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A visual Raman nano-delivery system (NS) is a widely used technique for the visualization and diagnosis of tumors and various biological processes. Thiophene-based organic polymers exhibit excellent biocompatibility, making them promising candidates for development as a visual Raman NS. However, materials based on thiophene face limitations due to their absorption spectra not matching with NIR (near-infrared) excitation light, which makes it difficult to achieve enhanced Raman properties and also introduces potential fluorescence interference. In this study, we introduce a donor–acceptor (D-A)-structured thiophene-based polymer, PBDB-T. Due to the D-A molecular modulation, PBDB-T exhibits a narrow bandgap of Eg = 2.63 eV and a red-shifted absorption spectrum, with the absorption edge extending into the NIR region. Upon optimal excitation with 785 nm light, it achieves ultra-strong pre-resonant Raman enhancement while avoiding fluorescence interference. As an intrinsically sensitive visual Raman NS for in vivo imaging, the PBDB-T NS enables the diagnosis of microtumor regions with dimensions of 0.5 mm × 0.9 mm, and also successfully diagnoses deeper tumor tissues, with an in vivo circulation half-life of 14.5 h. This research unveils the potential application of PBDB-T as a NIR excited visual Raman NS for microtumor diagnosis, introducing a new platform for the advancement of "Visualized Drug Delivery Systems". Moreover, the aforementioned platform enables the development of a more diverse range of targeted visual drug delivery methods, which can be tailored to specific regions. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop cholic-acid-stabilized itraconazole nanosuspensions (ITZ-Nanos) with the objective of enhancing drug dissolution and oral absorption. A laboratory-scale microprecipitation–high-pressure homogenization method was employed for the preparation of the ITZ-Nanos, while dynamic light scattering, transmission electron microscope analysis, X-ray diffraction, differential scanning calorimetry, and high-performance liquid chromatography analysis were utilized to evaluate their physicochemical properties. The absorption and bioavailability of the ITZ-Nanos were assessed using Caco-2 cells and rats, with Sporanox® pellets as a comparison. Prior to lyophilization, the particle size of the ITZ-Nanos measured approximately 225.7 nm. Both X-ray diffraction and differential scanning calorimetry confirmed that the ITZ remained crystalline within the nanocrystals. Compared to the pellets, the ITZ-Nanos exhibited significantly higher levels of supersaturation dissolution and demonstrated enhanced drug uptake by the Caco-2 cells. The AUC(0–t) value for the ITZ-Nanos in rats was 1.33-fold higher than that observed for the pellets. These findings suggest that cholic acid holds promise as a stabilizer for ITZ nanocrystals, as well as potentially other nanocrystals. [ABSTRACT FROM AUTHOR]

Background In the current work, co-rotating twin-screw processor (TSP) was utilized to formulate solid crystal suspension (SCS) of carvedilol (CAR) for enhancing its solubility, dissolution rate, permeation and bioavailability using mannitol as a hydrophilic carrier. Methods In-silico molecular dynamics (MD) studies were done to simulate the interaction of CAR with mannitol at different kneading zone temperatures (KZT). Based on these studies, the optimal CAR: mannitol ratios and the kneading zone temperatures for CAR solubility enhancement were assessed. The CAR-SCS was optimized utilizing Design-of-Experiments (DoE) methodology using the Box-Behnken design. Saturation solubility studies and in vitro dissolution studies were performed for all the formulations. Physicochemical characterization was performed using differential scanning calorimetry , Fourier transform infrared spectroscopy, X-ray diffraction studies, and Raman spectroscopy analysis. Ex vivo permeation studies and in vivo pharmacokinetic studies for the CAR-SCS were performed. Stability studies were performed for the DoE-optimized CAR-SCS at accelerated stability conditions at 40 ºC/ 75% RH for three months. Results Experimentally, the formulation with CAR: mannitol ratio of 20:80, prepared using a KZT of 120 ºC at 100 rpm screw speed showed the highest solubility enhancement accounting for 50-fold compared to the plain CAR. Physicochemical characterization confirmed the crystalline state of DoE-optimized CAR-SCS. In-vitro dissolution studies indicated a 6.03-fold and 3.40-fold enhancement in the dissolution rate of optimized CAR-SCS in pH 1.2 HCl solution and phosphate buffer pH 6.8, respectively, as compared to the pure CAR. The enhanced efficacy of the optimized CAR-SCS was indicated in the ex vivo and in vivo pharmacokinetic studies wherein the apparent permeability was enhanced 1.84-fold and bioavailability enhanced 1.50-folds compared to the plain CAR. The stability studies showed good stability concerning the drug content. Conclusions TSP technology could be utilized to enhance the solubility, bioavailability and permeation of poor soluble CAR by preparing the SCS.

