Coupling AFM, DSC and FT-IR towards Elucidation of Film-Forming Systems Transformation to Dermal Films: A Betamethasone Dipropionate Case Study.

Polymeric film-forming systems have emerged as an esthetically acceptable option for targeted, less frequent and controlled dermal drug delivery. However, their dynamic nature (rapid evaporation of solvents leading to the formation of thin films) presents a true characterization challenge. In this study, we tested a tiered characterization approach, leading to more efficient definition of the quality target product profiles of film-forming systems. After assessing a number of physico-chemico-mechanical properties, thermal, spectroscopic and microscopic techniques were introduced. Final confirmation of betamethasone dipropionate-loaded FFS biopharmaceutical properties was sought via an in vitro skin permeation study. A number of applied characterization methods showed complementarity. The sample based on a combination of hydrophobic Eudragit® RS PO and hydroxypropyl cellulose showed higher viscosity (47.17 ± 3.06 mPa·s) and film thickness, resulting in sustained skin permeation (permeation rate of 0.348 ± 0.157 ng/cm2 h), and even the pH of the sample with Eudragit® NE 30D, along with higher surface roughness and thermal analysis, implied its immediate delivery through the epidermal membrane. Therefore, this study revealed the utility of several methods able to refine the number of needed tests within the final product profile.

Curcumin Loaded PEGylated Nanoemulsions Designed for Maintained Antioxidant Effects and Improved Bioavailability: A Pilot Study on Rats.

The current study describes the experimental design guided development of PEGylated nanoemulsions as parenteral delivery systems for curcumin, a powerful antioxidant, as well as the evaluation of their physicochemical characteristics and antioxidant activity during the two years of storage. Experimental design setup helped development of nanoemulsion templates with critical quality attributes in line with parenteral application route. Curcumin-loaded nanoemulsions showed mean droplet size about 105 nm, polydispersity index <0.15, zeta potential of -40 mV, and acceptable osmolality of about 550 mOsm/kg. After two years of storage at room temperature, all formulations remained stable. Moreover, antioxidant activity remained intact, as demonstrated by DPPH (IC50 values 0.078-0.075 mg/mL after two years) and FRAPS assays. In vitro release testing proved that PEGylated phospholipids slowed down the curcumin release from nanoemulsions. The nanoemulsion carrier has been proven safe by the MTT test conducted with MRC-5 cell line, and effective on LS cell line. Results from the pharmacokinetic pilot study implied the PEGylated nanoemulsions improved plasma residence of curcumin 20 min after intravenous administration, compared to the non-PEGylated nanoemulsion (two-fold higher) or curcumin solution (three-fold higher). Overall, conclusion suggests that developed PEGylated nanoemulsions present an acceptable delivery system for parenteral administration of curcumin, being effective in preserving its stability and antioxidant capacity at the level highly comparable to the initial findings.

Ultra-performance liquid chromatography tandem mass spectrometry for the rapid, simultaneous analysis of ziprasidone and its impurities.

The separation and characterization of the unknown degradation product of second-generation antipsychotic drug ziprasidone are essential for defining the genotoxic potential of the compound. The aim of this study was to develop a simple UHPLC method coupled with tandem mass spectrometry (MS/MS) for chemical characterization of an unknown degradant, and the separation and quantification of ziprasidone and its five main impurities (I-V) in the raw material and pharmaceuticals. Chromatographic conditions were optimized by experimental design. The MS/MS fragmentation conditions were optimized individually for each compound in order to obtain both specific fragments and high signal intensity. A rapid and sensitive UHPLC-MS/MS method was developed. All seven analytes were eluted within the 7 min run time. The best separation was obtained on the Acquity UPLC BEH C18 (50 × 2.1 mm × 1.7 µm) column in gradient mode with ammonium-formate buffer (10 mm; pH 4.7) and acetonitrile as mobile phase, with the flow rate of 0.3 mL min-1 and at the column temperature of 30°C. The new UHPLC-MS/MS method was fully validated and all validation parameters were confirmed. The fragmentation pathways and chemical characterization of an unknown degradant were proposed and it was confirmed that there are no structural alerts concerning genotoxicity.

