Aqueous Solubility Research Articles

Boron functionalized and phosphorous doped molybdenum di-sulfide quantum dots for the photoluminescence based detection of HbA1c

Highly fluorescent transition metal dichalcogenides (TMDs) based quantum dots (QDs) have been the focus of immense research owing to their bio-compatibility, non-toxicity, easy chemical synthesis and broad spectrum of applications which includes biosensing, optoelectronics, energy storage devices, etc. Herein, we present a one-step hydrothermal growth of in-situ blue fluorescent phosphorous doped-molybdenum di sulfide QDs (P-MoS2 QDs) in aqueous media. A range of functional groups over the surface of chemically synthesized P-MoS2 QDs helps in conserving its fluorescence along with high aqueous stability and solubility. Besides, remarkable photoluminescence (PL) properties of P-MoS2 QDs were then explored to concoct an optical sensor with excellent selectivity and sensitivity for glycated hemoglobin (HbA1c) followed by functionalization with boronic acid. The response of the sensor was found to be linear in the range of 2–15 %, which is under the typical physiological aliquot range (0.75–22.93 mM with limit of detection to be 77.5 μM, under optimized conditions. Moreover, PL quenching processes and TRPL data of P-MoS2 QDs were explored to elucidate the plausible quenching mechanism which suggests mixed kind of quenching processes. In conclusion, we envisaged that the present methodology can provide an effective and potent tool for HbA1c sensing in real biological (hemolysate/whole blood-lysate) samples.

Co-sorption of volatile components in polymer-based pharmaceutical formulations

Amorphous Solid Dispersions (ASDs) are mixtures of active pharmaceutical ingredients (APIs) and polymers aiming to increase API aqueous solubility and bioavailability. ASDs are often produced using solvent-based manufacturing, such as spray drying. Due to solubility or miscibility limitations in one solvent, solvent mixtures are frequently used for this purpose. Drying solvents or solvent mixtures from polymer-based products like ASDs is an energy-intensive and time-consuming process. Designing and optimising this drying process requires knowledge of the sorption isotherms of the solvent(s) in these polymer-based products. In this work, we developed a novel approach for measuring the simultaneous absorption/desorption of two solvents in a polymer. Combining classical dynamic vapour sorption (DVS) measurements with Raman spectroscopy, this innovative approach provides a more detailed and accurate measurement of the sorption isotherms than common methods. Moreover, we developed an approach for precisely predicting the sorption equilibria in three-component systems just based on sorption data of the corresponding binary subsystems. Our modelling approach combines the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) with the Non-Equilibrium Thermodynamics of Glassy Polymers (NET-GP). Building on the description of the sorption isotherms of either water or ethanol in poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) and in indomethacin (IND), we were able to quantitatively predict the simultaneous sorption of water and ethanol in PVPVA64 and the one of ethanol in an IND/PVPVA64 ASD.

Leveraging solid solubility and miscibility of etoricoxib in Soluplus® towards manufacturing of 3D printed etoricoxib tablets by additive manufacturing

This research focuses on exploring the solid solubility and miscibility of Etoricoxib, a poorly water-soluble anti-inflammatory drug, within Soluplus®, a polymer used as a matrix for 3D-printed tablets. By utilizing hot-melt extrusion (HME), the drug was dispersed within Soluplus® to enhance its solubility. The extrudates were then employed in 3D printing to create customized solid oral dosage form. This study’s novelty lies in combining HME and 3D printing, aiming to improve drug incorporation, stability, and effectiveness in the final formulation. Comprehensive characterization techniques, including hot stage microscopy (HSM), scanning electron microscopy (SEM), micro-computed tomography (Micro-CT), florescence microscopy, optical microscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), solubility studies, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and aqueous solubility study were utilized to elucidate the physicochemical properties, thermal stability, and structural integrity for the extruded filaments (the printing ink), and 3D printed tablets made thereof. Furthermore, the in vitro drug release profile of the 3D printed tablet was systematically evaluated, revealing a controlled drug release pattern from the finished dosage form. The systematic investigation reported herein, starting from theoretical miscibility to the printing ink development through HME, detailed characterization of the extruded filaments, and further solid oral formulation development by additive manufacturing can be utilized as a platform technology or a pathway for the development of personalized medicine with drugs having similar physicochemical properties.

