Canine Mdr1 Knockout MDCK Cells Reliably Estimate Human Small Intestinal Permeability () and Fraction Absorbed ().

Human intestinal permeability is a key determinant of the oral fraction absorbed () of active pharmaceutical ingredients (APIs). This study evaluated the ability of an in-house canine Mdr1 (cMdr1) knockout (KO) Madin-Darby Canine Kidney (MDCK) cell line to correlate apparent permeability () with human small intestinal permeability (). values of 16 reference compounds with high, medium, or low permeabilities were measured in the in-house cMdr1 KO MDCK protocol under pH gradient (6.

pH-stat versus pH-shift lipolysis model: Exploring in vitro-in vivo relationships for lipid-based formulations of nilotinib.

The pH stat in vitro lipolysis method is well established for evaluating lipid-based formulations (LBFs), however the absence of a simulated gastrointestinal transition may lead to an overestimation of drug precipitation particularly in the case of weakly basic drugs. This study aimed to compare the conventional pH-stat method with a pH-shift lipolysis approach by evaluating a diverse set of LBFs using nilotinib, a weakly basic model drug. Additionally, the study sought to assess in vitro-in vivo relationships (IVIVRs) and enhance understanding of the predictive capabilities of these models.

Development of highly concentrated bedaquiline suspensions for usage as long-acting injectable formulations.

Tuberculosis (TB) remains a global health problem with an enormous treatment burden and poor treatment adherence, contributing to the emergence of drug resistance. This study investigated the potential of formulating a highly concentrated long-acting injectable (LAI) formulation with bedaquiline fumarate, which could potentially be used as a novel long-term treatment strategy against TB and the prevention of drug resistance. Using wet media milling, micro- and nanosuspensions of bedaquiline fumarate were prepared and evaluated to determine a suitable stabilizer, drug loading capacity, short- and long-term particle size stability, and pharmacokinetic behavior in rats.

A novel combined lipolysis-permeation screening approach in 96-well format: Method development using type I lipid-based formulations.

For release testing of lipid-based formulations (LBFs), lipid digestion using the pH-stat approach is widely used despite the fact that it is a laborious exercise and predictivity towards in vivo performance could not be demonstrated. A probable reason is the lack of differentiation between readily absorbable (molecularly dissolved) and less absorbable (colloid associated) drug fractions. This work describes the development and testing of an alternative approach designed to address both issues of the pH-stat method, the labor-intensive nature and the limited ability to estimate in vivo behavior.

Selecting a non-interacting buffer for α-cyclodextrin containing solutions.

Many active pharmaceutical ingredients suffer from poor water solubility, short plasma half-life, low permeability, or limited chemical stability in aqueous solutions, posing significant challenges for drug formulation. Cyclodextrins (CDs) can form inclusion complexes with various drugs, enhancing both their solubility and chemical stability in aqueous environments. In pharmaceutical formulations, pH control is crucial, and buffers are commonly used to maintain solution stability.

Guiding excipient selection for amorphous solid dispersions by combining an in vitro-in-silico approach - II: Supersaturation and drug release.

There is a growing industrial need for quick and early screening of amorphous solid dispersions (ASDs). While new technologies are emerging, including in-silico predictions and high-throughput experimentation, a significant gap exists due to a lack of comparative data. The aim of this work was thus to compare experimental data with calculations obtained by the Conductor like Screening Model for Real Solvents (COSMO-RS).

Versatile and sensitive dual-detection HPLC method for rapid quantification of apomorphine hydrochloride: application to ex vivo percutaneous permeation and deposition studies utilising novel transdermal pressure-sensitive adhesive patches.

Conventional delivery of apomorphine hydrochloride (APO) for management of 'OFF' periods in Parkinson's disease is limited to subcutaneous or sublingual delivery, and would substantially benefit from a transdermal drug delivery system (TDDS). Minimal progression has been made thus far in this area, with current literature presenting debatably flawed or inconsistent experimental design for ex vivo percutaneous permeation and deposition studies, a crucial step in understanding TDDS performance. Provided here is an improved, robust, versatile and easily-transferred analytical methodology, fully validated in accordance with guidelines provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH).

Application of Solvent Evaporation to Generate Supersaturated Lipid-Based Formulations: Investigation of Drug Load and Formulation Quality.