Prediction of in vivo Bioavailibility by in vitro Characterization of Ethylenediamine Dipropanoic Acid Derivatives with Cytotoxic Activity.

O,O'-diethyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate (DE-EDCP) is novel substance with cytotoxic activity in human leukemic cells. The aim of this study has been to predict in vivo bioavailability of the DE-EDCP and its potential metabolite (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid (EDCP) by in vitro characterization which includes determination of lipophilicity and passive membrane permeability. There has also been evaluated inter-laboratory reproducibility of the bio-analytical method which was previously developed and validated for non-clinical study of the DE-EDCP and EDCP. Distribution coefficient n-octanol/water was 1.68 and 0.03, and apparent permeability coefficient was 4 × 10-4 cm/s and 20 × 10-4 cm/s, for the DE-EDCP and EDCP, respectively. Observed results have shown that the DE-EDCP is more lipophilic with better membrane retention, but the EDCP has better pass through the membrane. Also, there has been demonstrated a reproducibility and robustness of the proposed bio-analytical method.

Oxidative Stress and Genetic Variants of Xenobiotic-Metabolising Enzymes Associated with COPD Development and Severity in Serbian Adults.

The genetic and non-genetic factors that contribute to the development of chronic obstructive pulmonary disease (COPD) are still poorly understood. We investigated the potential role of genetic variants of xenobiotic-metabolising enzymes (glutathione-S-transferase M1, GSTM1; glutathione-S-transferase T1, GSTT1; microsomal epoxide hydrolase, mEH), oxidative stress (assessed by urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-oxodG/creatinine), sex, ageing and smoking habits on susceptibility to development of COPD and its severity in Serbian population. The investigated population consisted of 153 healthy subjects (85 males and 68 females) and 71 patients with COPD (33 males and 38 females). Detection of GSTM1*null, GSTT1*null, mEH Tyr113His and mEH His139Arg gene variants was performed by PCR/RFLP method. Urinary 8-oxodG was determined using HPLC-MS/MS, and expressed as 8-oxodG/creatinine. We revealed that increased urinary 8-oxodG/creatinine and leucocytosis are the strongest independent predictors for COPD development. Increased level of oxidative stress increased the risk for COPD in males [odds ratio (OR), 95% confidence interval (CI): 8.42, 2.26-31.28], more than in females (OR, 95% CI: 3.60, 1.37-9.45). Additionally, independent predictors for COPD were ageing in males (OR, 95% CI: 1.29, 1.12-1.48), while in females they were at least one GSTM1 or GSTT1 gene deletion in combination (OR, 95% CI: 23.67, 2.62-213.46), and increased cumulative cigarette consumption (OR, 95% CI: 1.09, 1.01-1.16). Severity of COPD was associated with the combined effect of low mEH activity phenotype, high level of oxidative stress and heavy smoking. In conclusion, early identification of GSTM1*null or GSTT1*null genotypes in females, low mEH activity phenotype in heavy smokers and monitoring of oxidative stress level can be useful diagnostic and prognostic biomarkers.

The Role of Oxidative Stress in the Clinical Manifestations of Childhood Asthma.

INTRODUCTION: The significance of oxidative stress in pathogenesis of childhood asthma was recognized, but its role in the clinical manifestations of disease is still unclear. MATERIALS AND METHODS: The study was conducted in 96 asthmatic children. The urinary biomarker of oxidative stress, 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG/creatinine) was determined by using HPLC-MS/MS. ELISA was performed to measure myeloperoxidase (MPO) and Cu,Zn- superoxide dismutase (Cu,Zn-SOD) in serum. RESULTS: Logistic regression analysis revealed that female gender, tobacco smoke exposure, and increased 8-oxodG/creatinine were associated with risk for intermittent asthma, while the positive allergy test and increased Cu,Zn-SOD were associated with eczema in asthmatic children. Higher MPO (p = 0.033), and percent of granulocytes (p = 0.030) were found in severe persistent asthma in comparison to intermittent or mild persistent asthma. CONCLUSION: The main findings that TSE-induced oxidative stress is a risk for intermittent asthma and eczema may be clinically significant for the disease prevention and therapeutic improvements.

