AF4-to-SAXS: expanded characterization of nanoparticles and proteins at the P12 BioSAXS beamline.

Biological small-angle X-ray scattering (SAXS) is a versatile and powerful technique for investigating the structural and biophysical properties of biologically and pharmaceutically relevant macromolecules and nanoparticles. SAXS offers detailed insights into macromolecular composition, size, shape and internal structure, while addressing key aspects such as oligomeric state, stability, molecular interactions, and conformational flexibility. Recently, asymmetrical-flow field-flow fractionation (AF4) was successfully coupled to SAXS, enabling online size-based fractionation and analysis of polydisperse samples.

Assessing Impact of Food on Oral Drug Bioequivalence Supporting ICH M13 A with the Advancements of Physiologically Based Pharmacokinetic Modeling.

On October 12, 2023, the U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a public workshop on "Advances in PBPK Modeling and its Regulatory Utility for Oral Drug Product Development", which highlighted significant strides in physiologically based pharmacokinetic (PBPK) modeling, particularly its application in the regulatory decision-making processes.

Food Effect and Formulation: How Soluble Fillers Affect the Disintegration and Dissolution of Tablets in Viscous Simulated Fed State Media.

The food-induced viscosity of the media can alter tablet disintegration and eventually the release of the drug it contains. The extent of this retardation depends on tablet formulation factors, such as the solubility of its excipients. : This research aimed to study the effect of filler solubility on the disintegration and dissolution of tablets under different testing conditions.

Direct structural investigation of pH responsiveness in mRNA lipid nanoparticles: Refining paradigms.

Using small angle X-ray scattering measurements, structural coherencies in lipid nanoparticle (LNP) formulations comprising messenger RNA (mRNA) were elucidated in response to pH changes and as a function of RNA to lipid ratio. Formulations were assembled using selected ionizable lipids with well-known activity from previous experiments, with otherwise identical composition. Several structural parameters were determined, including internal organization, fraction of ordered material, the underlying repeating distance, and the fractal dimension of the overall particles.

Model-Supported dissolution methods for Modified-Release Products: Enteric-coated versus extended-release ketoprofen tablets.

Drug product development is often a challenging endeavor. However, model-supported dissolution test design trained by appropriate in silico models can lead to considerable reduction in the riskoffailure. Dissolution models have revealed that dissolution of poorly soluble ionizable pharmaceutical particles is slower in biorelevant bicarbonate than compendial buffers.

A new model for ionizable drug dissolution in intestinal bicarbonate buffer.

In order to achieve the desired effect in vivo, drugs taken orally must first be dissolved in the gastrointestinal tract. With the majority of the commercially available drugs having acidic and/or basic groups, ionization and intestinal buffering are important factors underlying adequate dissolution and, accordingly, bioavailability. The aim of this work was therefore to develop a dissolution model that properly takes these factors into account when dealing with the intestinal bicarbonate buffer.

Biowaiver monographs for immediate-release solid oral dosage forms: Voriconazole.

According to the ICH M9 Guideline, the triazole antifungal voriconazole is a Biopharmaceutics Classification System (BCS) class II drug, being highly soluble at the highest dose strength but not at the highest single dose. Although the ICH M9 allows for consideration of BCS-based biowaivers in such cases, voriconazole does not meet the additional requirement of dose proportional pharmacokinetics (PK) over the therapeutic dose range. By contrast, if the classification were based on the FDA solubility criteria that were in place prior to ICH M9 (based on the highest dose strength), voriconazole would belong to BCS class I and thus qualify for the BCS-based biowaiver.

Biowaiver monographs for immediate-release solid oral dosage forms: Lemborexant.

Lemborexant is a dual orexin receptor antagonist assigned to class II of the Biopharmaceutics Classification System (BCS). Thus, the ICH M9 Guideline excludes immediate-release (IR) solid oral dosage forms containing lemborexant from BCS-based biowaivers, irrespective of their in vitro dissolution behavior. By contrast, classification of lemborexant according to the refined Developability Classification System (rDCS) falls into class I, indicating few biopharmaceutics risks.

