European Journal of Pharmaceutical Sciences最新文献

Trazodone is a triazolpyridine derivative approved for the treatment of depression, and currently marketed as oral formulations. The transdermal administration of this drug could reduce side effects, related to peak plasma concentration, and improve patient adherence due to a reduced administration frequency. The aims of this work were: (a) the evaluation of the effect of pH vehicle and permeation enhancers on trazodone permeability across porcine skin ex-vivo; (b) the development and optimization of a transdermal drug delivery system containing trazodone hydrochloride. From the results obtained, it was found that the effect of pH of the vehicle on the permeation of trazodone across the skin is quite complex, because it influences both solubility and partitioning and that the presence of fatty acids in the vehicle has a notable effect on permeation (the enhancement factor obtained was approx. 100). For both the fatty acid selected (oleic and lauric) a parabolic relationship between the transdermal flux and the concentration was found, with an optimum activity in the range 2-3 %. In the second part of the work, different patches were prepared and tested ex-vivo. Overall, the results obtained seem to highlight that drug loading, rather than the components of the adhesive matrix, plays the most relevant role for the permeation of trazodone. The addition of lauric acid, which produced a considerable enhancement in solution, was not effective when included in the patch. The obtained data are promising although probably not clinically relevant for the treatment of depression, but might be interesting for the treatment of insomnia and anxiety disorder, which require much lower doses.

The goal of this research was to augment the deposition of caffeine loaded Transcutol® enriched cerosomes (TECs) gel for efficient topical treatment of cellulite utilizing the sonophoresis technique. Caffeine-loaded TECs were prepared using thin film hydration method applying 2³ factorial design to study the impact of different factors, each with two levels on the entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of the formulated TECs. The studied factors were cetyl trimethyl ammonium bromide (CTAB) amount (mg) (X₁), phosphatidylcholine (PC) amount (mg) (X₂), and Transcutol® amount (mg) (X₃). Design-Expert® software was utilized to determine the optimum TECs formulation. Afterward, the optimum TECs formulation was loaded into a gel and subjected to extra investigations. The optimum TECs formulation was (TEC5) which was prepared using 10 mg of CTAB, 150 mg of PC, and 10 mg of Transcutol®. TEC5 presented EE% of 87.44 ± 0.14 %, PS of 308.60 ± 13.38 nm, PDI of 0.455 ± 0.030, and ZP of 50.20 ± 1.55 mV. TEC5 had a fiber-like morphology, with elongated tubules of ceramide. Further, the optimum TECs formulation showed a high stability profile. Moreover, an in vivo dermatokinetic study showed superior deposition of caffeine from TEC5 gel coupled with the sonophoresis on rat skin compared to TEC5 gel and caffeine gel. Moreover, the histopathological study of TEC5 on rat skin confirmed the non-irritant nature of TEC 5 gel mediated by ultrasonic waves through the skin. Overall, the outcomes exposed the obvious superiority of sonophoresis delivered TECs-gel for topical delivery of caffeine for cellulite management.

Approval of drug products for market registration warrants, among other data, evidence to support their safety and effectiveness in the target populations. The extent of investigations to provide the supporting evidence varies between the new innovator products and their follow-on versions generally referred to as Generic Drugs Products in the United States and Hybrids in the Europe. The new drug applications entail large data sets encompassing both nonclinical and clinical product developments. Safety and effectiveness in man is studied in sequentially phased clinical trials, including post marketing evaluations (Where applicable). However, for the generic/hybrid products the safety and effectiveness are established through determination of bioequivalence in head-to-head comparison between the originator and the follow-ons. Methods for documentation of bioequivalence for drug products that reach target site(s) through systemic circulation are aligned worldwide. However, establishing bioequivalence of orally inhaled drug products is complex as drug delivery to the local site(s) of action is independent of the systemic circulation. Documentation of bioequivalence gets further complicated due to the Drug-Device combination nature of these products. The guidelines for establishment of BE of locally acting orally inhaled drugs products vary among certain geographies. This article examines the scientific underpinning of distinctions and similarities between the US and EU guidelines.

