Revolutionizing Psoriasis Topical Treatment: Enhanced Efficacy Through Ceramide/Phospholipid Composite Cerosomes Co-Delivery of Cyclosporine and Dithranol: In-Vitro, Ex-Vivo, and in-Vivo Studies

PURPOSE: Improving the treatment of psoriasis is a serious challenge today. Psoriasis is an immune-mediated skin condition affecting 125 million people worldwide. It is commonly treated with cyclosporine-A (CsA) and dithranol (DTH). CsA suppresses the activation of T-cells, immune cells involved in forming psoriatic lesions. Meanwhile, DTH is a potent anti-inflammatory and anti-proliferative drug that effectively reduces the severity of psoriasis symptoms such as redness, scaling, and skin thickness. CsA and DTH belong to BCS class II with limited oral bioavailability. We aim to develop a drug delivery system for topical co-delivery of CsA and DTH, exploring its therapeutic potential. METHODS: Firstly, we developed a niosomal drug delivery system based on ceramide IIIB to form Cerosomes. Cerosomes were prepared from a mixture of Ceramide, hyaluronic acid, and edge activator using a thin-film hydration technique. To co-deliver CsA and DTH topically for the treatment of psoriasis. These two hydrophobic drugs encapsulated into our synthesized positively charged particle cerosomes. RESULTS: Cerosomes had an average particle size of (222.36 nm± 0.36), polydispersity index of (0.415±0.04), Entrapment Efficiency of (96.91%± 0.56), and zeta potential of (29.36±0.38mV) for selected formula. In vitro, In silico, in vivo, permeation, and histopathology experiments have shown that cerosomes enhanced the skin penetration of both hydrophobic drugs by 66.7% compared to the CsA/DTH solution. Imiquimod (IMQ) induced psoriatic mice model was topically treated with our CsA/DTH cerosomes. We found that our formulation enhances the skin penetration of both drugs and reduces psoriasis area and severity index (PASI score) by 2.73 times and 42.85%, respectively, compared to the CsA/DTH solution. Moreover, it reduces the levels of proinflammatory cytokines, TNF-α, IL-10, and IL-6 compared to CsA/DTH solution administration. CONCLUSION: The Cerosomes nano-vesicle-containing CsA/DTH represents a more promising topical treatment for psoriasis, giving new hope to individuals with psoriasis, compared to commercial and other conventional alternatives

Construction of sublingual trilaminated Eszopiclone fast dissolving film for the treatment of Insomnia: Formulation, characterization and In vivo clinical comparative pharmacokinetic study in healthy human subjects

Background Disturbed sleep can cause to m health problems such as cognitive impairment, depressed mood, and negative effects on cardiovascular, endocrine, and immune function. This study formulates and optimizes Eszopiclone trilaminate fast dissolving film. Methods Prepared Eszopiclone trilaminate fast dissolving film (Eszopiclone TFDF) was characterized by disintegration time, drug release, tensile strength (TS), percentage elongation (EB%), folding endurance, taste masking test, and in vitro dissolution test. The selected formulas were F2 (0.5% xanthan gum, 10% propylene glycol), F4 (3% sodium alginate, 10% propylene glycol) and F6 (1.5% pullulan, 10% propylene glycol) were subjected to in vivo study compared to conventional Lunesta® tablet. Results The results indicated that disintegration time was in the range of 940 m. Drug release was found to be in the field of 78.51%–99.99%, while TS values and EB% differed from 11.12 to 25.74 (MPa) and 25.38%–36.43%, respectively. The folding endurance went between 200 and 300 times. All formulas exhibited acceptable uniformity content, surface pH, film thickness, and a good taste feeling. Conclusion F4 had the highest Cmax (39.741 ± 6.785-μg/l) and lower Tmax (1.063 hr) among other formulas and conventional tablets. Therefore, FDFs’ technology could increase the therapeutic effect of Eszopiclone. </jats:sec

Validity of Osteoprotegerin and Receptor Activator of NF-κB Ligand for the Detection of Bone Metastasis in Breast Cancer

