Development and Characterization of Transdermal Patches Using Novel Thymoquinone-L-Arginine-Based Polyamide Nanocapsules for Potential Use in the Management of Psoriasis.

Thymoquinone (TQ) is a phytochemical compound present in Nigella sativa and has potential benefits for treating dermatological conditions such as psoriasis. However, its clinical use is limited due to its restricted bioavailability, caused mainly by its low solubility and permeability. To overcome this, a new transdermal drug delivery system is required. Nanoparticles are known to enhance material solubility and permeability, and hence, this study aimed to synthesize TQ-loaded L-arginine-based polyamide (TQ/Arg PA) nanocapsules incorporated into transdermal patches for prolonged delivery of TQ. To achieve this, Eudragit E polymer, plasticizers, and aloe vera as penetration enhancer were used to develop the transdermal patch. Furthermore, novel TQ/Arg-PA was synthesized via interfacial polymerization, and the resultant nanocapsules (NCs) were incorporated into the matrix transdermal patch. The Arg-PA NCs' structure was confirmed via NMR and FTIR, and optimal TQ/Arg-PA NCs containing formulation showed high entrapment efficiency of TQ (99.60%). Molecular and thermal profiling of TQ/Arg-PA and the transdermal patch revealed the effective development of spherical NCs with an average particle size of 129.23 ± 18.22 nm. Using Franz diffusion cells and synthetic membrane (STRAT M®), the in vitro permeation profile of the prepared patches demonstrated an extended release of TQ over 24 h, with enhanced permeation by 42.64% when aloe vera was employed. In conclusion, the produced formulation has a potential substitute for corticosteroids and other drugs commonly used to treat psoriasis due to its effectiveness, safety, and lack of the side effects typically associated with other drugs.

Biological evaluation of combinations of tyrosine kinase inhibitors with Inecalcitol as novel treatments for human chronic myeloid leukemia.

Background: The use of tyrosine kinase inhibitors (TKIs) as a treatment for chronic myeloid leukemia (CML) has improved the natural history of the disease and increased the duration of survival. Tyrosine kinase inhibitors represent the success of target therapies that work on molecular targets, although some patients still have therapy failure. Vitamin D has antiproliferative, pro-apoptotic, and anti-angiogenic effects on cells, therefore it can be considered as a potential cancer preventative and treatment agent. Inecalcitol (TX-522) is the 14-epi-analogue of Calcitriol (1,25(OH)2-vitamin D3), and inhibits cancer cell proliferation more effectively than Calcitriol. This study was conducted to evaluate the antiproliferative and synergistic effects of the anticancer drugs Imatinib and Dasatinib in combinations with Inecalcitol on human chronic myeloid leukemia K-562 cells. Method: The growth inhibitory activities of Inecalcitol, Imatinib, Dasatinib, and different combinations of one of the two drugs (Imatinib and Dasatinib) with Inecalcitol, were determined in vitro using MTT assay against K-562 cell line. Results: Inecalcitol, Imatinib, and Dasatinib showed potent antiproliferative activities against K-562 cells with GI50 values of 5.6 µM, 0.327 µM, and 0.446 nM, respectively. Combinations of Imatinib or Dasatinib with different concentrations of Inecalcitol increased significantly the antiproliferative activities and potencies of both drugs (****p < 0.0001), with optimal GI50 values of 580 pM (Imatinib) and 0.51 pM (Dasatinib). Furthermore, the combination treatments showed synergistic interaction between the antileukemic drugs and Inecalcitol, with combination indices (CI) < 1. Conclusion: The study demonstrated that the human chronic myeloid leukemia K-562 cells were subjected to a synergistic growth inhibitory impact when antileukemic drugs (Imatinib or Dasatinib) were combined with Inecalcitol, therefore, it is recommended that these combinations be viewed as promising novel antileukemic medications and used in place of individual medications with lower dosages and negligible side effects in the treatment of CML.

In vivo and in vitro transdermal availability of Ibuprofen using novel solubility enhancing fluid nanosized carrier systems.