Dissimilar ferric derisomaltose formulations - In vitro comparisons between an originator and its intended similars.

Background: The complex nature of intravenous (IV) iron formulations makes manufacturing and characterising similars challenging. This study examined whether simple in vitro tests can distinguish the high-dose IV iron formulation, Monofer® (ferric derisomaltose [FDI]), from the first intended copies of FDI, Rapifer® (FDI intended similar A [FDIIS-A]) and Tosiron® (FDI intended similar B [FDIIS-B]), approved in India and Pakistan, respectively. Neither intended similar is available in Europe or the United States.

Microneedle-enhanced drug delivery: fabrication, characterization, and insights into release and permeation of nanocrystalline imiquimod.

Transcutaneous delivery systems bear several advantages over conventional needle-based injections. Considering the low bioavailability and poor water-solubility of imiquimod, a manufacturing process has been developed to incorporate imiquimod as suspended nanocrystals in different formulations. In this study, three formulations - fast-dissolving microneedle arrays that contain nanocrystalline imiquimod in a poly (vinyl)alcohol matrix and two semisolid preparations-were characterized and compared.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Fexofenadine.

In this monograph, the potential use of methods based on the Biopharmaceutics Classification System (BCS) framework to evaluate the bioequivalence of solid immediate-release (IR) oral dosage forms containing fexofenadine hydrochloride as a substitute for a pharmacokinetic study in human volunteers is investigated. We assessed the solubility, permeability, dissolution, pharmacokinetics, pharmacodynamics, therapeutic index, bioavailability, drug-excipient interaction, and other properties using BCS recommendations from the ICH, FDA and EMA. The findings unequivocally support fexofenadine's classification to BCS Class IV as it is neither highly soluble nor highly permeable.

Solubility vs Dissolution in Physiological Bicarbonate Buffer.

Background: Phosphate buffer is often used as a replacement for the physiological bicarbonate buffer in pharmaceutical dissolution testing, although there are some discrepancies in their properties making it complicated to extrapolate dissolution results in phosphate to the in vivo situation. This study aims to characterize these discrepancies regarding solubility and dissolution behavior of ionizable compounds.

Methods: The dissolution of an ibuprofen powder with a known particle size distribution was simulated in silico and verified experimentally in vitro at two different doses and in two different buffers (5 mM pH 6.

Aerosol Plumes of Inhalers Used in COPD.

Introduction: The selection of inhaler device is of critical importance in chronic obstructive pulmonary disease (COPD) as the interaction between a patient's inhalation profile and the aerosol characteristics of an inhaler can affect drug delivery and lung deposition. This study assessed the in vitro aerosol characteristics of inhaler devices approved for the treatment of COPD, including a soft mist inhaler (SMI), pressurized metered-dose inhalers (pMDIs), and dry powder inhalers (DPIs).

Methods: High-speed video recording was used to visualize and measure aerosol velocity and spray duration for nine different inhalers (one SMI, three pMDIs, and five DPIs), each containing dual or triple fixed-dose combinations of long-acting muscarinic receptor antagonists and long-acting β-agonists, with or without an inhaled corticosteroid.

Tumor-infiltrating CCR2 inflammatory monocytes counteract specific immunotherapy.

Tumor development and progression is shaped by the tumor microenvironment (TME), a heterogeneous assembly of infiltrating and resident host cells, their secreted mediators and intercellular matrix. In this context, tumors are infiltrated by various immune cells with either pro-tumoral or anti-tumoral functions. Recently, we published our non-invasive immunization platform DIVA suitable as a therapeutic vaccination method, further optimized by repeated application (DIVA).

Quantitative size-resolved characterization of mRNA nanoparticles by in-line coupling of asymmetrical-flow field-flow fractionation with small angle X-ray scattering.

