once validated, the in vitro porcine model was used to determine the CHX permeation enhancement abilities of a series of experimental compounds, including R6 polyarginine, glycolic acid and Kolliphor® HS15. The porcine stratum corneum was tape stripped following treatment with these compounds and ToF-SIMS and HPLC was used to analyse permeation enhancement. This research demonstrated the similarity in CHX permeation through in vivo human skin and the in vitro porcine skin permeation model. Using the porcine model, we determined that R6 polyarginine, glycolic acid and Kolliphor® HS15 significantly increased CHX delivery through the entire epidermis. Finally, we demonstrate that our permeation enhancer formulations improve skin antisepsis throughout the stratum corneum whilst causing no additional cytotoxicity to mammalian cells compared to clinical formulations. This research highlights three potential novel CHX formulation strategies for reducing SSI occurrence.

Efficient wound healing requires the design of advanced biomaterials that combine structural integrity, antimicrobial functionality, and the ability to promote tissue regeneration. The paper discusses the development of dual-layer tissue scaffolds (DLS) using poly (lactic acid) (PLA) and amoxicillin (AMOX) nanoparticles at different concentrations (0.5% w/v and 1% w/v). The scaffolds were characterized using scanning electron microscopy (SEM) for morphological analysis, Fourier-transform infrared spectroscopy (FTIR) for chemical interactions, differential scanning calorimetry (DSC) for thermal stability, and tensile testing for mechanical properties. Swelling, degradation, drug release and drug release kinetic analyses were performed. Antibacterial efficacy against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) was performed along with cytocompatibility via MTT assays using fibroblast cells. SEM revealed microporous scaffolds with approximate pore diameters of ∼370 µm for 0.05 AMOX and ∼302 µm for 0.1 AMOX. Mechanical testing demonstrated that tensile strength and strain decrease with increasing drug loading. Antibacterial testing showed activity against S. aureus but limited efficacy against E. coli. MTT assays confirmed cytocompatibility of the scaffold, showing enhanced cell viability for the DLS-0.05 AMOX scaffold. Considering the obtained results, dual-layer tissue scaffolds with antibacterial properties present significant potential for a wide range of wound care applications.

Low adherence to daily oral drug regimens is a significant obstacle in effectively managing chronic therapies like HIV treatment, pre-exposure prophylaxis (PrEP), and contraception. While long-acting injectables eliminate the need for daily compliance, they often require administration by healthcare professionals. To facilitate self-administration of long-acting treatments, we developed a microneedle patch (MNP) for the sustained release of islatravir or levonorgestrel, used for HIV treatment/PrEP or contraception, respectively. The MNPs were produced using a melt-casting technique to quickly create biodegradable polycaprolactone microneedles for continuous drug delivery. The low melting point of polycaprolactone and the high thermal stability of islatravir and levonorgestrel allowed melt casting at 65 °C. Incorporating centrifugation during fabrication improved the attachment of microneedles to the patch backing, making it easier to remove MNPs from the mold and ensuring effective microneedle insertion into skin. The MNPs demonstrated a sustained release of islatravir with roughly first-order release kinetics ∼40 days in vitro. We conclude that MNPs made with a simple melt-casting process can enable prolonged drug release for HIV treatment/PrEP, contraception, and other therapeutic applications.

Biologic drugs require specialized handling to maintain efficacy and safety, yet there is limited data on how healthcare professionals access information and comply with drug handling regulations. A 16-question survey was used to assess professional perspectives on procedures and regulations around biologic drugs handling. The survey yielded 36 valid responses. Participants included pharmacists, nurses, doctors, drug developers, academics and educators, primarily practicing in European countries. Information source and regulatory familiarity varied by professional role: pharmacists prioritized drug registries, doctors and nurses relied more on peer network and institutional guidance, and academics and drug developers utilized scientific literature and data. Respondents across roles recognized EU, national laws, and facility rules as strong influencers of biologic drugs handling procedures and approximately two-thirds reported rare conflicts between national regulations and EU guidance. However, over 90% of participants expressed a need for additional guidelines around drug safety, preparation, administration, with pharmacists recognized as key stakeholder. These findings provide insights into how different healthcare professionals apply information regarding drug handling, underscoring the need for focused, role-specific education, clear instructions, and regulatory guidance. While national and EU regulatory alignment appears strong, clearer guidelines and cross-professional communication could improve patient care, minimize risks, and maintain compliance.