Insights into antibacterial design: Computational modeling of eugenol derivatives targeting DNA gyrase

The rise of antibiotic resistance underscores the urgent need for novel antibacterial agents. DNA gyrase, an essential enzyme involved in bacterial DNA replication, is a promising target for antibacterial therapy. Computational approaches offer a cost-effective means to design and screen potential inhibitors, such as eugenol derivatives. This study aims to computationally design eugenol derivatives as potential antibacterial agents targeting DNA gyrase, assess their binding affinities, evaluate physicochemical properties, and toxicity, and select lead compounds for further investigation. Molecular docking simulations were conducted to investigate the binding affinities of eugenol derivatives and controls to DNA gyrase. Physicochemical properties and toxicity assessments of eugenol were evaluated. Lead compounds were selected based on drug likeness, toxicity, and binding affinity. Molecular docking studies revealed varying binding affinities of eugenol derivatives to DNA gyrase, with lead compounds exhibiting superior affinity compared to eugenol. Physicochemical properties indicated moderate lipophilicity and low aqueous solubility for eugenol. Toxicity assessment revealed mutagenicity and tumorigenicity. De novo compound synthesis generated 244 novel compounds, with 44 selected based on drug-likeness, toxicity, and binding affinity as lead candidates. These findings provide valuable insights for the development of novel antibacterial agents targeting DNA gyrase, with implications for combating antibiotic resistance.

Eutectic mixtures of nevirapine: Phase diagrams, solid-state characterization, and dissolution studies

Solid-state modifications can improve drug performance. Studies have shown that multicomponent crystals, such as cocrystals and eutectic compositions, have successfully improved the performance of certain drugs, including their solubility. Nevirapine (NEV) is an antiretroviral drug with low aqueous solubility, impacting its bioavailability. This work aimed to study different nevirapine/co-former solid eutectic systems, define their phase diagrams and evaluate their dissolution properties. Caffeine (CAF), Theobromine (TEOB), and Theophylline (THEO) were chosen as co-formers due to their functional groups that can interact with NEV. Aiming to determine both temperature and eutectic composition, phase and Tamman diagrams were obtained using the differential scanning calorimetry (DSC) analysis of the mixtures indifferent NEV-co-former compositions (%w/w). Powder X-ray diffraction (PXRD) and DSC were used to characterize the eutectic materials. To assess the influence of eutectic systems on dissolution properties, we determined the powder dissolution profiles and intrinsic dissolution rates of anhydrous NEV and eutectic systems NEV-CAF and NEV-THEO using different dissolution media (pH 1.2 and pH 6.8). The eutectic compositions were calculated through the phase diagrams, interpolating the curves obtained by linear regression. Thus, the eutectic composition of the NEV-CAF system was determined to be 36.55 % NEV and eutectic temperature at 201.1 °C, while in the NEV-THEO system, the eutectic was obtained in a composition of 71.04 % NEV and eutectic temperature at 217.8 °C. Tamman diagrams were generated using the enthalpy values obtained from the DSC curves, and eutectic compositions were calculated using linear regression. The analysis revealed a eutectic composition of 36.51 % of NEV for the NEV-CAF system, and a eutectic composition of 70.94 % of NEV for the NEV-THEO system. It was not possible to determine the eutectic mass fraction of NEV-TEOB. A comparison of dissolution profiles and intrinsic dissolution rates in different dissolution media showed a significant improvement in the NEV dissolution rate in both eutectic systems. In an acidic medium, NEV dissolved 16 times faster in the NEV-CAF sample and 4 times faster in the NEV-THEO sample compared to pure anhydrous NEV. In a neutral medium, the dissolution profile of NEV was even more favorable in the same eutectic systems, showing that the increase in dissolution is relevant in a wide range of pH. In addition, the intrinsic dissolution rate in the two eutectic systems was higher than that of anhydrous NEV in all employed dissolution mediums. These eutectic systems improve the dissolution rate compared to pure NEV, offering the potential for enhancing the dissolution of poorly water-soluble drugs in the future.