We present a generically applicable approach to determine an extensive set of size-dependent critical quality attributes inside nanoparticulate pharmaceutical products. By coupling asymmetrical-flow field-flow fractionation (AF4) measurements directly in-line with solution small angle X-ray scattering (SAXS), vital information such as (i) quantitative, absolute size distribution profiles, (ii) drug loading, (iii) size-dependent internal structures, and (iv) quantitative information on free drug is obtained. Here the validity of the method was demonstrated by characterizing complex mRNA-based lipid nanoparticle products.

Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejection.

Introduction: Transcutaneous immunization (TCI) is a non-invasive vaccination method promoting strong cellular immune responses, crucial for the immunological rejection of cancer. Previously, we reported on the combined application of the TLR7 agonist imiquimod (IMQ) together with the anti-psoriatic drug dithranol as novel TCI platform DIVA (dithranol/IMQ based vaccination). In extension of this work, we further optimized DIVA in terms of drug dose, application pattern and established a new IMQ formulation.

Polysarcosine-Functionalized mRNA Lipid Nanoparticles Tailored for Immunotherapy.

Lipid nanoparticles (LNPs) have gained great attention as carriers for mRNA-based therapeutics, finding applications in various indications, extending beyond their recent use in vaccines for infectious diseases. However, many aspects of LNP structure and their effects on efficacy are not well characterized. To further exploit the potential of mRNA therapeutics, better control of the relationship between LNP formulation composition with internal structure and transfection efficiency in vitro is necessary.

Quality by Design (QbD) Approach for a Nanoparticulate Imiquimod Formulation as an Investigational Medicinal Product.

The present article exemplifies the application of the concept of quality by design (QbD) for the systematic development of a nanoparticulate imiquimod (IMQ) emulsion gel formulation as an investigational medicinal product (IMP) for evaluation in an academic phase-I/II clinical trial for the treatment of actinic keratosis (AK) against the comparator Aldara (EudraCT: 2015-002203-28). The design of the QbD elements of a quality target product profile (QTPP) enables the identification of the critical quality attributes (CQAs) of the drug product as the content of IMQ, the particle-size distribution, the pH, the rheological properties, the permeation rate and the chemical, physical and microbiological stability. Critical material attributes (CMAs) and critical process parameters (CPPs) are identified by using a risk-based approach in an Ishikawa diagram and in a risk-estimation matrix.

Novel food drug interaction mechanism involving acyclovir, chitosan and endogenous mucus.

Drug absorption from drug products may be affected by pharmaceutical excipients and/or food additives through different mechanisms. Chitosan is a recognized nutraceutical, with potential as an excipient due to its permeability enhancer properties. While chitosan properties have been evaluated in in vitro and pre-clinical models, studies in humans are scarce.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Levocetirizine Dihydrochloride.

Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for pharmacokinetic studies in human volunteers to appraise the bioequivalence of immediate-release (IR) oral, solid dosage forms containing levocetirizine dihydrochloride was investigated, using data from the literature and in-house testing. Levocetirizine's solubility and permeability properties, as well as its dissolution from commercial products, its therapeutic uses, therapeutic index, pharmacokinetics and pharmacodynamic traits, were reviewed in accordance with the BCS, along with any reports in the literature about failure to meet bioequivalence (BE) requirements, bioavailability issues, drug-excipient interactions as well as other relevant information.

Biowaiver Monograph for Immediate-Release Dosage Forms: Levamisole Hydrochloride.

This work describes the potential applicability of the BCS-based Biowaiver to oral solid dosage forms containing Levamisole hydrochloride, an anthelmintic drug on the WHO List of Essential Medicines. Solubility and permeability data of levamisole hydrochloride were searched in the literature and/or measured experimentally. Levamisole hydrochloride is a highly soluble drug, but there is no clear evidence of high permeability in humans, indicating that it should provisionally be assigned to BCS class III.