Lipid-based formulations (LBFs) are enabling formulations for poorly water-soluble, mostly lipophilic drugs. In LBFs, the drug is pre-dissolved in the formulation which can consist of lipids, surfactants, and/or cosolvents. In cases where the administration of high amounts of a drug is required, exceeding the drug solubility in the lipidic vehicle at the administration temperature, supersaturated LBFs are an option.

Detailed physicochemical characterization of charged and neutral LeciPlex®: loading efficiency and in vitro activity of Voriconazole and Amphotericin B.

In the present study, Voriconazole (VCNZ) and Amphotericin B (AmpB), drugs from BCS class II and IV, respectively, were selected for loading in phospholipid vesicular system, LeciPlex® fabricated by the nanoprecipitation method. The influence of biocompatible solvent and lipid type on VCNZ and AmpB loading in cationic, anionic, and nonionic LeciPlex® was studied for particle size, size distribution, and encapsulation efficiency. Transmission electron microscopy revealed the formation of vesicular systems in the blank, VCNZ, and AmpB-loaded LeciPlex®.

Guiding excipient selection for physically stable amorphous solid dispersions: A combined in-vitro in-silico approach.

Fast screening of amorphous solid dispersions (ASDs) is a need in the pharmaceutical industry. To support this, several emerging technologies have been developed ranging from in-silico prediction to miniaturized high-throughput experimentation. However, a notable challenge lies in the absence of comparative data.

Absorption of cinnarizine from type IIIb lipid-based formulations: Impact of supersaturation, digestion and precipitation inhibition.

In line with previous studies using a similar protocol for the more lipophilic type I, type II and type IIIa lipid-based formulations (LBFs), the impact of supersaturation, lipase inhibition, and precipitation inhibition on type IIIb LBFs containing the poorly water soluble drug cinnarizine was investigated after oral administration to rats. Supersaturated type IIIb LBFs outperformed non-supersaturated LBFs, with statistically significant 58 - 124 % increases in the area under the curve (AUC) and 26 - 82 % increases in the maximal plasma concentration (C), which also were significant in most cases. The advantage of supersaturated LBFs in terms of AUC vanished upon dose-normalization, but C still tended to be higher for the supersaturated formulations.

Can the pH-stat lipolysis model be used to assess the performance of supersaturated lipid-based type I formulations?

A recent in vivo study investigated the impact of supersaturation, lipid chain length, and lipase- and precipitation inhibition on the oral absorption of cinnarizine from type I Lipid-based formulations (LBFs). The aim of the current work was to investigate these formulations using the pH-stat lipolysis model, a well-established method for in vitro investigation of LBFs. This method allows the determination of the extent of lipolysis and of the drug distribution during lipolysis.

Exploring supersaturated type IV lipid-based formulations: Impact of supersaturation, digestion and precipitation wInhibition on cinnarizine absorption.

Building up on previous publications for type I, II, IIIa, and IIIb Lipid-based formulations (LBFs), the supersaturation potential for cinnarizine in type IV LBFs and the effect of supersaturation, lipid digestion, and precipitation inhibition in vivo was investigated. The supersaturation potential for cinnarizine-loaded type IV LBFs was high and this was investigated in vivo in rats. Supersaturated LBFs tended to show higher drug exposures in vivo than their non-supersaturated counterparts (22 - 92 % increase in AUC, not dose-normalized), but this was only statistically significant for the formulation containing a precipitation inhibitor under lipase-inhibited conditions, so the overall impact was limited.

Continuing along the lipid formulation classification system: Effects of lipid chain length, supersaturation, digestion, and precipitation inhibition on cinnarizine absorption from type IIIa lipid-based formulations.

Lipid-based formulations (LBFs) are classified according to the content of each component and the hydrophilicity of the surfactant into types I - IV, with LBFs type IIIa consisting of 40 - 80 % oils, 20 - 40 % water-soluble surfactant with HLB > 12, and 0 - 40 % cosolvents. In cases where high drug loads are required, e.g.

Long-term versus short-term stress physical stability assessment of pharmaceutical nano- and microsuspensions.

The physical stability of nano- and microsuspensions is a crucial factor to consider during formulation investigation and optimization. Short-term stress studies are often used as predictive studies to evaluate the long-term physical stability of pharmaceutical suspensions. The short-term stress stability of cinnarizine suspensions prepared with dual centrifugation (1 mL scale) was therefore compared to the long-term storage stability, i.