Encapsulating Rhodamine 6G in Oxidized Sodium Alginate Polymeric Hydrogel for Photodynamically Inactivating Cancer Cells.

As cancer therapy progresses, challenges remain due to the inherent drawbacks of conventional treatments such as chemotherapy, gene therapy, radiation therapy, and surgical removal. Moreover, due to their associated side effects, conventional treatments affect both cancerous and normal cells, making photodynamic therapy (PDT) an attractive alternative. As a result of its minimal toxicity, exceptional specificity, and non-invasive characteristics, PDT represents an innovative and highly promising cancer treatment strategy using photosensitizers (PSs) and precise wavelength excitation light to introduce reactive oxygen species (ROS) in the vicinity of cancer cells. Poor aqueous solubility and decreased sensitivity of Rhodamine 6G (R6G) prevent its use as a photosensitizer in PDT, necessitating the development of oxidized sodium alginate (OSA) hydrogelated nanocarriers to enhance its bioavailability, targeted distribution, and ROS-quantum yield. The ROS quantum yield increased from 0.30 in an aqueous environment to 0.51 when using alginate-based formulations, and it was further enhanced to 0.81 in the case of OSA. Furthermore, the nanoformulations produced fluorescent signals suitable for use as cellular imaging agents, demonstrating contrast-enhancing capabilities in medical imaging and showing minimal toxicity.

Molecular-properties based formulation guidance tree for amorphous and supersaturable mesoporous silica preparations of poorly soluble compounds

A huge majority of new chemical entities (NCEs) advancing through the drug discovery pipeline often have poor aqueous solubility. This requires formulation scientists to search for solubility enhancement strategies, within the constraints of time and material. To address these challenges, a strategic platform formulation is often required for a rapid compound screening to enable early exploratory PK and toxicology studies. Through this work, we present an option of a material-sparing, high yielding and solubility-enabling amorphous API and HPMCAS-L co-loaded mesoporous silica-based formulation. The usability of this platform formation strategy was assessed for a physico-chemically diverse set of eleven compounds. The formulation approach was successful in stabilizing the model compounds mesoporous silica. Additionally, through the presence of HPMCAS-L, the precipitation risk in supersaturable aqueous environment was significantly reduced. Finally, this manuscript provides fundamental, computational and experimental molecular-properties based formulation guidance tree to a priori gauge the (1) possibility of generating solid-state stable amorphous formulations and (2) sustaining in vitro supersaturation in extreme non-sink dissolution conditions. This unique and conceptual formulation guidance tree is believed to be extremely beneficial to drug discovery formulators to triage NCEs and streamline solubility-enabling formulation efforts.

Coumarin-Derived Caging Groups in the Spotlight: Tailoring Physiochemical and Photophysical Properties.

The development of light-responsive molecular tools enables spatiotemporal control of biochemical processes with superior precision. Amongst these molecular tools, photolabile caging groups are employed to prevent critical binding interactions between a bioactive molecule and its corresponding target. Only upon irradiation with light, the bioactive is released in its 'active' form and is now readily available to bind to its target. Coumarin-derived caging groups constitute one of the most popular classes of photolabile protecting groups, due to their facile synthetic accessibility, ease of tuning photophysical properties via structural modification and rapid photolysis reactions. Herein, we highlight the recent progress made on the development of coumarin-derived caging groups, in which the red-shifting of absorption spectra, improving aqueous solubility and tailoring sub-cellular localisation has been of particular interest.