To enhance the retention times and therapeutic efficacy of paeoniflorin (PF), a liver-targeted drug delivery system has been developed using glycyrrhetinic acid (GA) as a ligand. The development and optimization of GA-modified PF liposomes (GPLs) have shown promising potential for targeted delivery to the liver, opening up new possibilities for liver disease treatment. This study aimed to identify the best prescriptions using single-factor experiments and response surface methodology. The formulation morphology was determined using transmission electron microscopy. Tissue distribution was observed through in vivo imaging, and pharmacokinetic studies were conducted. The results indicated that GPLs, prepared using the thin film dispersion method and response surface optimization, exhibited well-dispersed and uniformly sized particles. The in vitro release rate of GPLs was slower compared to PF monomers, suggesting a sustained release effect. The liver-targeting ability of GA resulted in stronger fluorescence signals in the liver for targeted liposomes compared to non-targeted liposomes. Furthermore, pharmacokinetic studies demonstrated that GPLs significantly prolonged the residence time of PF in the bloodstream, thereby contributing to prolonged efficacy. These findings suggest that GPLs are more effective than PF monomers in terms of controlling drug release and delivering drugs to specific targets, highlighting the potential of PF as a liver-protective drug. [ABSTRACT FROM AUTHOR]

This study aimed to develop a mixed polymeric micelle formulation incorporating candesartan cilexetil (CAND) drug to enhance its oral bioavailability for the better treatment of hypertension. A Box–Behnken design was utilized to optimize the CAND-incorporated mixed polymeric micelles formulation (CAND-PFLC) consisting of Pluronics (P123 and F68) and lecithin (LC). The optimized CAND-PFLC micelles formulation was characterized for size, shape, zeta potential, polydispersity index (PDI), and entrapment efficiency (%EE). An in vitro release study, ex vivo permeability investigation, and an in vivo pharmacokinetic analysis were carried out to evaluate the performance of the formulation. The optimized CAND-PFLC micelles formulation demonstrated a spherical shape, a particle size of 44 ± 2.03 nm, a zeta potential of −7.07 ± 1.39 mV, a PDI of 0.326 ± 0.06, and an entrapment efficiency of 87 ± 3.12%. The formulation exhibited excellent compatibility, better stability, and a noncrystalline nature. An in vitro release study revealed a faster drug release of 7.98% at gastric pH in 2 hrs and 94.45% at intestinal pH within 24 hrs. The ex vivo investigation demonstrated a significantly enhanced permeability of CAND, with 94.86% in the micelle formulation compared to 9.03% of the pure drug. In vivo pharmacokinetic analysis showed a 4.11-fold increase in oral bioavailability of CAND compared to the marketed formulation. The CAND-PFLC mixed micelle formulation demonstrated improved performance compared to pure CAND, indicating its potential as a promising oral drug delivery system for the effective treatment of hypertension. [ABSTRACT FROM AUTHOR]

Background In the current work, co-rotating twin-screw processor (TSP) was utilized to formulate solid crystal suspension (SCS) of carvedilol (CAR) for enhancing its solubility, dissolution rate, permeation and bioavailability using mannitol as a hydrophilic carrier. Methods In-silico molecular dynamics (MD) studies were done to simulate the interaction of CAR with mannitol at different kneading zone temperatures (KZT). Based on these studies, the optimal CAR: mannitol ratios and the kneading zone temperatures for CAR solubility enhancement were assessed. The CAR-SCS was optimized utilizing Design-of-Experiments (DoE) methodology using the Box-Behnken design. Saturation solubility studies and in vitro dissolution studies were performed for all the formulations. Physicochemical characterization was performed using differential scanning calorimetry , Fourier transform infrared spectroscopy, X-ray diffraction studies, and Raman spectroscopy analysis. Ex vivo permeation studies and in vivo pharmacokinetic studies for the CAR-SCS were performed. Stability studies were performed for the DoE-optimized CAR-SCS at accelerated stability conditions at 40 ºC/ 75% RH for three months. Results Experimentally, the formulation with CAR: mannitol ratio of 20:80, prepared using a KZT of 120 ºC at 100 rpm screw speed showed the highest solubility enhancement accounting for 50-fold compared to the plain CAR. Physicochemical characterization confirmed the crystalline state of DoE-optimized CAR-SCS. In-vitro dissolution studies indicated a 6.03-fold and 3.40-fold enhancement in the dissolution rate of optimized CAR-SCS in pH 1.2 HCl solution and phosphate buffer pH 6.8, respectively, as compared to the pure CAR. The enhanced efficacy of the optimized CAR-SCS was indicated in the ex vivo and in vivo pharmacokinetic studies wherein the apparent permeability was enhanced 1.84-fold and bioavailability enhanced 1.50-folds compared to the plain CAR. The stability studies showed good stability concerning the drug content. Conclusions TSP technology could be utilized to enhance the solubility, bioavailability and permeation of poor soluble CAR by preparing the SCS.

Background: In the current work, co-rotating twin-screw processor (TSP) was utilized to formulate solid crystal suspension (SCS) of carvedilol (CAR) for enhancing its solubility, dissolution rate, permeation and bioavailability using mannitol as a hydrophilic carrier. Methods: In-silico molecular dynamics (MD) studies were done to simulate the interaction of CAR with mannitol at different kneading zone temperatures (KZT). Based on these studies, the optimal CAR: mannitol ratios and the kneading zone temperatures for CAR solubility enhancement were assessed. The CAR-SCS was optimized utilizing Design-of-Experiments (DoE) methodology using the Box-Behnken design. Saturation solubility studies and in vitro dissolution studies were performed for all the formulations. Physicochemical characterization was performed using differential scanning calorimetry , Fourier transform infrared spectroscopy, X-ray diffraction studies, and Raman spectroscopy analysis. Ex vivo permeation studies and in vivo pharmacokinetic studies for the CAR-SCS were performed. Stability studies were performed for the DoE-optimized CAR-SCS at accelerated stability conditions at 40 ºC/ 75% RH for three months. Results: Experimentally, the formulation with CAR: mannitol ratio of 20:80, prepared using a KZT of 120 ºC at 100 rpm screw speed showed the highest solubility enhancement accounting for 50-fold compared to the plain CAR. Physicochemical characterization confirmed the crystalline state of DoE-optimized CAR-SCS. In-vitro dissolution studies indicated a 6.03-fold and 3.40-fold enhancement in the dissolution rate of optimized CAR-SCS in pH 1.2 HCl solution and phosphate buffer pH 6.8, respectively, as compared to the pure CAR. The enhanced efficacy of the optimized CAR-SCS was indicated in the ex vivo and in vivo pharmacokinetic studies wherein the apparent permeability was enhanced 1.84-fold and bioavailability enhanced 1.50-folds compared to the plain CAR. The stability studies showed good stability concerning the drug content. Conclusions: TSP technology could be utilized to enhance the solubility, bioavailability and permeation of poor soluble CAR by preparing the SCS.