Background

In the European Union, rare diseases are defined as diseases that affect maximum 5 in 10,000 citizens. These diseases are typically associated with a high unmet medical need. To stimulate development and authorisation of medicines for rare diseases (‘orphan conditions’), the European Commission (EC) can grant orphan designations. In order to enable systematic evaluation and communication of the diseases for which designated orphan medicines have (not) been developed and authorised, we aimed to investigate the feasibility of important disease terminology systems for mapping orphan conditions and therapeutic indications.

Methods

We selected all designated orphan medicines that were authorised by the EC during 2022–2023 from the EC's Union Register of medicinal products. For these medicines, we extracted orphan conditions and associated therapeutic indications at initial marketing authorisation. The orphan conditions and separate elements of therapeutic indications such as target disease or condition, severity criteria and target population were assessed for availability in six major disease terminology systems: ICD-10, ICD-11, MedDRA, MeSH, Orphanet nomenclature of rare diseases, and SNOMED CT. Descriptive statistics were used to describe the ability of each disease terminology system to map orphan conditions and elements of therapeutic indications.

Results

During 2022–2023, 37 designated orphan medicines were authorised that were designated for 40 orphan conditions (of which 37 unique) and granted 39 therapeutic indications (of which 37 unique). Overall, SNOMED CT covered most descriptions of orphan conditions (33/37, 89 %) and target diseases or conditions within therapeutic indications (28/37, 76 %). However, when allowing descriptions to be partly included and/or complemented by additional words, SNOMED CT, the Orphanet nomenclature, ICD-11 and MedDRA all had high coverage (92–97 %). Other elements than target diseases or conditions within therapeutic indications were mostly lacking.

Conclusions

Regulatory data concerning orphan conditions and therapeutic indications of designated orphan medicines seem to be best covered by SNOMED CT. However, which disease terminology system best facilitates systematic evaluation and communication about development and authorisation of designated orphan medicines also depends on the specific use case. Given the frequent use of SNOMED CT in healthcare settings, it may also facilitate interoperability between regulatory and healthcare data, while for example ICD-11 may be better suited to generate statistics concerning drug development for rare diseases.

BACE-1 plays a pivotal role in the production of β-amyloid (Aβ) peptides, implicated in Alzheimer's Disease (AD) pathology. We previously described edaravone N-benzyl pyridinium derivatives (EBPDs) that exhibited multifunctional activity against multiple AD targets. In this study we explored the EBPDs BACE-1 inhibitory activity to potentially enhance the compounds therapeutic profile. The EBPDs exhibited moderate BACE-1 inhibitory activity (IC₅₀ = 44.10 µM - 123.70 µM) and obtained IC₅₀ values between 2.0 and 5.8-fold greater than resveratrol, a known BACE-1 inhibitor (IC₅₀ = 253.20 µM), in this assay. Compound 3 was the most potent inhibitor with an IC₅₀ of 44.10 µM and a Ki of 19.96 µM and a mixed-type mode of inhibition that favored binding in a competitive manner. Molecular docking identified crucial interactions with BACE-1 active site residues, supported by 100 ns MD simulations. The study highlighted the EBPDs therapeutic potential as BACE-1 inhibitors and multifunctional anti-AD therapeutic agents.

Drug metabolism in the intestinal wall affects bioavailability of orally administered drugs and is influenced by age. Hence, it is important to fully understand the drug metabolizing capacity of the gut to predict systemic exposure. The aim of this study was to investigate the potential of enteroids as a tool to study CYP3A4/5 -mediated metabolism in both children and adults.

Bioconversion of midazolam, a CYP3A4/5 model substrate, was studied using enteroid monolayers as well as tissue explants in the Ussing chamber, both derived from pediatric [median (range age): 54 weeks (2 days – 13 years), n = 21] and adult (n = 5) tissue. Caco-2 cellular monolayers were employed as controls. In addition, mRNA expression of CYP3A4 was determined in enteroid monolayers (n = 11), tissue (n = 23) and Caco-2 using RT-qPCR.