Effects of Aqueous Solubility and Geochemistry on CO2 Storage in Offshore Basins

The increasing global focus on carbon capture and storage (CCS) has highlighted the potential for offshore CO2 sequestration, particularly following recent successes in onshore projects. This research investigates the qualitative analysis of carbon trapping efficiency in offshore basins, employing a GEM simulator to incorporate factors such as aqueous solubility and geochemistry. The findings reveal that anticlines represent ideal geological structures for carbon storage, effectively trapping a significant portion of injected CO2. For effective mineralization, it is crucial to dissolve CO2 into saline aquifers to generate H+, which facilitates the release of Ca2+ and Al3+ from anorthite. This process leads to the dissolution of anorthite and the precipitation of kaolinite, while calcite transitions from a dissolved state to a precipitated state over time. The analysis indicates that structural trapping provides the highest storage contribution during the injection phase, whereas residual gas trapping becomes dominant by the end of the simulation. Notably, it is observed that the storage contribution of structural trapping decreases from 28.39% to 19.05%, and the percentage increase in storage contributions of residual gas, solubility, ionic, and mineral trapping are 4.12%, 3.25%, 1.69%, and 0.28% for CO2 plus water injection, thereby improving the long-term security of CO2 storage in offshore basins. It is most beneficial to optimize the layout and design of the injection well to ensure a uniform distribution of carbon dioxide and to increase the injection rate.

Enhancing lutein stability and bioaccessibility with high internal phase emulsions stabilized by octenylsuccinylated starch

AbstractLutein possesses antioxidant properties and is a main component of the macular pigment, vital for infant eye and brain development. However, its use is constrained by its poor aqueous solubility and low stability. High internal phase emulsions (HIPEs) are valued in food development for encapsulating and protecting hydrophobic nutraceuticals. The objective of this study is to improve lutein's stability and bioaccessibility using HIPEs stabilized by biopolymer octenylsuccinylated starch (OSS). Three types of commercial OSS, including CAPSUL TA (CTA), HI‐CAP 100 (HC), and Purity Gum 2000, were tested for their emulsification properties in forming lutein HIPEs. Lutein HIPEs stabilized by 15%–25% CTA and 15%–30% HC had no phase separation and were selected for subsequent testing. After 21 days of storage at room temperature, lutein HIPEs showed higher lutein retention compared to free lutein. Lutein HIPEs stabilized with higher emulsifier concentrations (25% CTA and 30% HC) exhibited greater droplet diameter stability than those with lower concentrations. Additionally, lutein HIPEs significantly enhanced lutein retention under UV exposure and thermal stress. The in vitro bioaccessibility of lutein was highest in the HIPE stabilized by 20% CTA, reaching 54.36%. In conclusion, lutein HIPEs stabilized by 20% CTA demonstrated superior lutein stability and bioaccessibility, showing significant potential as an effective lutein delivery system.

Exploratory study on physicochemical properties of nitazoxanide nanocrystalline suspension obtained by evaporative solvent-antisolvent technique

Nitazoxanide (NTZ) is a broad-spectrum antiparasitic drug with low bioavailability due to its poor aqueous solubility, classified as a Biopharmaceutical Classification System (BCS) class II drug. This study aimed to improve the understanding of NTZ nanocrystalline suspensions produced via the solvent-antisolvent technique. NTZ was extracted from commercially available coated tablets and characterized using DSC, TG, UV-Vis, and FTIR, revealing the presence of impurities likely from excipients. Nanocrystalline suspensions were prepared using three different stabilizers (Lecithin, Poloxamer 188, and Tween® 80) and evaluated for particle size distribution (PSD) and polydispersity index (PDI) over a one-week stability study. Poloxamer 188 was the most effective in reducing particle size (934.7 nm), though Lecithin achieved a more favorable PDI (0.289), indicating better particle uniformity. These findings suggest the solvent-antisolvent technique is a promising approach for producing NTZ nanocrystalline suspensions, but further reduction in particle size and exploration of alternative stabilizers are needed to optimize stability and performance.

In Vitro Cytotoxicity and Pharmacokinetic Study for Bosutinib Solid Lipid Nanoparticles.