Resistance to isoniazid (INH) is common and increases the possibility of acquiring multidrug-resistant tuberculosis. For this study, isoniazid-loaded nanostructured lipid carriers (INH-NLCs) were developed and effectively functionalized with mannose (Man) to enhance the residence time of the drug within the lungs via specific delivery and increase the therapeutic efficacy of the formulation. The mannose-functionalized isoniazid-loaded nanostructured lipid carrier (Man-INH-NLC) formulation was evaluated with respect to various formulation parameters, namely, encapsulation efficiency (EE), drug loading (DL), average particle size (PS), zeta potential (ZP), polydispersity index (PDI), in vitro drug release (DR), and release kinetics. The in vitro inhalation behavior of the developed formulation after nebulization was investigated using an Andersen cascade impactor via the estimation of the mass median aerosolized diameter (MMAD) and geometric aerodynamic diameter (GAD) and subsequently found to be suitable for effective lung delivery. An in vivo pharmacokinetic study was carried out in a guinea pig animal model, and it was demonstrated that Man-INH-NLC has a longer residence time in the lungs with improved pharmacokinetics when compared with unfunctionalized INH-NLC, indicating the enhanced therapeutic efficacy of the Man-INH-NLC formulation. Histopathological analysis led us to determine that the extent of tissue damage was more severe in the case of the pure drug solution of isoniazid compared to the Man-INH-NLC formulation after nebulization. Thus, the nebulization of Man-INH-NLC was found to be safe, forming a sound basis for enhancing the therapeutic efficacy of the drug for improved management in the treatment of pulmonary tuberculosis. [ABSTRACT FROM AUTHOR]

Approximately 1 billion people are affected by neglected diseases around the world. Among these diseases, schistosomiasis constitutes one of the most important public health problems, being caused by Schistosoma mansoni and treated through the oral administration of praziquantel (PZQ). Despite being a common disease in children, the medication is delivered in the form of large, bitter-tasting tablets, which makes it difficult for patients to comply with the treatment. In order to mask the taste of the drug, allow more appropriate doses for children, and enhance the absorption by the body, different polymer matrices based on poly(methyl methacrylate) (PMMA) were developed and used to encapsulate PZQ. Polymer matrices included PMMA nano- and microparticles, PMMA-co-DEAEMA (2-(diethylamino)ethyl methacrylate), and PMMA-co-DMAEMA (2-(dimethylamino)ethyl methacrylate) microparticles. The performances of the drug-loaded particles were characterized in vitro through dissolution tests and in vivo through pharmacokinetic analyses in rats for the first time. The in vitro dissolution studies were carried out in accordance with the Brazilian Pharmacopeia and revealed a good PZQ release profile in an acidic medium for the PMMA-DEAEMA copolymer, reaching values close to 100 % in less than 3 h. The in vivo pharmacokinetic analyses were conducted using free PZQ as the control group that was compared with the investigated matrices. The drug was administered orally at doses of 60 mg/kg, and the PMMA-co-DEAEMA copolymer microparticles were found to be the most efficient release system among the investigated ones, reaching a Cmax value of 1007 ± 83 ng/mL, even higher than that observed for free PZQ, which displayed a Cmax value of 432 ± 98 ng/mL. [ABSTRACT FROM AUTHOR]

Introduction: Accurate diagnosis and personalized treatments involving site-targeted cancer localization, drug delivery, therapeutic strategy, and disease pathways identification, rely on a precise understanding of biomarker kinetics, drug pharmacokinetics, and mechanistic behaviour of functionalized tracers through in vitro and in vivo studies. X-ray fluorescence (XRF) computed tomography (XFCT) offers a potential alternative to current 3D imaging techniques for spatiotemporal localization of nanoparticle-tracers with high spatial resolution and sensitivity. In this work, the applicability of a benchtop cone-beam system with a polychromatic X-ray source was examined with regard to physical constraints of engineered tissue models.Methods: A tissue engineering approach based on a decellularized scaffold was used to establish a 3D breast cancer model with MDA-MB-231 cells in co-culture with primary human fibroblasts. The 3D breast cancer system, in combination with small-animal-sized phantoms, was used to demonstrate the novel integrated pre-clinical imaging approach to perform in vitro surrogate investigations and non-destructive analysis on biophantoms. These models are adopted to evaluate the functionality and optimize the setup for high-spatial-resolution, fast, and fully-3D quantitative imaging. Polychromatic X-rays from a microfocus source are used for XRF stimulation from conventional Gadolinium (Gd) and nanoparticle-based Molybdenum (MoNPs) contrast agents.Results and Discussion: The intestinal scaffold allowed the invasion of the breast cancer cells over this barrier and therefore provides a valuable tool to study metastasis formation of tumor cells from epithelial origin. The breast cancer model was well suited for the development and validation of the proposed XRF imaging, with spatial resolution under