Midazolam metabolism was successfully detected in all enteroid monolayers, as well as in all tissue explants studied in the Ussing chamber, whereas Caco-2 showed no significant metabolite formation. The extracted fraction of midazolam was similar between enteroid monolayers and tissue. The fraction of midazolam extracted increased with age in enteroid monolayers derived from 0 to 70 week old donors. No statistically significant correlation was observed in tissue likely due to high variability observed and the smaller donor numbers included in the study. At the level of gene expression, CYP3A4 increased with age in tissues (n = 32), while this was not reflected in enteroid monolayers (n = 16). Notably, asymmetric metabolite formation was observed in enteroids and tissue, with higher metabolite formation on the luminal side of the barrier.

In summary, we demonstrated that enteroids can be used to measure CYP3A4/5 midazolam metabolism, which we show is similar as observed in fresh isolated tissue. This was the case both in children and adults, indicating the potential of enteroids to predict intestinal metabolism. This study provides promising data to further develop enteroids to study drug metabolism in vitro and potentially predict oral absorption for special populations as an alternative to using fresh tissue.

Objective

To prepare chitosan-loaded nanoparticles (NPs) that enhance the oral bioavailability of puerarin (Pur) and render it responsive to reactive oxygen species (ROS).

Significance

This research makes substantial progress towards the theory of intelligent drug delivery, offering a new reference for combining Pur with other natural medicinal active ingredients.

Methods

The acylation reaction between chitosan and ROS-sensitive 3-carboxyphenylboronic acid (PBA) was used to synthesise ROS-sensitive phenylboronylated chitosan (PBACS). Subsequently, PBACS-PBA-Pur-NPs and PBACS-TPP-Pur-NPs were prepared via ion gelation after the addition of PBA and sodium tripolyphosphate(TPP), respectively. The physicochemical and functional properties of both NPs were compared, and their differences were preliminarily studied through molecular docking.

Results

Reactive oxygen species-sensitive PBACS was successfully synthesised. Of the two NPs prepared, PBACS-TPP-Pur-NPs had a size of 127.2 ± 0.80 nm, polydispersity index (PDI) of 0.129 ± 0.0008, and an encapsulation rate of 95.75 ± 0.387 %, whereas PBACS-PBA-Pur-NPs had a size of 149.8 ± 0.1414 nm, PDI of 0.389 ± 0.0012, and an encapsulation rate of 91.77 ± 0.279 %. The micromorphology of the PBACS-TPP-Pur-NPs exhibited better physical properties. However, PBACS-PBA-Pur-NPs demonstrated a faster in vitro release and more significant in vitro anti-inflammatory effects. Pharmacokinetically, the AUC_0–24, T_max, and C_max of PBACS-PBA-Pur-NPs were 3.485, 2.117, and 3.339 times higher, respectively, than those of Pur. The AUC_0–24, T_max, and C_max of PBACS-TPP-Pur-NPs were 2.41, 1.33, and 2.03 times higher, respectively, than those of Pur. Molecular simulation revealed that the binding energy of PBACS-PBA-Pur -NPs was approximately −4.34 kcal/mol and that of PBACS-TPP-Pur-NPs was even lower, approximately −5.93 kcal/mol, suggesting that the NPs prepared with TPP are more densely packed than those designed with PBA, resulting in slower and reduced drug release.

Conclusion

The NPs constructed in this study effectively reduced inflammatory factors at the disease site, providing a theoretical and experimental basis for the application of nano drugs in inflammatory disease models. In addition, the molecular docking study of the two NPs offered insights into the relationship between the release and structure of subsequent nano drugs.

Retinoblastoma is the most common pediatric intraocular malignant tumor affecting 1:15 000–1:20 000 live births. Even though the survival rate in developed countries is over 90 %, more efficient treatment options are needed for better vision salvage and reduction of the adverse effects. Therefore, we investigated fluorescein-labeled PL3 peptide targeting properties towards the Y79 retinoblastoma cell line in vitro. Through the application of cellular imaging and flow cytometry techniques, the PL3 peptide exhibited a rapid and specific internalization within Y79 cells, with subsequent translocation to the cell nuclei, showcasing notable accumulation in the nucleoli. This phenomenon was not present in other investigated cell lines and was not observable with similarly charged and length control peptide. However, the exact mechanism behind this Y79 cell line-specific nuclear and nucleolar targeting pattern remains elusive. In the future, this targeting process could facilitate specific treatment modalities of retinoblastoma with PL3 peptide-coupled drug delivery technologies.