Gender-related differences in susceptibility to oxidative stress in healthy middle-aged Serbian adults.

Gender-related differences in the association between polymorphism of xenobiotic-metabolising enzymes or non-genetic biomarkers and susceptibility to oxidative stress was assessed in healthy middle-aged Serbian adults, by urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG/creatinine) and total antioxidant status in serum (TAOS). Females were more susceptible to oxidative stress. In both genders, positive predictor of the antioxidative protection was serum triglyceride, while BMI <25 kg/m(2) was associated with oxidative stress. Susceptibility to oxidative stress in males was associated with GSTT1*null allele and increased serum iron, but in females, it was decreased serum bilirubin. Early identification of the risk factors could be important in the prevention of oxidative stress-related diseases.

X-ray detectors at the Linac Coherent Light Source.

Free-electron lasers (FELs) present new challenges for camera development compared with conventional light sources. At SLAC a variety of technologies are being used to match the demands of the Linac Coherent Light Source (LCLS) and to support a wide range of scientific applications. In this paper an overview of X-ray detector design requirements at FELs is presented and the various cameras in use at SLAC are described for the benefit of users planning experiments or analysts looking at data. Features and operation of the CSPAD camera, which is currently deployed at LCLS, are discussed, and the ePix family, a new generation of cameras under development at SLAC, is introduced.

Design, synthesis, and local anti-inflammatory activity of 17ß-carboxamide derivatives of glucocorticoids.

Molecular docking studies were performed on 18 17ß-carboxamide steroids in order to select compounds with potential local anti-inflammatory activity. These derivatives are amides of cortienic acids (obtained from hydrocortisone, prednisolone, and methylprednisolone) with methyl or ethyl esters of six amino acids. Interactions with the glucocorticoid receptor (GR), binding energies and ligand efficiency values of these compounds were compared with dexamethasone and cortienic acid obtained from prednisolone (inactive metabolite). On the basis of molecular docking studies, seven compounds were selected and their binding affinities for the GR were predicted by use of the exponential model created in this study. Subsequently, selected compounds were synthesized in good yields by use of modified N,N'-dicyclohexylcarbodiimide (DCC)/1-hydroxybenzotriazole (HOBt) coupling procedure. Finally, the local anti-inflammatory activity of the synthesized compounds was examined by use of the croton oil-induced ear edema test. In vivo evaluation of systemic side effects as well as in silico prediction of metabolism were performed on the derivative with the best local anti-inflammatory activity. The combination of molecular docking studies and the exponential model for the GR binding affinity prediction could be used as an in silico tool for the rational design of novel 17ß-carboxamide steroids with potentially better biological profile than dexamethasone.

Development of a prospective isopropyl alcohol-loaded pharmaceutical base using simultaneous in vitro/in vivo characterization methods of skin performance.

CONTEXT: Approaching of pharmaceutical and cosmetic industries in some aspects inevitably influence formulation of topical pharmaceuticals, urging researchers to introduce novel excipients with proven benefits over traditional ones. In that context, alkyl polyglucosides (APG) emerge as prominent natural-origin emulsifiers with numerous favorable features (biodegradability, dermatological acceptability, desirable sensory properties). OBJECTIVE: To evaluate APG-stabilized bases (alone and upon addition of isopropyl alcohol) and their impact on skin performance. A simultaneous in vitro/in vivo skin absorption study was conducted to evaluate whether the tape stripping technique could be recommended as an in vivo tool for skin penetration assessment during formulation optimization process. MATERIALS AND METHODS: After a comprehensive physicochemical characterization, biopharmaceutical properties of APG-bases versus reference ones were assessed through a combined in vitro (release/permeation) and in vivo approach. RESULTS AND DISCUSSION: Physicochemical characterization revealed substantial difference in structural ordering due to the formation of various mesomorphic phases. The enhancer-loaded APG base resulted in significantly higher drug levels at all depths into the stratum corneum, indicating that the selected enhancer along with specific colloidal structure has increased the extent of drug delivery. CONCLUSION: Results recommend the investigated emulsifier for stabilization of topical drug delivery systems, not only for their ability to sustain the addition of isopropyl alcohol which proved to be a valuable enhancer, but also satisfactory skin absorption and tolerability when compared to samples stabilized by conventional emulsifier. Tape stripping proved to be a useful and yet inexpensive tool for in vivo trials, able to discriminate subtle differences in dermal availability.

