European Journal of Pharmaceutical Sciences最新文献

A number of baby wipe formulations contain 2-phenoxyethanol (PE) as a preservative and cetylpyridinium chloride (CPC) as a surfactant with antimicrobial activity. Previously, we reported the skin absorption of PE in porcine skin and human skin in vitro. In the present work, the permeation of PE from preparations with CPC and without CPC was investigated in human skin in vivo. The studies were conducted using Confocal Raman Spectroscopy (CRS) and tape stripping (TS) methods. The CRS studies showed that the area under the curve (AUC) of PE for the formulation with and without CPC were not significantly different (p > 0.05). The TS data indicated no significant difference in the amounts of PE recovered from tapes 1–6 for the preparation with and without CPC (p > 0.05). When comparing the in vitro and in vivo data, a correlation was observed between the cumulative amount of PE permeated through human skin in vitro at 24 h and the AUC as measured by CRS (r² = 0.97). In addition, the cumulative amount of PE permeated through human skin in vitro at 24 h was found to correlate with the amount of PE recovered from tape 1 to 6 in vivo (r² = 0.95). Both CRS and TS techniques demonstrated limitations in assessing the distribution of PE and CPC in the skin in vivo, primarily attributed to the Raman signal intensities of compounds under investigation and the variability in the amount of SC collected by TS. Despite the limitations of CRS and TS, the results from the present study add further insights to the in vitro permeation data. Additionally, the findings of the present study encourage the further development and application of CRS for non-invasive evaluation of topical skin formulations in vivo.

Phenotyping serves to estimate enzyme activities in healthy persons and patients in vivo. Low doses of enzyme-specific substrates are administered, and activities estimated using metabolic ratios (MR, calculated as AUC_metabolite/AUC_parent). We administered the Basel phenotyping cocktail containing caffeine (CYP1A2 substrate), efavirenz (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6) and midazolam (CYP3A) to 36 patients with liver cirrhosis and 12 control subjects and determined free and total plasma concentrations over 24 h. Aims were to assess whether MRs reflect CYP activities in patients with liver cirrhosis and whether MRs calculated with free plasma concentrations (MR_free) provide better estimates than with total concentrations (MR_total). The correlation of MR_total with MR_free was excellent (R² >0.910) for substrates with low (<30 %, caffeine and metoprolol) and intermediate protein binding (≥30 and <99 %, midazolam and omeprazole) but weak (R² <0.30) for substrates with high protein binding (≥99 %, efavirenz and flurbiprofen). The correlations between MR_total and MR_free with CYP activities were good (R² >0.820) for CYP1A2, CYP2C19 and CYP2D6. CYP3A4 activity was reflected better by midazolam elimination than by midazolam MR_total or MR_free. The correlation between MR_total and MR_free with CYP activity was not significant or weak for CYP2B6 and CYP2C9. In conclusion, MRs of substrates with an extensive protein binding (>99 %) show high inter-patient variabilities and do not accurately reflect CYP activity in patients with liver cirrhosis. Protein binding of the probe drugs has a high impact on the precision of CYP activity estimates and probe drugs with low or intermediate protein binding should be preferred.

(Aim)

K_p,uu,BBB values are crucial indicators of drug distribution into the brain, representing the steady-state relationship between unbound concentrations in plasma and in brain extracellular fluid (brainECF). K_p,uu,BBB values < 1 are often interpreted as indicators of dominant active efflux transport processes at the blood-brain barrier (BBB). However, the potential impact of brain metabolism on this value is typically not addressed. In this study, we investigated the brain distribution of remoxipride, as a paradigm compound for passive BBB transport with yet unexplained brain elimination that was hypothesized to represent brain metabolism.

(Methods)

The physiologically-based LeiCNS pharmacokinetic predictor (LeiCNS-PK model) was used to compare brain distribution of remoxipride with and without Michaelis-Menten kinetics at the BBB and/or brain cell organelle levels. To that end, multiple in-house (IV 0.7, 3.5, 4, 5.2, 7, 8, 14 and 16 mg kg^-1) and external (IV 4 and 8 mg kg^-1) rat microdialysis studies plasma and brainECF data were analysed.

(Results)

The incorporation of active elimination through presumed brain metabolism of remoxipride in the LeiCNS-PK model significantly improved the prediction accuracy of experimentally observed brainECF profiles of this drug. The model integrated with brain metabolism in both barriers and organelles levels is named LeiCNS-PK3.5.

(Conclusion)

For drugs with K_p,uu,BBB values < 1, not only the current interpretation of dominant BBB efflux transport, but also potential brain metabolism needs to be considered, especially because these may be concentration dependent. This will improve the mechanistic understanding of the processes that determine brain PK profiles.