A new series of 5-(4-chlorophenyl)-1,3,4-thiadiazole-based compounds featuring pyridinium (3), substituted piperazines (4a–g), benzyl piperidine (4i), and aryl aminothiazoles (5a–e) heterocycles were synthesized. Evaluation of the cytotoxicity potential of the new compounds against MCF-7 and HepG2 cancer cell lines indicated that compounds 4e and 4i displayed the highest activity toward the tested cancer cells. A selectivity study demonstrated the high selective cytotoxicity of 4e and 4i towards cancerous cells over normal mammalian Vero cells. Cell cycle analysis revealed that treatment with either compound 4e or 4i induced cell cycle arrest at the S and G2/M phases in HepG2 and MCF-7 cells, respectively. Moreover, the significant increase in the Bax/Bcl-2 ratio and caspase 9 levels in HepG2 and MCF-7 cells treated with either 4e or 4i indicated that their cytotoxic effect is attributed to the ability to induce apoptotic cell death. Finally, an in vivo radioactive tracing study of compound 4i proved its targeting ability to sarcoma cells in a tumor-bearing mice model. [ABSTRACT FROM AUTHOR]

The purpose of this experiment was to explore the effect of Solid lipid nanoparticles (SLNs) on improving the oral absorption and bioavailability of cinnamaldehyde (CA). CA-SLNs were prepared by high-pressure homogenization and characterized by particle size, entrapment efficiency, and morphology, thermal behavior and attenuated total reflection Fourier transform infrared (ATR-FTIR). In vitro characteristics of release, stability experiments, cytotoxicity, uptake and transport across Caco-2 cell monolayer of CA-SLNs were studied as well. In addition, CA-SLNs underwent pharmacokinetic and gastrointestinal mucosal irritation studies in rats. CA-SLNs exhibited a spherical shape with a particle size of 44.57 ± 0.27 nm, zeta potential of −27.66 ± 1.9 mV and entrapment efficiency of 83.63% ± 2.16%. Differential scanning calorimetry (DSC) and ATR-FTIR confirmed that CA was well encapsulated. In vitro release of CA-SLNs displayed that most of the drug (90.77% ± 5%) was released in the phosphate buffer, and only a small amount of drug (18.55% ± 5%) was released in the HCl buffer. CA-SLNs were taken up by an energy-dependent, endocytic mechanism mediated by caveolae mediated endocytosis across Caco-2 cells. The CA permeation through Caco-2 cell was facilitated by CA-SLNs. The outcome of the gastrointestinal irritation test demonstrated that CA-SLNs had no irritation to the rats' intestines. Compared with CA dispersions, incorporation of SLNs increased the oral bioavailability of CA more than 1.69-fold. It was concluded that CA-SLNs improved the absorption across Caco-2 cell model and improved the oral administration bioavailability of CA in rats. [ABSTRACT FROM AUTHOR]

89Zr represents a highly favorable positron emitter for application in immuno-PET (Positron Emission Tomography) imaging. Clinically, the 89Zr4+ ion is introduced into antibodies by complexation with desferrioxamine B. However, producing complexes of limited kinetic inertness. Therefore, several new chelators for 89Zr introduction have been developed over the last years. Of these, the direct comparison of the most relevant ones for clinical translation, DFO* and 3,4,3-(LI-1,2-HOPO), is still missing. Thus, we directly compared DFO with DFO* and 3,4,3-(LI-1,2-HOPO) immunoconjugates to identify the most suitable agent stable 89Zr-complexation. The chelators were introduced into cetuximab, and an optical analysis method was developed, enabling the efficient quantification of derivatization sites per protein. The cetuximab conjugates were efficiently obtained and radiolabeled with 89Zr at 37 °C within 30 min, giving the [89Zr]Zr-cetuximab derivatives in high radiochemical yields and purities of >99% as well as specific activities of 50 MBq/mg. The immunoreactive fraction of all 89Zr-labeled cetuximab derivatives was determined to be in the range of 86.5–88.1%. In vivo PET imaging and ex vivo biodistribution studies in tumor-bearing animals revealed a comparable and significantly higher kinetic inertness for both [89Zr]Zr-3,4,3-(LI-1,2-HOPO)-cetuximab and [89Zr]Zr-DFO*-cetuximab, compared to [89Zr]Zr-DFO-cetuximab. Of these, [89Zr]Zr-DFO*-cetuximab showed a considerably more favorable pharmacokinetic profile with significantly lower liver and spleen retention than [89Zr]Zr-3,4,3-(LI-1,2-HOPO)-cetuximab. Since [89Zr]Zr-DFO* demonstrates a very high kinetic inertness, paired with a highly favorable pharmacokinetic profile of the resulting antibody conjugate, DFO* currently represents the most suitable chelator candidate for stable 89Zr-radiolabeling of antibodies and clinical translation. [ABSTRACT FROM AUTHOR]