Recombinant adeno-associated virus (rAAV) vectors are prominent vectors for in-vivo gene therapies. However, achieving consistent product quality is a major challenge due to the inherent complexity of their structure and the associated production process. During manufacturing and storage, virus particles are exposed to a variety of stresses, which can have a direct impact on product attributes, thereby potentially also affecting safety and efficacy. Current understanding of stress-induced degradation for rAAVs is still fragmented, both on a mechanistic level and regarding the identification of the most appropriate analytical tools to detect the underlying changes. To address these gaps, the impact of different stress conditions, namely freeze-thaw, elevated temperature, high/low pH and light exposure, was tested on two different serotypes. For this, a comprehensive panel of orthogonal analytical methods was applied to identify significant changes in capsid and genome titer, full-to-total ratio, content of aggregates, payload integrity and post-translational modifications. By correlating this extensive dataset with potency results, this study provides detailed insights into the degradation behavior of the employed rAAVs and the suitability of state-of-the-art analytical techniques to indicate the stability of the product. Overall, substantial differences in stress responses were observed between the two serotypes investigated, and changes in transduction efficiency were mostly represented inadequately at the structural or molecular level by the analytical methods employed. Based on these findings, this study serves as a framework for refining the analytical control strategy of rAAV-based gene therapies and for developing robust, stability-indicating assays.

As a leading vector for gene therapy, recombinant adeno-associated virus (rAAV) has been widely investigated and used. Forced degradation analysis is required to understand the molecular properties and stability of rAAV. In this study, we have applied an analytical anion exchange chromatography (AEX) method to evaluate the degradation behavior of rAAV serotype 8 (rAAV8) stored at a relatively high temperature (40 °C), coupled to orthogonal characterization. This versatile methodology was then used to assess the full-particle (FP) property of rAAV8 after accelerated storage under a wide range of pH conditions (pH 2.5-9.5). Under neutral and basic conditions, prolongation of chromatographic retention and decreases in peak area were identified, and were associated with changes in deamidation-related surface charge, aggregation, and nonspecific adsorption, which is likely caused by the externalization of viral proteins 1 and 2 (VP1/VP2). In contrast, unusual chromatographic variations under acidic conditions were identified, and suggested substantial degradation, including fragmentation and the release of encapsidated DNA, as well as the cleavage of VP1 and VP2. Thus, we have demonstrated the potential of the combined methodology and provided valuable insight into rAAV stability during manufacturing and storage.

Advances in immunotherapies across cancer, vaccines, autoimmunity, and biologics have highlighted the critical need for comprehensive metrics that capture immune dynamics beyond traditional reductionist measures such as antibody levels, lymphocyte counts or cytokine profiles. The concept of an ImmunoScore, a quantitative, algorithmic measure of immune activity, can address the gap by integrating multidimensional data on immune cell composition, localization, activation states, and structural context. Originally developed in oncology to stratify prognosis based on CD3⁺ and CD8⁺ T-cell density and spatial distribution within tumors, ImmunoScore has demonstrated superior predictive value compared to conventional staging systems. With the advent of high-dimensional platforms including single-cell sequencing, spatial transcriptomics, imaging mass cytometry, and systems serology, the ImmunoScore framework has expanded to encompass vaccine-induced signatures, tumor microenvironment profiling, autoimmune disease markers, and in silico modeling of immune responses. This review synthesizes the advances and clinical applications of ImmunoScore across four domains: i) systems immunology in vaccinology, ii) cancer immuno profiling and therapy prediction, iii) autoimmune disease-activity markers, and iv) computational approaches for predicting immune response to biologic therapeutics. We propose that a standardized ImmunoScore can serve as a unifying metric to assess immune competence, guide therapeutic decisions, predict adverse events, and enable precision medicine across diverse clinical settings.

Freezing and thawing are critical steps in the manufacturing of biologics, as they help preserve product quality during storage and transport. However, these processes can also introduce stresses that affect protein stability. This study investigates the representativeness of a scale down device (SDD) developed by SmartFreez® in replicating the stress-time distribution and cryo-concentration profile of larger manufacturing containers (2-liter and 5-liter bottles) under slow freezing and thawing conditions. Additionally, the study evaluates the use of a surrogate solution to predict freezing kinetics, thawing kinetics, stress-time distribution, and protein concentration profiles. Computational fluid dynamics (CFD) simulations were used to design the SDD, and experimental validation was performed under low heat transfer regimes.