High-shear (HS) melt granulation and hot melt extrusion (HME) were compared as perspective melt-based technologies for preparation of amorphous solid dispersions (ASDs). ASDs were prepared using mesoporous carriers (Syloid^Ⓡ 244FP or Neusilin^Ⓡ US2), which were loaded with carvedilol dispersed in polymeric matrix (polyethylene glycol 6000 or Soluplus^Ⓡ). Formulations with high carvedilol content were obtained either by HME (11 extrudates with polymer:carrier ratio 1:1) or HS granulation (6 granulates with polymer:carrier ratio 3:1).

DSC and XRD analysis confirmed the absence of crystalline carvedilol for the majority of prepared ADSs, thus confirming the stabilizing effect of selected polymers and carriers over amorphous carvedilol. HME produced larger particles compared to HS melt granulation, which was in line with better flow time and Carr index of extrudates. Moreover, SEM images revealed smoother surface of ASDs obtained by HME, contributing to less obstructed flow. The rougher and more porous surface of HS granules was correlated to larger granule specific surface area, manifesting in faster carvedilol release from Syloid^Ⓡ 244FP-based granules, as compared to their HME counterparts. Regarding dissolution, the two HS-formulations performed superior to pure crystalline carvedilol, thereby confirming the suitability of HS melt granulation for developing dosage forms with improved carvedilol dissolution.

The advanced age population may be susceptible to an increased risk of adverse effects due to increased drug exposure after oral dosing. Factors such as high-interindividual variability and lack of data has led to poor characterization of absorption's role in pharmacokinetic changes in this population. Physiologically based pharmacokinetic (PBPK) models are increasingly being used during the drug development process, as their unique qualities are advantageous in atypical scenarios such as drug-drug interactions or special populations such as older people. Along with relying on various sources of data, auxiliary tools including parameter estimation and sensitivity analysis techniques are employed to support model development and other applications. However, sensitivity analyses have mostly been limited to localized techniques in the majority of reported PBPK models using them. This is disadvantageous, since local sensitivity analyses are unsuitable for risk analysis, which require assessment of parametric interactions and proper coverage of the input space to better estimate and subsequently mitigate the effects of the phenomenon of interest. For this reason, this study seeks to integrate a global sensitivity analysis screening method with PBPK models based in PK-Sim® to characterize the consequences of potential changes in absorption that are often associated with advanced age. The Elementary Effects (Morris) method and visualization of the results are implemented in R and three model drugs representing Biopharmaceutical Classification System classes I-III that are expected to exhibit some sensitivity to three age-associated hypotheses were successfully tested.

The aim of this study was to investigate the impact of genetic polymorphisms on methotrexate (MTX) metabolism in Korean children and young adults with acute lymphoblastic leukemia, specifically focusing on MTX polyglutamates (MTX-PGs) in erythrocytes, which have been rarely studied. Korean children and young adult patients undergoing maintenance therapy for acute lymphoblastic leukemia, who were receiving weekly oral MTX doses of 20 mg/m²/week, were prospectively included. We investigated erythrocyte MTX-PG (PG1 to PG5) levels, MTX-PG/MTX dose ratios, and 222 genetic polymorphisms spanning 78 genes and three intergenic areas related to MTX transport, folate cycle metabolism, purine/pyrimidine pathways, and non-pathway genes (including TPMT and NUDT15 genotypes) to explore their association with MTX metabolism. MTX-PG levels were associated with MTX dose (p < 0.05), and MTX-PG3 comprised the majority of the total MTX-PGs, with a median of 39.3 %. Various polymorphisms within the same gene demonstrated differing associations with each type of MTX-PG, underscoring the complexity of MTX pharmacogenetics. Among the polymorphisms examined, 14 across 13 genes showed significant associations with MTX-PG2–5 levels, even after adjusting for the false discovery rate (ABCC5, ATG16L1, CEP72, FSTL5, GMPS, HTR3A, IMPDH1, NT5C2, SLC28A3, SLCO1B3, SUCLA2, TPMT, and TYMS). This study enhances our understanding of genetic polymorphisms in MTX metabolism and therapeutic monitoring for MTX maintenance, promoting personalized medicine in acute lymphoblastic leukemia patients.