Effect of small changes in natural origin-based emulsion systems on hydrocortisone skin absorption and performance: a comparison of two in vivo methods.

CONTEXT: Alkyl polyglucoside surfactants (APG) remain prominent natural origin stabilizers offering a prospect of combining satisfactory stability with mild dermatological properties and complete biodegradability. OBJECTIVE: With the purpose of adjusting the dose to a patient's needs, dilution of commercial corticosteroid formulations is a practice which may modify efficacy uncontrolledly. The rational of the study was to investigate whether a simple change in ready-to-use bases (co-solvent addition) could address these needs in a more predictive manner. METHODS: Hydrocortisone (HC) delivery from such emulsion systems was comparatively assessed employing two in vivo methods: the established human skin blanching assay versus skin stripping technique. RESULTS: HC permeation data obtained after three dose durations showed better overall performance of the APG-stabilized bases relative to reference ones. Although the solubility study showed that all the assessed active samples retained equal thermodynamic activity, diverse HC permeation/penetration implies the importance of the applied base's colloidal structure and/or changes endured. Isopropyl alcohol (IPA) addition offered faster drug penetration enhancement, while glycerol as a moisturizing agent influenced HC penetration through the increase in skin hydration. CONCLUSION: Although the performed in vivo methods cannot be considered alternative, skin stripping technique proved to be a cost-efficient mode of percutaneous penetration assessment, providing additional information on vehicle-skin interactions.

Estimation of passive gastrointestinal absorption of new dual DNA gyrase and topoisomerase IV inhibitors using PAMPA and biopartitioning micellar chromatography and quantitative structure-retention relationship analysis.

DNA gyrase and topoisomerase IV play significant role in maintaining the correct structure of DNA during replication and they have been identified as validated targets in antibacterial drug discovery. Inadequate pharmacokinetic properties are responsible for many failures during drug discovery and their estimation in the early phase of this process maximizes the chance of getting useful drug candidates. Passive gastrointestinal absorption of a selected group of thirteen dual DNA gyrase and topoisomerase IV inhibitors was estimated using two in vitro tests - parallel artificial membrane permeability assay (PAMPA) and biopartitioning micellar chromatography (BMC). Due to good correlation between obtained results, passive gastrointestinal absorption of remaining ten compounds was estimated using only BMC. With this experimental setup, it was possible to identify compounds with high values of retention factors (k) and highest expected passive gastrointestinal absorption, and compounds with low values of k for which low passive gastrointestinal absorption is predicted. Quantitative structure-retention relationship (QSRR) modelling was performed by creating multiple linear regression (MLR), partial least squares (PLS) and support vector machines (SVM) models. Descriptors with the highest influence on retention factor were identified and their interpretation can be used for the design of new compounds with improved passive gastrointestinal absorption.

Quantification of oxidative stress markers in the blood sera following subacute administration of different oximes in rats.