Osteoprotegerin (OPG) is a robust antiresorptive molecule that acts as a decoy receptor for the receptor activator of nuclear factor κB ligand (RANKL), the mediator of osteoclastogenesis. This study was designed to explore the possible role of serum OPG and RANKL in detecting bone metastasis in breast cancer and its interaction with clinicopathologic parameters. Serum levels of RANKL and OPG were estimated in 44 metastatic and 36 nonmetastatic breast cancer patients using ELISA kits. Serum OPG levels were significantly reduced in patients with bone metastasis and correlated negatively with the number of bone lesions and CA 15-3 levels. At concentrations ≤82 pg/ml, OPG showed a high specificity in identifying the presence of bone metastasis (92%), albeit with low sensitivity (59%), which improved after the exclusion of diabetics and patients treated with aromatase inhibitors (AI). Serum RANKL levels were significantly higher in the presence of bone metastasis and hypercalcemia. At concentrations &gt;12.5 pg/ml, RANKL had an associated sensitivity of 86%, albeit with low specificity (53%), in detecting bone metastasis. The RANKL/OPG ratio significantly increased in the presence of bone metastasis with appropriate sensitivity and specificity (73% and 72%, respectively) at a cutoff of ≥0.14 for the detection of bone metastasis. Serum OPG and RANKL/OPG ratios are promising biomarkers for detecting bone metastasis in breast cancer patients.</jats:p

Composition of medicated fast dissolving film containing eszopiclone.

Composition of medicated fast dissolving film containing eszopiclone.</p

TASTE MASKED CLOPERASTINE HYDROCHLORIDE AND RUPATADINE ORAL DISPERSIBLE TABLETS: FORMULATION DESIGN, DEVELOPMENT, CHARACTERIZATION AND PHARMACOKINETICS STUDY ON WISTAR RATS

Objective: The main objective of our study was formulating oral dispersible tablets (ODTs) of taste masked Cloperastine HCl and Rupatadine Fumarate by using the lyophilization technique that also enhanced the dissolution of poor solubility of these active substances.  Methods: Taking 3 super disintegrants as variables using the Minitab® 18 factorial design method, 27 formulae of ODTs were obtained. The powdered mixtures before direct compression were characterized using Carr’s index, Hausner’s ratio, and angle of repose. The best-powdered formulae were elected to be prepared as ODTs by direct compression to undergo characterization tests such as wetting time, invitro disintegration test, and in-vivo taste masking. According to the Quality by Design QbD approach; the best formula of ODTs prepared by direct compression was elected to be optimized by the lyophilization technique. Incorporating Eudragit E PO® has a major role in the taste masking of lyophilized ODTs. A comparative invivo pharmacokinetic study of market products of two active substances was carried out for the conventional ODTs, lyophilized tablets, and market products using Wistar rats by oral administration of (0.75 mg/mL) for each active substance. Results: The bitter taste was apparently masked in the lyophilized ODTs assessed by invivo taste masking. The highest Cmax of Cloperastine HCl was found at 17.25 mcg/mL in the group of Lyophilized ODTs. Furthermore; the highest Cmax of Rupatadine was found at 78.88 mcg/mL in the same group. Conclusion: Lyophilized tablets owned the best bioavailability for both active substances with the highest Cmax compared to market products and ODTs prepared by direct compression

DSC thermograms of drug and excipients.

DSC thermograms of drug and excipients.</p

<i>In vitro</i> evaluation of medicated fast dissolving films (FDF).

In vitro evaluation of medicated fast dissolving films (FDF).</p

Fig 3 -

a. Design of Pharmacokinetics study. b. LC-MS_MS chromatograms of Eszopiclone. c. Average plasma drug level of Eszopiclone.</p

<i>In vitro</i> dissolution in phosphate buffer pH 6.8.

F7 (2.5% gelatin and 5% propylene glycol) have the lowest percentage drug release within the first seven minutes (78.51%). The percentage of drug released within the first seven minutes from F2, F6, and F2 and formula containing 10% propylene glycol shows higher drug release than other formula (97.7%, 98.52% 99.99%, respectively).</p

<i>In vivo</i> pharmacokinetic parameters & data represent the mean value ± standard deviation (SD).

In vivo pharmacokinetic parameters & data represent the mean value ± standard deviation (SD).</p