Bosutinib (BST) is a Biopharmaceutics Classification System Class II drug having very low solubility and high permeability. Low aqueous solubility and poor dissolution of BST lead to poor bioavailability, Thus, limited aqueous solubility is the bottleneck for the therapeutic outcome of BST. Animal data suggest that the absolute bioavailability of BST is about 14-34% due to an extensive first-pass effect. To overcome hepatic first-pass metabolism and to enhance oral bioavailability, lipid-based drug delivery systems such as solid lipid nanoparticles (SLNs) can be used. SLNs are submicron colloidal carriers having a size range of 50-1000 nm. These are prepared with physiological lipid and dispersed in water or aqueous surfactant solution. BST can be conveniently loaded into SLNs to improve the oral bioavailability by exploiting the intestinal lymphatic transport. An optimal system was evaluated for bioavailability study in rats compared with that of BST suspension (SUS). An in vitro cytotoxicity study was done by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay method through ATCC cell lines; the percent inhibition was more in SLN when compared with SUS. The pharmacokinetics of BST-SLNs after oral administration in male Wistar rats was studied. The bioavailability of BST was increased by 2.28 fold when compared with that of a BST SUS. The results are indicative of SLNs as suitable lipid-based carrier system for improving the oral bioavailability of BST.

A novel temperature-controlled media milling device to produce drug nanocrystals at the laboratory scale

Poor aqueous solubility of preexisting and emerging drug molecules is a common issue faced in the field of pharmaceutics. To address this, particle size reduction techniques, including drug micro- and nanonisation have been widely employed. Nanocrystals (NCs), drug particles with particle sizes below 1 µm, offer high drug content, improved dissolution, and long-acting capabilities. Media milling is the most used method to prepare NCs using of-the-shelf machinery, both at the laboratory and industrial scales. However, early NCs development, especially when limited amounts of the active are available, require the use of milligram-scale media milling. This study introduces a novel mini-scale milling device (Mini-mill) that incorporates temperature control through a water-cooled jacket. The device was used to produce NCs of three model hydrophobic drugs, itraconazole, ivermectin and curcumin, with lowest particle sizes of 162.5 ± 0.4 nm, 178 ± 2 nm, and 116.7 ± 0.7 nm, respectively. Precise control of milling temperature was achieved at 15, 45, and 75°C, with drug dependent particle size reduction trends, with no adverse effects on the milling materials or polymorphic changes in the NCs, as confirmed by calorimetric analysis. Finally, a scale-up feasibility study was carried out in a lab-scale NanoDisp®, confirming that the novel Mini-mills are a material-efficient tool for early formulation development, with potential for scale-up to commercial mills.

Experimental measurement, thermodynamic analysis, and mathematical modeling for budesonide solubility in 1-propanol + water mixtures at T = (293.2 to 313.2) K.

Budesonide (BDS) a steroid-based anti-inflammatory drug widely prescribed for various diseases, has a low aqueous solubility. In this study, we investigated cosolvency approach to study the thermodynamic specifications related to the solubility of BDS at the temperature range of 293.2-313.2K in (1-propanol + water) mixtures applying the shaking flask method. The predictive power of different mathematical models for experimental data in the cosolvency systems was evaluated. For this purpose, the linear and nonlinear mathematical equations such as van't Hoff model (as a linear model), Buchowski-Ksiazczak equation (as a non-linear), CNIBS/R-K and MRS models (as a linear model for solvent composition at an isothermal condition), modified Wilson model (as a non-linear model for isothermal condition), the Jouyban-Acree model (as a model that considers temperature and solvent composition), and Jouyban-Acree-van't Hoff model (as a model with no further input data) were studied. Also, the Williams-Amidon excess Gibbs energy model was investigated. In addition, the related apparent thermodynamics of the BDS dissolution process in the desired temperature such as Gibbs free energy, enthalpy, and entropy, were computed by the corresponding equations. Moreover, based on the inverse Kirkwood-Buff integrals, it is demonstrated that BDS is preferentially solvated by water in water-rich mixtures. The accuracy of the fitness was evaluated with mean relative deviations (MRDs%) for back-calculated molar BDS solubility data. The result showed that the maximum solubility of BDS was obtained at 0.7 mass fraction of 1-propanol at all temperatures. Thermodynamic studies demonstrated that BDS dissolution procedures were obtained as endothermic and entropy-driven in almost all cases. The overall MRDs% values for the back-computed BDS solubility in the aqueous mixture of 1-propanol based on van't Hoff model, Buchowski-Ksiazczak equation, CNIBS/R-K model, modified Wilson model, Jouyban-Acree model, Jouyban-Acree-van't Hoff model, MRS model, and Williams-Amidon excess Gibbs energy model were found 1.93%, 1.80%, 11.68%, 33.32%, 12.30%, 9.24%, 10.70%, and 6.57%, respectively.