Oxidative stress status, as a disruption of redox homeostasis, in the blood sera of Wistar rats caused by repeated application of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, K074, and K075 were evaluated. Throughout this study, each oxime in a dose of 0.1 of LD50/kg im was given 2x/week for 4 weeks. Then, seven days after the last oximes' application, markers of lipid peroxidation (malondialdehyde, MDA), and protein oxidation (advanced oxidation protein products, AOPP), as well as the activity of antioxidant enzymes (catalase, CAT, superoxide dismutase, SOD, reduced glutathione, GSH, and oxidized glutathione, GSSG), were determined. Oxidative stress parameters, MDA and AOPP were significantly highest in the K048-, K074- and K075-treated groups (p < 0.001). The activity of CAT was significantly elevated in the obidoxime-treated group (p < 0.05), while treatment with K027, K048, and K074 induced high elevation in SOD levels (p < 0.01, p < 0.001). Interestingly, the activity of GSH in each oxime-treated group was significantly elevated. Unlike, treatment with obidoxime caused elevation in GSSG levels (p ˂ 0.01). As a continuation of our previously published data, these results assure that applied oximes following subacute treatment ameliorated the oxidative status and further adverse systemic toxic effects in rats.

Oxidative stress-related risk of the multiple sclerosis development.

Background: Multiple sclerosis (MS) is characterized by inflammation, demyelination and axonal degeneration. Oxidative stress (OS) plays a significant role in the pathogenesis of the disease. The aim of the study was to examine the association between OS and smoking on the MS development. Methods: The study included 175 patients with relapsing-remitting multiple sclerosis (RRMS) (76 males, 99 females) and 254 healthy subjects (81 males and 173 females). Oxidative stress biomarkers in serum, Total Antioxidant Status (TAS) and Total Oxidative Status (TOS) were determined spectrophotometrically. Oxidative Stress Index (OSI) was calculated as the ratio of TOS and TAS. Urinary 8-oxo7,8-dihydro-2'-deoxyguanosine were determined by HPLC-MS/MS and expressed as 8-oxodG/creatinine. Results: In females with RRMS were higher TOS, OSI and 8-oxodG/creatinine than in females in control group. The group of males with RRMS had lower level of TAS than the males in control group. Higher levels of 8-oxodG/creatinine was obtained in active, passive and former smokers with RRMS than in control group with the same exposition to tobacco smoke. Independent predictors of MS are passive smoking, increased OSI and increased levels of urinary 8-oxodG/creatinine. Conclusions: Our results demonstrate that the OS parameters should be included in the assessment of the risk for MS development. Due to the more sensitivity to oxidative stress, females may be at higher risk of MS development. This data indicates the importance of introducing the antioxidant therapy as a complementary treatment in patients with RRMS.

Oxidative stress status assessment of rats' brains injury following subacute exposure to K-oximes.

Oxidative stress status and morphological injuries in the brain of Wistar rats induced by repeated application of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, K074, and K075 were evaluated. Each oxime in a dose of 0.1 of LD50/kg im was given 2x/week for 4 weeks. Markers of lipid peroxidation (malondialdehyde, MDA), and protein oxidation (advanced oxidation protein products, AOPP), as well as the activity of antioxidant enzymes (catalase, CAT, superoxide dismutase, SOD, glutathione reductase, GR, and glutathione peroxidase, GPx), were estimated in the brain tissue homogenates on day 35 of the study. Brain alterations were carefully quantified by semiquantitative grading scales - brain damage score (BDS). Oxidative stress parameters, MDA and AOPP were significantly highest in the asoxime-, obidoxime- and K075-treated groups (p < 0.001). The activity of SOD and CAT was significantly elevated in the obidoxime-, K048-, and K075-treated groups (p < 0.001). Besides, GR was markedly decreased in the obidoxime- and K074-treated groups (p < 0.01), while treatment with K048, K074 and K075 induced extremely high elevation in GPx levels (p < 0.001). In the same groups of rats, brain alterations associated with polymorphonuclear cell infiltrate were significantly more severe than those observed in animals receiving only asoxime or K027 (p < 0.001). The presented results confirmed that treatment with different oximes significantly improved the oxidative status and attenuated signs of inflammation in rats' brains. Presented results, together with our previously published data can help to predict likely adverse systemic toxic effects, and target organ systems, which are crucial for establishing risk categories, as well as in dose selection of K-oximes as drug candidates.