The objective of this study was to explore the benefits of transdermal drug delivery systems as an alternative option for patients who are unable to tolerate oral administration of drugs, such as ibuprofen (IB). To achieve this, nonionic surfactants and three cosolvents were employed to develop new microemulsions (MEs) that contained IB as nanocarriers. The aim was to enhance the solubility and bioavailability of the drug after transdermal administration. The MEs were characterised by droplet size, polydispersity index (PDI), and rheological properties. Furthermore, the flux of IB was evaluated by Franz diffusion cells using excised rat skin and in vivo bioavailability using rats. The results showed that the MEs had ideal viscosity and droplet size below 100 nm. Moreover, using the developed MEs, an improvement in the solubility (170 mg/mL) and flux through the rat skin (94.6 ± 8.0 µg/cm2.h) was achieved. In addition, IB demonstrated a maximum plasma level of 0.064 mg/mL after 8 h of transdermal administration in rats using the ME with an increase in the bioavailability of about 1.5 times in comparison to the commercial IB gel. In conclusion, the developed nonionic MEs containing IB can be ideal nanocarriers and promising formulations for the transdermal administration of IB.

Potential biomarkers and metabolomics of acetaminophen-induced liver injury during alcohol consumption: A preclinical investigation on C57/BL6 mice.

The toxic effects of alcohol consumption on population health are significant worldwide and the synergistic toxic effects of concurrent intake of Acetaminophen and alcohol is of clinical concern. The understanding of molecular mechanisms beneath such synergism and acute toxicity may be enhanced through assessing underlying metabolomics changes. The molecular toxic activities of the model hereby, is assessed though metabolomics profile with a view to identifying metabolomics targets which could aid in the management of drug-alcohol interactions. In vivo exposure of C57/BL6 mice to APAP (70 mg/kg), single dose of ethanol (6 g/kg of 40%) and APAP after alcohol consumption was employed. Plasma samples were prepared and subjected to biphasic extraction for complete LC-MS profiling, and tandem mass MS2 analysis. Among the detected ions, 174 ions had significant (VIP scores >1 and FDR <0.05) changes between groups and were selected as potential biomarkers and significant variables. The presented metabolomics approach highlighted several affected metabolic pathways, including nucleotide and amino acid metabolism; aminoacyl-tRNA biosynthesis as well as bioenergetics of TCA and Krebs cycle. The impact of APAP on the concurrent administration of alcohol showed great biological interactions in the vital ATP and amino acid producing processes. The metabolomics changes show distinct metabolites which are altered to alcohol-APAP consumption while presenting several unneglectable risks on the vitality of metabolites and cellular molecules which shall be concerned.

Dermal and Transdermal Macromolecule Delivery Using Enhancer Molecules and Colloidal Carrier Systems - Part 2: Percutaneous Administration of Heparin.

INTRODUCTION: Heparin is a commonly used anti-coagulant administered either by intravenous or subcutaneous injection for a systemic effect or topically for the treatment of peripheral vascular disorders. OBJECTIVE: This study aimed to formulate heparin in non-ionic colloidal carrier systems (CCSs) having enhanced percutaneous absorption for systemic and topical administration. METHODS: Five CCSs were developed and characterized for their rheological properties, droplet size, and drug loading. The percutaneous absorption of heparin was evaluated in vitro using Franz diffusion cells with rats' skin and with the aid of a developed high-pressure chromatography method. Furthermore, the efficacy of two developed heparin CCSs was tested percutaneously in rats by measuring the response against the time in comparison to subcutaneous administration. RESULTS: The rheograms and droplet size measurements showed that the developed drug delivery systems have Newtonian properties with a droplet size between 109 and 460 nm. As much as 500 mg of heparin could be loaded in around 5 mL of CCS. Furthermore, using Franz diffusion cells, a diffusion rate of 19.216 ± 2.01 USP U/cm2.h could be achieved for heparin-loaded CCSs. Moreover, the estimated percutaneous in vivo relative bioavailability in comparison to subcutaneous administration could reflect that at least more than 50% of the drug passed through the skin. CONCLUSION: The developed novel non-toxic CCSs containing heparin can be good candidates for percutaneous administration as alternative delivery systems for subcutaneous and intravenous invasive administration.

Visual health and prevalence of dry eye syndrome among university students in Iraq and Jordan.