Evaluating polymer influence on resuspendability of indomethacin suspensions produced by microfluidization.

Long-acting injectables improve treatment outcomes for chronic diseases by reducing dosing frequency. Long-acting injectables may be formulated as nano- or microsuspensions produced by wet bead milling and homogenization often facing physical instability. This study investigates different stabilizers' ability to prevent particle growth, caking and the influence on resuspendability.

Mixed dry reverse micelles: potential carriers for oral protein delivery via SEDDS.

The aim of this study was to evaluate the potential of mixed dry reverse micelles (dRMs) to increase the lipophilicity of therapeutic proteins and allow their incorporation into self-emulsifying drug delivery systems (SEDDS). Horseradish peroxidase (HRP) was incorporated in mixed dRMs, forming HRP-dRMs, using soybean phosphatidylcholine (SPC) and sodium docusate (SD) as surfactants. HRP-dRMs were characterized with respect to their distribution coefficient and stability in simulated physiological fluids.

Advancing Inflammatory Bowel Disease Treatment by Targeting the Innate Immune System and Precision Drug Delivery.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, involves chronic inflammation of the gastrointestinal tract. Current immune-modulating therapies are insufficient for 30-50% of patients or cause significant side effects, emphasizing the need for new treatments. Targeting the innate immune system and enhancing drug delivery to inflamed gut regions are promising strategies.

Optimizing hydrophilic drug incorporation into SEDDS using dry reverse micelles: a comparative study of preparation methods.

Aim: It was the aim of this study to compare two different dry reverse micelle (RM) preparation methods for the incorporation of hydrophilic drugs into oral self-emulsifying drug delivery systems (SEDDS).

Methods: Cationic ethacridine lactate, anionic fluorescein sodium salt and the antibiotic peptide bacitracin were solubilized in RM containing sodium docusate, soy phosphatidylcholine and sorbitan monooleate in highly lipophilic oils such as squalane. In the dry addition (DA) method, drugs were directly added to empty RM in their powder form.

Two in One: Size Characterization and Accelerated Short-Term Physical Stability of Dual-Drug Suspensions with Two Acidic Compounds (Indomethacin and Naproxen).

Co-delivering dual-drug systems have proven to be effective in, for example, anticancer therapy or HIV prophylaxis due to a higher target selectivity and therapeutic efficacy from compound synergism. However, various challenges regarding physical stability can arise during the formulation definition when multiple drug compounds are included in the same formulation. In this work, the focus was on aqueous suspensions, which could be applied as long-acting injectable formulations to release the drug compounds over weeks to months after administration.

Advantages of the refined developability classification system in early discovery.

Rat pharmacokinetic studies are commonly utilized in early discovery to support absorption, distribution, metabolism, and excretion optimization of active pharmaceutical ingredients (APIs). The aim of this work was to compare exposures from fit-for-purpose oral suspension and solution formulations in rats to guidance provided by the refined Developability Classification System (rDCS) with respect to identifying potential limits to oral absorption, formulation strategy selection, and to optimize oral bioavailability (BA). This investigation utilized six diverse APIs covering a large range of biorelevant solubility, metabolic stability, and oral BA in rats.

Hydrophobic ion pairing: lipophilicity improvement of anionic macromolecules by divalent cation mediated complex formation.

The aim of this study was to develop an alternative strategy to sufficiently increase the lipophilicity of anionic model macromolecules (MM) without the use of cationic counterions. Enoxaparin (ENO), insulin (INS) and poly-L-glutamic acid (PLG) were ion paired with anionic surfactants (sodium decanoate (DEC), sodium dodecyl sulfate (SDS), sodium stearate (SS) and sodium octadecyl sulfate (SOS)), mediated by divalent cations such as magnesium, calcium and zinc. Complexes were evaluated regarding their precipitation efficiency and logD.

Machine learning strengthened formulation design of pharmaceutical suspensions.

Many different formulation strategies have been investigated to oppose suboptimal treatment of long-term or chronic conditions, one of which are the nano- and microsuspensions prepared as long-acting injectables to prolong the release of an active pharmaceutical compound for a defined period of time by regulating the size of particles by milling. Typically, surfactant and/or polymers are added in the dispersion medium of the suspension during processing for stabilization purposes. However, current formulation investigations with milling are heavily based on prior expertise and trial-and-error approaches.

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.