Oral administration of BCS class IV anticancer agents has always remained challenging and frequently results in poor oral bioavailability. The goal of the current study was to develop hybrid nanoparticles (HNPs) employing cholesterol and poloxamer-407 to boost paclitaxel's (PTX) oral bioavailability. A series of HNPs with different cholesterol and poloxamer-407 ratios were developed utilizing a single-step nanoprecipitation technique. The PTX loaded HNPs were characterized systematically via particle size, zeta potential, polydispersity index, surface morphology, in vitro drug release, FTIR, DSC, XRD, acute oral toxicity analysis, hemolysis evaluation, accelerated stability studies, and in vivo pharmacokinetic analysis. The HNPs were found within the range of 106.6±55.60 – 244.5±88.24 nm diameter with the polydispersity index ranging from 0.20±0.03 – 0.51±0.11. SEM confirmed circular, nonporous, and smooth surfaces of HNPs. PTX loaded HNPs exhibited controlled release profile. The compatibility between the components of formulation, thermal stability, and amorphous nature of HNPs were confirmed by FTIR, DSC, and XRD, respectively. Acute oral toxicity analysis revealed that developed system have no deleterious effects on the animals' cellular structures. HNPs demonstrated notable cytotoxic effects and were hemocompatible at relatively higher concentrations. In vivo pharmacokinetic profile (AUC 0-∞ , AUMC 0-∞ , t 1/2, and MRT 0-∞) of the PTX loaded HNPs was improved as compared to pure PTX. It is concluded from our findings that the developed HNPs are hemocompatible, biocompatible and have significantly enhanced the oral bioavailability of PTX. [Display omitted] • Development of a novel core shell type, PTX loaded Cs-Chol HNPs system. • Aqueous solubility of PTX was significantly enhanced by HNPs. • PTX loaded HNPs exhibited a controlled release profile. • Cs-Chol HNPs are stable, hemocompatible and biocompatible. • PTX loaded Cs-Chol HNPs are safe for oral delivery. [ABSTRACT FROM AUTHOR]

Continuous drug monitoring is a promising alternative to current therapeutic drug monitoring strategies and has a strong potential to reshape our understanding of pharmacokinetic variability and to improve individualised therapy. This review highlights recent advances in biosensing technologies that support continuous drug monitoring in real time. We focus primarily on aptamer-based biosensors, wearable and implantable devices. Emphasis is given to the approaches employed in constructing biosensors. We pay attention to sensors’ biocompatibility, calibration performance, long-term characteristics stability and measurement quality. Last, we discuss the current challenges and issues to be addressed in continuous drug monitoring to make it a promising, future tool for individualised therapy. The ongoing efforts are expected to result in fully integrated implantable drug biosensing technology. Thus, we may anticipate an era of advanced healthcare in which wearable and implantable biochips will automatically adjust drug dosing in response to patient health conditions, thus enabling the management of diseases and enhancing individualised therapy.

The cosmetic industry has flourished in recent years. Accordingly, the safety of cosmetic ingredients is increasing. Bromochlorophene (BCP) is a commonly used cosmetic preservative. To evaluate the effects of BCP exposure, in vitro dermal absorption and in vivo pharmacokinetic (PK) studies were conducted using gel and cream formulations. The Franz diffusion cell system and rat dorsal skin were used for tests according to the Korea Ministry of Food and Drug Safety guidelines for in vitro skin absorption methods. After the dermal application (1.13 mg/cm2) of BCP in the gel and cream formulations, liquid chromatography–mass spectrometry (LC–MS/MS) was used to evaluate the amount of BCP that remained unabsorbed on the skin (WASH), and that was present in the receptor fluid (RF), stratum corneum (SC), and (epi)dermis (SKIN). The total dermal absorption rate of BCP was 7.42 ± 0.74% for the gel formulation and 1.5 ± 0.9% for the cream formulation. Total recovery in an in vitro dermal absorption study was 109.12 ± 8.79% and 105.43 ± 11.07% for the gel and cream formulations, respectively. In vivo PK and dermal absorption studies of BCP were performed following the Organization for Economic Cooperation and Development guidelines 417 and 427, respectively. When intravenous (i.v.) pharmacokinetics was performed, BCP was dissolved in glycerol formal and injected into the tail vein (n = 3) of the rats at doses of 1 and 0.2 mg/kg. Dermal PK parameters were estimated by the application of the gel and cream formulations (2.34 mg/kg of BCP as an active ingredient) to the dorsal skin of the rats. Intravenous and dermal PK parameters were analyzed using a non-compartmental method. The dermal bioavailability of BCP was determined as 12.20 ± 2.63% and 4.65 ± 0.60% for the gel and cream formulations, respectively. The representative dermal absorption of BCP was evaluated to be 12.20 ± 2.63% based on the results of the in vivo PK study. [ABSTRACT FROM AUTHOR]

Objectives: Recently, a growing resistance to antimalarial drugs such as chloroquine, sulfadoxine–pyrimethamine, artemisinin derivatives and mefloquine has been observed. The pharmacokinetic limitation of the current therapy and multi-drug resistance has resulted in an urgent need to study the new antimalarial combinations with existing drugs. This study investigated the activity of a novel triple combination of atovaquone (nanosized)–proguanil–artesunate as an alternative artemisinin combination therapy. Atovaquone in this combination was formulated as a freeze–dried nanosuspension and its pharmacokinetic parameters were also evaluated. Methods: The suppressive and curative effect of atovaquone nanosuspension, proguanil, and artesunate were studied in a murine model. The in vivo pharmacokinetics of the newly developed atovaquone nanosuspension with particle size less than 200 nm was investigated. Results: Prophylactic efficacy of atovaquone nanosuspension alone at 1/80th the therapeutic dose was proven. In the curative test, atovaquone nanosuspension and proguanil at 1/10th the therapeutic dose was the minimum effective dose that resulted in complete cure of parasitaemia. As a triple combination, atovaquone nanosuspension in combination with proguanil at 1/80th the therapeutic dose of each and 1/5th the therapeutic dose of artesunate resulted in a complete cure. The in vivo pharmacokinetics of the nanosuspension showed a significant (three times) reduction in Tmax value and the area under the curve of the nanosuspension was 1.9 times greater as compared with the plain suspension. Conclusions: The potential of the synergistic combination of atovaquone nanosuspension–proguanil–artesunate in curing the multi-drug resistant malarial infection at reduced doses of all three drugs could be a solution to pill burden observed with the current therapy.