The anticancer potential of tetrahydrocurcumin-phytosomes against oral carcinoma progression

BackgroundHerbal medicine combined with nanotechnology offers an alternative to the increasing burden of surgery and/or chemotherapy, the main therapeutics of oral carcinoma. Phytosomes are nano-vesicular systems formed by the interaction between phospholipids and phyto-active components via hydrogen bonding, exhibiting superior efficacy over pure phytocomponents in drug delivery.MethodsTetrahydrocurcumin (THC)-phytosomes were prepared by thin film hydration method. After characterization, in vitro cytotoxicity, antiproliferative capacity, antioxidant potential and full apoptotic workup were paneled on oral squamous cell carcinoma (SCC4) in comparison with native THC-solution and cisplatin (3.58 µg/mL intravenous injection), as positive controls. In addition, we tested the three medications on normal oral keratinocytes and gingival fibroblasts to attest to their tissue-selectivity.ResultsSuccessful preparation of THC-phytosomes using 1:1 molar ratio of THC to phospholipid exhibited significantly increased aqueous solubility, good colloidal properties, and complete drug release after one hour. On SCC4 cells, THC-phytosomes, at their dose-/time-dependency at ~ 60.06 µg/mL escalated cell percentages in the S-phase with 32.5 ± 6.22% increase, as well as a startling 29.69 ± 2.3% increase in apoptotic population. Depletion of the cell colonies survival to 0.29 ± 0.1% together with restraining the migratory rate by -6.4 ± 6.8% validated THC-phytosomes’ antiproliferative capacity. Comparatively, the corresponding results of THC-solution and cisplatin revealed 12.9 ± 0.9% and 25.8 ± 1.1% for apoptosis and 0.9 ± 0.1% and 0.7 ± 0.08% for colony survival fraction, respectively. Furthermore, the nanoformulation exhibited the strongest immuno-positivity to caspase-3, which positively correlated with intense mitochondrial fluorescence by Mitotracker Red, suggesting its implication in the mitochondrial pathway of apoptosis, a finding further explained by the enormously high Bax and caspase-8 expression by RT-qPCR. Finally, the THC groups showed the lowest oxidative stress index, marking their highest free radical-scavenging potential among the test groups.ConclusionsTHC-phytosomes are depicted to be an efficient nanoformulation that enhanced the anticancer efficacy over the free drug counterpart and the conventional chemotherapeutic. Additionally, being selective to cancer cells and less cytotoxic to normal cells makes THC-phytosomes a potential candidate for tissue-targeted therapy.

Discovery of Arylpiperazines with Broad-Spectrum Antimicrobial Activity and Favorable Pharmacokinetic Profiles.

Microorganisms can induce diseases with significant clinical implications for human health. Multidrug-resistant microorganisms have been on the rise worldwide over the past few decades, and no new antibiotics have been introduced to the market in a considerable amount of time. Such situation highlights the urgency of discovering new antimicrobial drugs to address this pressing issue. Therefore, the objective of this study was to identify bioactive compounds against 15 species of bacteria and 5 species of fungi of clinical relevance through in vitro screening of 58 synthetic compounds from four chemical classes of our internal library of synthetic compounds. Our findings highlight arylpiperazines 18, 20, 26, 27, and 29, and the aminothiazole 50, as potent broad-spectrum antimicrobials (MICs = 12.5 - 15.6 mg.mL-1) against clinically relevant bacteria and fungi. Additionally, these compounds displayed low cytotoxicity against various host cells and a favorable in vitro pharmacokinetic profile for oral administration. Indeed, all six showed adequate lipophilicity, high gastrointestinal permeability, metabolic stability in human and mouse liver microsomes, and satisfactory aqueous solubility. Thus, they emerge as promising starting points for hit-to-lead studies towards new antibacterial and antifungal agents, especially against Staphylococcus epidermidis, Staphylococcus aureus, Lactobacillus paracasei and Candida orthopsilosis.