Nasal systemic drug delivery may provide an easy way to substitute parenteral or oral dosing, however, the excipients have an important role in nasal formulations to increase the permeability of the mucosa and prolong the residence time of the drug. In this work, we aimed to produce meloxicam potassium monohydrate (MXP) containing nasal powders by a nano spray drier with the use of a neutral, an anionic and a cationic β-cyclodextrin as permeation enhancers, and (polyvinyl)alcohol (PVA) as a water soluble polymer. The following examinations were performed in order to study the effect of the applied excipients on the nasal applicability of the formulations: laser scattering, scanning electron microscope measurement, XRPD, DSC and FTIR measurements, adhesivity, in vitro drug release and permeability tests through an artificial membrane and RPMI 2650 cells. Based on our results, spherical particles were prepared with a size of 1.89–2.21 µm in which MXP was present in an amorphous state. Secondary interactions were formed between the excipients and the drug. The charged cyclodextrin-based formulations showed significantly higher adhesive force values regardless of the presence of PVA. The drug release was fast and complete. The passive diffusion of MXP was influenced not only by the charge of the cyclodextrin, but the presence of PVA, too. The permeation of the drug was enhanced in the presence of the anionic cyclodextrin testing it on RPMI 2650 cell model.

After oral administration, the intestine is the first site of drug absorption, making it a key determinant of the bioavailability of a drug, and hence drug efficacy and safety. Existing non-clinical models of the intestinal barrier in vitro often fail to mimic the barrier and absorption of the human intestine. We explore if human enteroid monolayers are a suitable tool for intestinal absorption studies compared to primary tissue (Ussing chamber) and Caco-2 cells.

Bidirectional drug transport was determined in enteroid monolayers, fresh tissue (Ussing chamber methodology) and Caco-2 cells. Apparent permeability (P_app) and efflux ratios for enalaprilat (paracellular), propranolol (transcellular), talinolol (P-glycoprotein (P-gp)) and rosuvastatin (Breast cancer resistance protein (BCRP)) were determined and compared between all three methodologies and across intestinal regions. Bulk RNA sequencing was performed to compare gene expression between enteroid monolayers and primary tissue.

All three models showed functional efflux transport by P-gp and BCRP with higher basolateral to apical (B-to-A) transport compared to apical-to-basolateral (A-to-B). B-to-A P_app values were similar for talinolol and rosuvastatin in tissue and enteroids. Paracellular transport of enalaprilat was lower and transcellular transport of propranolol was higher in enteroids compared to tissue. Enteroids appeared show more region- specific gene expression compared to tissue.

Fresh tissue and enteroid monolayers both show active efflux by P-gp and BCRP in jejunum and ileum. Hence, the use of enteroid monolayers represents a promising and versatile experimental platform to complement current in vitro models.

Background

Valproic acid (VPA) is a commonly used broad-spectrum antiepileptic drug. For elderly epileptic patients, VPA plasma concentrations have a considerable variation. We aim to establish a prediction model via a combination of machine learning and population pharmacokinetics (PPK) for VPA plasma concentration.

Methods

A retrospective study was performed incorporating 43 variables, including PPK parameters. Recursive Feature Elimination with Cross-Validation was used for feature selection. Multiple algorithms were employed for ensemble model, and the model was interpreted by Shapley Additive exPlanations.

Results

The inclusion of PPK parameters significantly enhances the performance of individual algorithm model. The composition of categorical boosting, light gradient boosting machine, and random forest (7:2:1) with the highest R² (0.74) was determined as the ensemble model. The model included 11 variables after feature selection, of which the predictive performance was comparable to the model that incorporated all variables.

Conclusions

Our model was specifically tailored for elderly epileptic patients, providing an efficient and cost-effective approach to predict VPA plasma concentration. The model combined classical PPK with machine learning, and underwent optimization through feature selection and algorithm integration. Our model can serve as a fundamental tool for clinicians in determining VPA plasma concentration and individualized dosing regimens accordingly.

This review considers the role of in vitro permeation testing (IVPT) for the evaluation of drug delivery from topical formulations applied to the skin. The technique was pioneered by Franz in the 1970′s and today remains an important tool in the development, testing and optimization of such topical formulations. An overview of IVPT as well as selection of skin for the experiment, integrity testing of the membrane, and required number of replicate skin samples is discussed. In the literature many researchers have focused solely on permeation and have not reported amounts of the active remaining on and in the skin at the end of the IVPT. Therefore, a particular focus of this article is determination of the complete mass balance of the drug. It is noteworthy that for the evaluation of bioequivalence of topical formulations the draft guideline issued by the European Medicines Agency (EMA) requires the IVPT method to report on both the skin deposition and distribution of the active in the skin as well as amount permeated. Other aspects of current guidance from the EMA and United States Food and Drug Agency for IVPT are also compared and contrasted. Ultimately, harmonisation of IVPT protocols across the regulatory agencies will expedite the development process for novel topical formulations as well as the availability of generic products.