Modern drug delivery research focuses on developing biodegradable nanopolymer systems. The present study proposed a polymer-based composite nanogel as a transdermal drug delivery system for the pH-responsive targeted and controlled delivery of anticancer drug doxorubicin (DOX). Nanogels have properties of both hydrogels and nanomaterials. The β-cyclodextrin-based nanogels can enhance the loading capacity of poorly soluble drugs and promote a sustained drug release. The β-cyclodextrin-grafted methacrylic acid conjugated hyaluronic acid composite nanogel was successfully synthesized. β-Cyclodextrin was first grafted onto methacrylic acid. The composite nanogel-based drug carrier was prepared by controlled radical polymerization (CRP) of β-cyclodextrin-grafted methacrylic acid with hyaluronic acid. The doxorubicin-loaded carrier was characterized by Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, ultraviolet-visible (UV-vis) spectroscopy, zeta potential analysis, dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The drug loading and release efficiencies were carried out at different pH levels. The maximum drug loading and encapsulation efficiencies of the synthesized final nanogel composite material at pH 8.0 were 86.44 ± 2.12 and 96.07 ± 2.01%, respectively. The DOX-loaded final material showed a 90.0 ± 2.6% release percentage of DOX at pH 5.5, whereas at pH 7.4, the release percentage of DOX was observed to be only 35.0 ± 0.3%. In vitro swelling, degradation, hemocompatibility, drug release kinetics, cytotoxicity, apoptosis, cell colocalization, skin irritation, and skin permeation studies, along with in vivo pharmacokinetic studies, were performed to prove the efficacy of the synthesized nanogel composite as a transdermal carrier for doxorubicin.

The cosmetic industry has flourished in recent years. Accordingly, the safety of cosmetic ingredients is increasing. Bromochlorophene (BCP) is a commonly used cosmetic preservative. To evaluate the effects of BCP exposure, in vitro dermal absorption and in vivo pharmacokinetic (PK) studies were conducted using gel and cream formulations. The Franz diffusion cell system and rat dorsal skin were used for tests according to the Korea Ministry of Food and Drug Safety guidelines for in vitro skin absorption methods. After the dermal application (1.13 mg/cm2) of BCP in the gel and cream formulations, liquid chromatography–mass spectrometry (LC–MS/MS) was used to evaluate the amount of BCP that remained unabsorbed on the skin (WASH), and that was present in the receptor fluid (RF), stratum corneum (SC), and (epi)dermis (SKIN). The total dermal absorption rate of BCP was 7.42 ± 0.74% for the gel formulation and 1.5 ± 0.9% for the cream formulation. Total recovery in an in vitro dermal absorption study was 109.12 ± 8.79% and 105.43 ± 11.07% for the gel and cream formulations, respectively. In vivo PK and dermal absorption studies of BCP were performed following the Organization for Economic Cooperation and Development guidelines 417 and 427, respectively. When intravenous (i.v.) pharmacokinetics was performed, BCP was dissolved in glycerol formal and injected into the tail vein (n = 3) of the rats at doses of 1 and 0.2 mg/kg. Dermal PK parameters were estimated by the application of the gel and cream formulations (2.34 mg/kg of BCP as an active ingredient) to the dorsal skin of the rats. Intravenous and dermal PK parameters were analyzed using a non-compartmental method. The dermal bioavailability of BCP was determined as 12.20 ± 2.63% and 4.65 ± 0.60% for the gel and cream formulations, respectively. The representative dermal absorption of BCP was evaluated to be 12.20 ± 2.63% based on the results of the in vivo PK study.

Continuous drug monitoring is a promising alternative to current therapeutic drug monitoring strategies and has a strong potential to reshape our understanding of pharmacokinetic variability and to improve individualised therapy. This review highlights recent advances in biosensing technologies that support continuous drug monitoring in real time. We focus primarily on aptamer-based biosensors, wearable and implantable devices. Emphasis is given to the approaches employed in constructing biosensors. We pay attention to sensors' biocompatibility, calibration performance, long-term characteristics stability and measurement quality. Last, we discuss the current challenges and issues to be addressed in continuous drug monitoring to make it a promising, future tool for individualised therapy. The ongoing efforts are expected to result in fully integrated implantable drug biosensing technology. Thus, we may anticipate an era of advanced healthcare in which wearable and implantable biochips will automatically adjust drug dosing in response to patient health conditions, thus enabling the management of diseases and enhancing individualised therapy. Image 1 • The review summarizes biosensing technologies in real-time continuous drug monitoring. • The review focuses on aptamer-based sensors, wearables and implantable sensors. • The review summaries challenges and issues to address in continuous drug monitoring. [ABSTRACT FROM AUTHOR]