Ionic Liquid-Mediated Transdermal Delivery of Organogel Containing Cyclosporine A for the Effective Treatment of Psoriasis.

The dermal delivery of peptide therapeutics that are of high molecular weight is a challenge. Cyclosporine A (CsA) is a cyclic undecapeptide with poor aqueous solubility and high molecular weight (1202 Da) indicated for psoriasis. The objective of the study was to evaluate the effect of ionic liquids mixed with the Pluronic F127 matrix in skin permeation of CsA and its efficacy in psoriasis treatment. Choline and geranic acid (CAGE) ionic liquids in a 1:2 molar ratio were mixed with Pluronic F127 (22.7%) and PEG 400 (45%) to prepare an organogel formulation. The CsA-loaded CAGE (CsA-CAGE) and CAGE-Pluronic F127 gels (CsA-CAGE-P gel) were characterized for physical and rheological characteristics. The skin transport studies showed that free CsA did not permeate across the excised porcine skin after 48 h. The amount of CsA permeated across the oleic acid (0.25% v/v) and palmitic acid (0.25% w/v) cotreated skin was found to be 244 ± 4 and 1236 ± 17 μg/cm2, respectively. The application of CsA-CAGE and CsA-CAGE-P gel enhanced CsA flux by 110- and 135-fold, respectively, compared with the control. The thermal analysis and biophysical studies changed the barrier property of the skin significantly (p < 0.05) after incubation with CAGE and CAGE-P gel. The pharmacokinetic studies in the rat model showed that topical application of CsA-CAGE-P gel provided 2.6- and 1.9-fold greater C max and AUC0-t, respectively, compared to the control group. In vitro-in vivo level A correlations were established with R 2 values of 0.991 and 0.992 for both linear and polynomial equations for the CsA-CAGE-P gel formulation using the Wagner-Nelson method. The topical application of CsA-CAGE-P gel (10 mg/kg) on an imiquimod-induced plaque psoriatic model reduced the area of the psoriasis and severity index (PASI) score significantly for erythema and scaling, reversing the changes to skin thickness, blood flow rate, and transepidermal water loss. Together, CAGE-Pluronic F127 organogel was developed as an effective topical formulation for the local and systemic delivery of CsA for the treatment of psoriasis.

Formulation and Evaluation of Nano-particles Loaded with Salvia miltiorriza by Homogenization Method