Dry eye syndrome (DES), is a multifactorial disease that affects the ocular surface and contributes to the ocular symptoms. The COVID-19 pandemic influenced the general population and university students' health in different ways. The pandemic forced many people including university students around the world to use virtual platforms on their digital devices, such as computers and smartphones, to work from a distance. This study aimed to explore the visual health and prevalence of dry eye syndrome among university students in Iraq and Jordan. This was a cross-sectional study that was conducted in Iraq and Jordan using online questionnaire tool for the duration between November 2021 and January 2022. University students in Jordan and Iraq were invited to participate in this study and formed the study population. No restrictions on study level or field of study were applied. A previously developed and validated questionnaire tools were used in this study (National Eye Institute Visual Functioning Questionnaire - 25 (VFQ-25) and the Women's Health Study Questionnaire (WHS), which was developed by Schaumberg et al.). A total of 1,431 university students were involved in this study (1,018 students from Iraq, 71.1%). Around one third the study participants (29.0%) reported that have been diagnosed by a clinician as having dry eye syndrome. Around15.3% of the total study participants reported that they feel their eyes are dry (not wet enough) and 17.3% reported that they feel their eyes are irritated. Based on Women's Health Study Questionnaire (WHS) criteria, a total of 479 participants (33.4%) are symptomatically diagnosed with DES. Students aged 27-29 years, those at their fifth year of study, and those who wear contact lenses are at higher risk of developing DYS compared to others. Dry eye syndrome is common health problem among university students. Further studies are required to identify other risk factors associated with DES. Future research should focus on identifying strategies that could help reduce the risk of developing DES as a result of the inevitability of long-term use of digital devices among many categories of society, including university students.

Dermal and transdermal peptide delivery using enhancer molecules and colloidal carrier systems. Part V: Transdermal administration of insulin.

In this study, insulin was loaded into non-ionic colloidal carrier systems (CCS) to be used as nano-sized drug delivery systems for transdermal administration. The CCS were characterized for their rheological properties, droplet size and drug loading. Also, the transdermal flux of insulin was estimated using Franz diffusion cells through the epidermis and all the layers of the rats' skin. The efficacy of the administration of the CCS was assessed in vivo transdermally in rats. Based on the rheological properties and droplet size results, the formulated fluids were identified as nano-sized systems having an aqueous colloidal phase, where the hydrophilic peptide is located. Also, a flux of insulin as high as 0.119 ± 0.016 and 1.328 ± 0.047 iu/cm2.h through the rat's skin and epidermis, respectively, could be achieved using CCSIn2. Moreover, the monitoring of the blood sugar level over 6.5 h after a single transdermal administration of CCS exhibited a slight decrease. However, a significant drop in the blood sugar level was observed when they were administered once every two days over 10 days. The developed insulin-loaded CCS containing the penetration enhancer DMSO are nano-sized drug delivery systems and can induce a delayed therapeutic effect by repeating the administration.

Investigation of the potential application of sodium bentonite as an excipient in formulation of sustained release tablets.

In this study, the application of sodium bentonite (SB) in formulation of tablets prepared by direct compression for oral administration was tested. Three different model drugs with different solubilities: paracetamol, diclofenac sodium and metformin HCl were tested. Each drug was mixed with SB at ratio of 50% and the mixtures were subsequently compressed. Compatibility studies were conducted using both Deferential Scanning Calorimeter (DSC) and Fourier Transform Infrared Spectroscopy (FTIR). The dissolution profile for each drug was determined in USP-buffers at different time intervals. Diclofenac sodium in pH 6.8 buffer and paracetamol in both pH 6.8 and pH 4.5 buffers showed extended release. However, metformin HCl showed immediate release at the different pH values. The study showed that using SB was possible to prepare tablets with different release profiles. However, these profiles differ depending on dissolution media and drug type.

Development and characterization of microemulsions containing hyaluronic acid.