This study aimed to systematically explore compositional effects for a series of lipid systems, on the in vitro drug solubilization and in vivo bioavailability of three poorly water-soluble drugs with different physico-chemical properties. While many lipid-based drug products have successfully reached the market, there is still a level of uncertainty on the design guidelines for such drug products with limited understanding on the influence of composition on in vitro and in vivo performance. Lipid-based drug delivery systems were prepared using either single excipient systems based on partially digested triglycerides (i.e. mono- and/or di-glycerides) or increasingly complex systems by incorporating surfactants and/or triglycerides. These lipid systems were evaluated for both in vitro and in vivo behavior. Results indicated that simple single component long chain lipid systems are more beneficial for the absorption of the weak acid celecoxib and the weak base cinnarizine compared to equivalent single component medium chain lipid systems. Similarly, a two-component system produced by incorporating small amount of hydrophilic surfactant yields similar overall pharmacokinetic effects. The lipid drug delivery systems based on medium chain lipid excipients improved the in vivo exposure of the neutral drug JNJ-2A. The higher in vivo bioavailability of long chain lipid systems compared to medium chain lipid systems was in agreement with in vitro dilution and dispersion studies for celecoxib and cinnarizine. The present study demonstrated the benefits of using mono-/di-glycerides as single component excipients in LBDDS to streamline formulation screening and improve oral bioavailability for the three tested poorly water-soluble drugs. [ABSTRACT FROM AUTHOR]

Borneol can enhance the bioavailability of several other drugs by opening the blood-brain barrier and inhibiting P-glycoprotein (P-gp) efflux. However, whether borneol will impact the bioavailability and the mechanism of compound Danshen colon-specific osmotic pump capsule (CDCOPC) remains unclear. This study aimed to determine the effects of borneol on the in vitro release and in vivo pharmacokinetic characteristics of CDCOPC. Besides, the in vitro release behavior of CDCOPC was further assessed by chromatographic fingerprints. The in vitro release studies showed that borneol followed the zero-order release and hardly impacted the in vitro release of Salvia miltiorrhiza and Panax notoginseng in CDCOPC. Moreover, as revealed from the similarity results of fingerprints, the in vitro release of different components of CDCOPC was almost simultaneous. Compared with the commercially available tablets, the pharmacokinetics studies suggested that both CDCOPCs containing and lacking borneol could significantly prolong the retention time of these effective components; their average relative bioavailability values increased to 448.70% and 350.97%, respectively. Notably, borneol significantly improved the relative bioavailability of some components of CDCOPC, such as salvianolic acid B (SAB), tanshinone IIA (Tan IIA), notoginsenoside R1 (R1), ginsenoside Rg1 (Rg1), and ginsenoside Re (Re) from CDCOPC, while it slightly impacted ginsenoside Rb1 (Rb1) and ginsenoside Rd (Rd). Summarily, borneol is capable of improving the bioavailability of some effective components in CDCOPC, which is critical to design with CDCOPC for enhanced bioavailability. This study could also help reveal the composition principle of the compound Danshen formula (CDF). [ABSTRACT FROM AUTHOR]

For designing nanoparticles as drug carriers, a covalently crosslinked structure is necessary for the structural stability in vivo. In this study, we prepared core crosslinked nanoparticles through the formation of nanoemulsions stabilized by poly(ethylene glycol) (PEG)-bearing surfactants. The structural characteristics of these particles were carefully evaluated using small-angle scattering techniques including dynamic, static, X-ray, and neutron scattering. The particles demonstrated high stability even in vivo , with the suppression of premature drug release owing to the crosslinked structure. Interestingly, the ability to retain encapsulated molecules was dependent on the molecular weight of PEG in vivo , presumably due to the difference in the crowding density of PEG chains at the outermost surface. This suggests that conferring structural stability via a core crosslinked structure is surely important, but we also need to consider controlling the crowding density of the hydrophilic polymer chains in the particle shell when designing drug carriers. Unlabelled Image • Synthesizing core crosslinked nanoparticles via the formation of nanoemulsions. • Precise structural characterization of nanoparticles using small angle scattering. • Correlation of the polymer density on nanoparticles with the in vivo stability. [ABSTRACT FROM AUTHOR]

Background:Salvia miltiorrhiza polyphenolic acid (SMPA) is effective in the treatment of cardiovascular diseases and currently it is administered orally or intravenously. However, SMPA is poorly absorbed orally and quickly eliminated in vivo. A long-term frequent intravenous administration leads to poor patient compliance. Therefore, it is urgently demanded to find a new alternative route of noninjection drug delivery system for SMPA. Methods: Two dry powder inhalation (DPI) formulations of spray-dried SMPA formulation (P1) and spray-dried SMPA–L-leucine formulation (P2) were prepared by spray drying method and their physicochemical properties were assessed by thermogravimetric analysis, X-ray diffraction, scanning electron microscopy, particle size distribution analysis, and in vitro aerodynamic analysis. Moreover, In vitro cytotoxicity of SMPA and P2 was conducted with NR8383 cells. In vivo pharmacokinetics were carried out by Penn-Century endotracheal intubation technique to deliver P2 to the lungs of rats. Results and Conclusions: The moisture content of P1 and P2 were 5.81% ± 0.005%, and 4.08% ± 0.002%, respectively. P1 and P2 were in an amorphous state. Moreover, P1 had slightly corrugated surfaces, whereas P2 exhibited severely corrugated surfaces with invagination due to the presence of L-leucine. In addition, there were more hollow particles with smooth surface in P1 than that in P2. Compared with P1, P2 has shown optimal physical particle size and aerosolization behavior with D (v, 50) of 2.64 ± 0.01 μm and fine particle fraction of 37.55% ± 2.63%. The findings of in vitro cytotoxicity showed that P2 did not inhibit cell viability and could be safe for pulmonary administration. The absolute bioavailability of salvianolic acid B (Sal B) for pulmonary administration was 19.15% ± 7.44%, which is significantly higher than the oral bioavailability of Sal B (<5.56%). In this study, we have shown the feasibleness of pulmonary administration of SMPA in the form of DPIs for systemic delivery to treat cardiovascular diseases. [ABSTRACT FROM AUTHOR]