A PAMPA assay as fast predictive model of passive human skin permeability of new synthesized corticosteroid C-21 esters.

The permeation properties of twenty newly synthesized α-alkoxyalkanoyl and α-aryloxyalkanoyl C-21 esters of standard corticosteroids: Fluocinolone acetonide, dexamethasone, triamcinolone acetonide and hydrocortisone were established using a PAMPA assay (70% silicone oil and 30% isopropyl myristate). The data were compared with parent corticosteroids with addition of mometasone furoate and hydrocortisone acetate. All newly synthesized corticosteroid C-21 esters have effective permeability coefficients higher then -6, mostly followed with high values of retention factors and low permeation. The examined compounds were grouped through relationship between obtained retention factors and permeation parameters (groups I-III). The classification confirmed group I (membrane retentions as well as permeation lower then 30%) for all corticosteroid standards except mometasone furoate, a potent topical corticosteroid which, with high membrane retention (81%) and low permeation (7.7%) fits into group III. The largest number of new synthesized corticosteroids C-21 esters, among them all fluocinolone acetonide C-21 esters, have high membrane retentions (32.4%-86.5%) and low permeations (1.3%-27.1%), fitting in group III. The classification was related to previously obtained anti-inflammatory activity data for the fluocinolone acetonide C-21 esters series. According to the PAMPA results the new synthesized esters could be considered as potential new prodrugs with useful benefit/risk ratio.

The Effects of Disease-Modifying Therapies on Oxidative Stress in Patients With Relapsing-Remitting Multiple Sclerosis.

OBJECTIVE: Oxidative stress (OS) has a role in the pathogenesis and progression of multiple sclerosis. The effects of disease-modifying therapies (DMTs) on OS are unclear. We aimed to explore the association between DMTs and OS in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: The study conducted in 167 patients (102 received and 65 not received the DMTs). The DMTs included interferon beta-1a (n = 15), interferon beta-1b (n = 20), glatiramer acetate (n = 10), and sphingosine-1-phosphate receptor modulators (n = 57). Oxidative stress assessed by total antioxidant status (TAS) and total oxidant status (TOS) (determined by spectrophotometric method), oxidative index (OSI was calculated), and urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG/creatinine was determined by high-performance liquid chromatography and tandem mass spectrometry). Patients were classified by Multiple Sclerosis Severity Score (MSSS) to mild/moderate (MSSS, <6.7) and severe (MSSS, >6.7). RESULTS: Disease-modifying therapies are associated with increased TAS, decreased TOS, OSI, and 8-oxodG/creatinine. Regardless of therapy, women had a less favorable redox status (lower TAS, higher TOS and OSI). Patients with MSSS>6.7 and without DMTs had higher OSI than patients who received DMTs. Women with MSSS>6.7 without DMTs had lower TAS than women with DMTs, whereas in the same stage of MS, men without DMTs had higher TOS than patients with DMTs. Women with MSSS<6.7 and with DMTs had lower 8-oxodG/creatinine compared with those without DMT therapy. CONCLUSIONS: The antioxidant effects of DMTs were evidenced in this study. The gender-related effects of DMTs on the OS imply the personalized antioxidant pharmacotherapy, especially for the women. The OS biomarkers have a potential as the prognostic for the assessment of DMTs outcomes in patients with RRMS.

Optimization of Extraction and HPLC-MS/MS Profiling of Phenolic Compounds from Red Grape Seed Extracts Using Conventional and Deep Eutectic Solvents.