Aims: The aim of the present study is to formulate and evaluate the Salvia miltorrhizaloaded Nano-structured lipid carriers(SM-NLC) in order to enhance the aqueous solubility and bioavailability as the efficacy of Salvia miltiorriza extract has been restricted due to less solubility and low bioavailability. Introduction: Salvia miltiorrhiza is a well-known Chinese herb that belongs to the family Labiatae. The herb has been widely used to treat various kinds of ailments, and its main phytochemical constituents are Tanshinone I, Tanshinone II, Miltirone, and Salvionolic acid, which are mainly found in the extract of roots. These Phytochemical constituents are responsible for several pharmacological activities such as anti-oxidant, anti-microbial, anti-hyperlipidemic, anti-inflammatory, cardiovascular diseases etc. Objective: Nano-lipid carriers are useful in enhancing the solubility of poor water-soluble drugs. The faulty lattice arrangement of Nano-lipid carriers (NLC) provides better entrapment, thus providing more space for the drug to incorporate in the lattice structure of NLC, improving the stability of the formulation and preventing the drug leakage from the matrix. Methods: SM-NLCs were prepared by using oleic acid and stearic acid as liquid and solid lipids, respectively and tween 80 as the surfactant by high-speed homogenization method. The optimization of SM- NLC was performed by applying the Box-Behnken experimental design. The independent variables were chosen as the amount of lipids, surfactant concentration, and sonication time, whereas dependent variables were opted as particle size and entrapment efficiency. The influence of different proportions of the lipids (Stearic acid and Oleic acid) and the surfactant (Tween 80) was analysed on the dependent variables. The optimized formulation was evaluated for Particle size (241.7nm±3), Polydispersity index (.249 ±0.05), Zeta Potential (-14.6±5), and entrapment efficiency (82.49%). Scanning Electron Microscopy (SEM) was performed to identify the surface morphology, and the entrapment of the drug into the nanostructured matrix was verified by Differential Scanning Calorimetry. The interaction between the formulations was confirmed by performing FTIR. The dialysis bag method was performed to calculate the in vitro drug release from the optimized formulation. Additionally, a stability study was performed for 1 month of duration. Result: The SM NLCs were successfully formulated based on the Box-Behnken design. Particle size, PDI, zeta potential, and EE demonstrated less than a 5% difference compared to the predicted value. The formulations did not show any possible interactions with the lipids. The optimized formulations were found stable after one month of stability studies. Conclusion: The above results confirmed that Salvia miltiorrhiza could be effectively formulated in the form of a nanostructured-lipid carrier system. The formulation and evaluation of nanoparticles have been performed successfully using the homogenization method.

Exocyclic and Linker Editing of Lys63-linked Ubiquitin Chains Modulators Specifically Inhibits Non-homologous End-joining Repair.

Despite the great advances in discovering cyclic peptides against protein targets, their reduced aqueous solubility, cell permeability, and activity of the cyclic peptide restrict its utilization in advanced biological research and therapeutic applications. Here we report on a novel approach of structural alternation of the exocyclic and linker parts that led to a new derivative with significantly improved cell activity allowing us to dissect its mode of action in detail. We have identified an effective cyclic peptide (CP7) that induces approximately a 9-fold increase in DNA damage accumulation and a remarkable increase in apoptotic cancer cell death compared to the reported molecule. Notably, treating cells with CP7 leads to a dramatic decrease in the efficiency of non-homologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs), which is accompanied by an increase in homologous recombination (HR) repair. Interestingly, treating BRCA1-deficient cells with CP7 restores HR integrity, which is accompanied by increased resistance to CP7. Additionally, CP7 treatment increases the sensitivity of cancer cells to ionizing radiation. Collectively, our findings demonstrate that CP7 is a selective inhibitor of NHEJ, offering a potential strategy to enhance the effectiveness of radiation therapy.

Exocyclic and Linker Editing of Lys63‐linked Ubiquitin Chains Modulators Specifically Inhibits Non‐homologous End‐joining Repair

AbstractDespite the great advances in discovering cyclic peptides against protein targets, their reduced aqueous solubility, cell permeability, and activity of the cyclic peptide restrict its utilization in advanced biological research and therapeutic applications. Here we report on a novel approach of structural alternation of the exocyclic and linker parts that led to a new derivative with significantly improved cell activity allowing us to dissect its mode of action in detail. We have identified an effective cyclic peptide (CP7) that induces approximately a 9‐fold increase in DNA damage accumulation and a remarkable increase in apoptotic cancer cell death compared to the reported molecule. Notably, treating cells with CP7 leads to a dramatic decrease in the efficiency of non‐homologous end joining (NHEJ) repair of DNA double‐strand breaks (DSBs), which is accompanied by an increase in homologous recombination (HR) repair. Interestingly, treating BRCA1‐deficient cells with CP7 restores HR integrity, which is accompanied by increased resistance to CP7. Additionally, CP7 treatment increases the sensitivity of cancer cells to ionizing radiation. Collectively, our findings demonstrate that CP7 is a selective inhibitor of NHEJ, offering a potential strategy to enhance the effectiveness of radiation therapy.