Tween80 and Span20 were used as surfactant mixture for developing non-ionic microemulsions (MEs) containing hyaluronic acid 22 kDa (HA). The effect of Tween80:Span20 ratio (T:S ratio) on microemulsion (ME) water intake and stability was studied. Moreover, the effect of HA on the consumed surfactant amount which is for stabilizing the MEs, for reducing water intake was investigated. Two W/O MEs containing HA were optimized. The first ME was composed of 2% HA, 13.8% Tween:80:Span20 (2:3), 4.2% water and 79.9% isopropylpalmitate (IPP). The second was composed of 2% HA, 16% Span20, 9.6% water:dimethyl sulfoxide (W:DMSO) (6:3.6) and 72.4% medium chain triglycerides (MCTG). The droplet sizes of MEs were determined using dynamic light scattering (DLS). The multilayer membrane system (MLMS) was used for testing the release of HA from both MEs and the released amount of HA was quantified using capillary zone electrophoresis (CZE). Furthermore, three phase diagrams and relevant rheological characteristics were generated. The droplet size of the ME without HA decreased and increased with increasing the temperature. Furthermore, the droplet size of the IPP-ME and MCTG-ME without HA and of the MCTG-ME with HA decreased with increasing temperature. In contrast to this results, the droplet size of the IPP-ME with HA increased with increased temperature. This ME belongs to the Newtonian fluids. Compared to the first ME, the second ME shows droplet sizes at 25 °C of 6.5 nm without and 37 nm with HA. The droplet size in the second ME decreased proportionally with an increase of the temperature with and without HA. The release of HA was faster from the IPP ME compared to the MCTG-ME. The two developed MEs were stable, isotropic and their properties comply with ME properties concerning the droplet size and viscosity.

The release profiles of intact and enzymatically digested hyaluronic acid from semisolid formulations using multi-layer membrane system.

A multi-layer membrane system was used to measure in vitro release of hydrophilic macromolecules such as hyaluronic acid (HA) from semisolid formulations. One enzymatically digested HA-derivative with molecular mass of 22 kDa (HA-D) and 1200 kDa intact HA (HA) were incorporated into three semisolid formulations: water-containing hydrophilic ointment (WHO), amphiphilic cream (AC) and water-containing wool wax alcohol ointment (WWO). Because of the high hydrophilic properties of HA-D and HA, the artificial model membranes consisted of collodion as the matrix and glycerol as the hydrophilic acceptor phase. The area under the concentration-time curve and the mean dissolution time were used as a quantitative parameter to characterise the rate and extent of release in vitro. This study showed that the HA-D and HA release as hydrophilic substances from WHO was higher than both from AC and WWO. It was observed that 83% of HA-D1 was released from WHO after 2 h; in contrast, only 10% was released from 2% HA from the same vehicle during the same time. In conclusion, the in vitro availability of enzymatically digested HA-D was higher for WHO than for the other formulations, AC and WWO. Similarly, the availability of HA-D was higher than that of HA from the same formulations.

Characterization of enzymatically digested hyaluronic acid using NMR, Raman, IR, and UV-Vis spectroscopies.

Hyaluronic acid (HA) is a linear polysaccharide formed from disaccharide units containing N-acetylglucosamine and glucuronic acid. When HA was digested with the enzyme hyaluronidase, a double bond is formed. It is known that this double bond forms a complex (radical scavenger) with the radicals (ROO, HO) during UV irradiation, and reduced the toxicity of the radicals before they are absorbed in the human skin. Therefore, the characterization of the double bond formed after the enzymatic digestion of HA is very important. In this study, 1H NMR, 13C NMR, Raman, infrared (IR), and UV-Vis spectroscopies were used for characterization of the double bond of HA after enzymatic digestion. HA derivatives in shape of films were tested using Raman and infrared (IR) spectroscopies and the wavenumber of the double bond and some other assignment were determined. The 1H and 13C NMR spectra were measured for HA derivatives in D(2)O solutions. The chemical shifts and coupling constant of 1H and 13C were assigned to the CH=C fragment. The relative amount of olefinic proportion in the mixture was obtained from 1H and 13C NMR spectra. The spectroscopy measurement showed an increase in the double bond amount with increasing enzymatic digestion time.

New approaches for quantifying hyaluronic acid in pharmaceutical semisolid formulations using HPLC and CZE.

HA was quantified in pharmaceutical formulations using HPLC-UV-detector and spectrophotometrically after the digestion with concentrated H(2)SO(4). Intact HA was quantified by capillary zone electrophoresis (CZE) using direct and indirect methods. The results were compared with the carbazole reaction established by Bitter et al. (Anal. Biochem. 4 (1997) 330) and with established method from Pläzer et al. (J. Pharm. Biomed. Anal. 21 (1997) 491) regarding detection limits, linearity, reproducibility and simplicity. The present results show that the investigation using HPLC and CZE led to a considerable improvement of the detection limit [0.3 ng/ml (HPLC1), 1 microgram/ml (HPLC2) and 5 microgram/ml (CE-D1)] compared with other methods (10 microgram/ml).