Winemaking generates large quantities of grape waste consisting of seeds, skin and stalks. Given that grape seeds are a rich source of different bioactive compounds, the main goal of this research was to optimize grape seed phenol extraction using a Box-Behnken design. The following conditions were derived from the optimization process: sample:solvent ratio of 1:10 w/v, extraction time of 30 min and extraction temperature of 50 °C. In addition, a sustainable (green) approach for obtaining extracts was developed by comparing choline chloride:citric acid-ChCit (natural deep eutectic solvent (NADES)) and ethanol extraction methods with respect to phenol profiles and antioxidant activity. This study was conducted on seeds from eight different red grape varieties. Phenolic acids, flavan-3-ols and procyanidins were characterized using HPLC-MS/MS, and the concentration of procyanidin B1 was above 1 mg/g of dry weight in all analyzed samples. The contents of all phenol classes and antioxidant activities were found to not differ significantly between the solvents, but NADES was found to offer valuable advantages. Importantly, ChCit showed a strong affinity toward procyanidins and a strong correlation between antioxidant activity and quantified phenolic compounds.

Chemical vs. Physical Methods to Improve Dermal Drug Delivery: A Case Study with Nanoemulsions and Iontophoresis.

So far, various approaches have been proposed to improve dermal drug delivery. The use of chemical penetration enhancers has a long history of application, while methods based on the electrical current (such as iontophoresis) stand out as promising "active" techniques. Aiming to evaluate the contribution of different approaches to dermal delivery, in this work curcumin-loaded nanoemulsions with and without monoterpenes (eucalyptol or pinene) as chemical penetration enhancers, and a custom-made adhesive dermal delivery system based on iontophoresis were designed and assessed. In an in vivo study applying skin bioengineering techniques, their safety profile was proven. Three examined iontophoresis protocols, with total skin exposure time of 15 min (continuous flow for 15 min (15-0); 3 min of continuous flow and 2 min pause (3-2; 5 cycles) and 5 min of continuous flow and 1 min pause (5-1; 3 cycles) were equally efficient in terms of the total amount of curcumin that penetrated through the superficial skin layers (in vivo tape stripping) (Q3-2 = 7.04 ± 3.21 µg/cm2; Q5-1 = 6.66 ± 2.11 µg/cm2; Q15-0 = 6.96 ± 3.21 µg/cm2), significantly more efficient compared to the referent nanoemulsion and monoterpene-containing nanoemulsions. Further improvement of an efficient mobile adhesive system for iontophoresis would be a practical contribution in the field of dermal drug application.

The Impact of the Oil Phase Selection on Physicochemical Properties, Long-Term Stability, In Vitro Performance and Injectability of Curcumin-Loaded PEGylated Nanoemulsions.

A nanotechnology-based approach to drug delivery presents one of the biggest trends in biomedical science that can provide increased active concentration, bioavailability, and safety compared to conventional drug-delivery systems. Nanoemulsions stand out amongst other nanocarriers for being biodegradable, biocompatible, and relatively easy to manufacture. For improved drug-delivery properties, longer circulation for the nanoemulsion droplets should be provided, to allow the active to reach the target site. One of the strategies used for this purpose is PEGylation. The aim of this research was assessing the impact of the oil phase selection, soybean or fish oil mixtures with medium chain triglycerides, on the physicochemical characteristics and injectability of curcumin-loaded PEGylated nanoemulsions. Electron paramagnetic resonance spectroscopy demonstrated the structural impact of the oil phase on the stabilizing layer of nanoemulsions, with a more pronounced stabilizing effect of curcumin observed in the fish oil nanoemulsion compared to the soybean oil one. The design of the experiment study, employed to simultaneously assess the impact of the oil phase, different PEGylated phospholipids and their concentrations, as well as the presence of curcumin, showed that not only the investigated factors alone, but also their interactions, had a significant influence on the critical quality attributes of the PEGylated nanoemulsions. Detailed physicochemical characterization of the NEs found all formulations were appropriate for parenteral administration and remained stable during two years of storage, with the preserved antioxidant activity demonstrated by DPPH and FRAP assays. In vitro release studies showed a more pronounced release of curcumin from the fish oil NEs compared to that from the soybean oil ones. The innovative in vitro injectability assessment, designed to mimic intravenous application, proved that all formulations tested in selected experimental setting could be employed in prospective in vivo studies. Overall, the current study shows the importance of oil phase selection when formulating PEGylated nanoemulsions.