PSTi8 is a pancreastatin inhibitory peptide that is effective in the treatment of diabetic models. This study investigates the pharmacokinetic (PK) properties of PSTi8 in Sprague Dawley rats, for the first time. In vitro and in vivo PK studies were performed to evaluate the solubility, stability in plasma and liver microsomes, plasma protein binding, blood–plasma partitioning, bioavailability, dose proportionality, and gender difference in PK. Samples were analyzed using the validated LC-MS/MS method. The solubility of PSTi8 was found to be 9.30 and 25.75 mg/mL in simulated gastric and intestinal fluids, respectively. The protein binding of PSTi8 was estimated as >69% in rat plasma. PSTi8 showed high stability in rat plasma and liver microsomes and the blood–plasma partitioning was >2. The bioavailability of PSTi8 after intraperitoneal and subcutaneous administration was found to be 95.00 ± 12.15 and 78.47 ± 17.72%, respectively, in rats. PSTi8 showed non-linear PK in dose proportionality studies, and has no gender difference in the PK behavior in rats. The high bioavailability of PSTi8 can be due to high water solubility and plasma protein binding, low clearance and volume of distribution. Our in vitro and in vivo findings support the development of PSTi8 as an antidiabetic agent.

Critical adverse effects and frequent administration, three times per day, limit the use of flutamide (FLT) as a chemotherapeutic agent in the treatment of prostate cancer. Therefore, our research aimed to develop new cholesterol-based nanovesicles for delivering FLT to malignant cells in an endeavor to maximize its therapeutic efficacy and minimize undesired adverse effects. Draper–Lin small composite design was used to optimize the critical quality attributes of FLT-loaded niosomes and ensure the desired product quality. The influence of the selected four independent variables on mean particle size (Y1), zeta potential (Y2), drug entrapment efficiency (Y3), and the cumulative drug release after 24 h (Y4) was examined. The optimized nanovesicles were assessed for their in vitro cytotoxicity, ex-vivo absorption via freshly excised rabbit intestine as well as in vivo pharmacokinetics on male rats. TEM confirmed nanovescicles’ spherical shape with bilayer structure. Values of dependent variables were 748.6 nm, −48.60 mV, 72.8% and 72.2% for Y1, Y2, Y3 and Y4, respectively. The optimized FLT-loaded niosomes exerted high cytotoxic efficacy against human prostate cancer cell line (PC-3) with an IC50 value of 0.64 ± 0.04 µg/mL whilst, it was 1.88 ± 0.16 µg/mL for free FLT. Moreover, the IC50 values on breast cancer cell line (MCF-7) were 0.27 ± 0.07 µg/mL and 4.07 ± 0.74 µg/mL for FLT-loaded niosomes and free FLT, respectively. The permeation of the optimized FLT-loaded niosomes through the rabbit intestine showed an enhancement ratio of about 1.5 times that of the free FLT suspension. In vivo pharmacokinetic study displayed an improvement in oral bioavailability of the optimized niosomal formulation with AUC and Cmax values of 741.583 ± 33.557 μg/mL × min and 6.950 ± 0.45 μg/mL compared to 364.536 ± 45.215 μg/mL × min and 2.650 ± 0.55 μg/mL for the oral FLT suspension. With these promising findings, we conclude that encapsulation of FLT in cholesterol-loaded nanovesicles enhanced its anticancer activity and oral bioavailability which endorse its use in the management of prostate cancer.

Background: In the current work, co-rotating twin-screw processor (TSP) was utilized to formulate solid crystal suspension (SCS) of carvedilol (CAR) for enhancing its solubility, dissolution rate, permeation and bioavailability using mannitol as a hydrophilic carrier., Methods: In-silico molecular dynamics (MD) studies were done to simulate the interaction of CAR with mannitol at different kneading zone temperatures (KZT). Based on these studies, the optimal CAR: mannitol ratios and the kneading zone temperatures for CAR solubility enhancement were assessed. The CAR-SCS was optimized utilizing Design-of-Experiments (DoE) methodology using the Box-Behnken design. Saturation solubility studies and in vitro dissolution studies were performed for all the formulations. Physicochemical characterization was performed using differential scanning calorimetry , Fourier transform infrared spectroscopy, X-ray diffraction studies, and Raman spectroscopy analysis. Ex vivo permeation studies and in vivo pharmacokinetic studies for the CAR-SCS were performed. Stability studies were performed for the DoE-optimized CAR-SCS at accelerated stability conditions at 40 ºC/ 75% RH for three months., Results: Experimentally, the formulation with CAR: mannitol ratio of 20:80, prepared using a KZT of 120 ºC at 100 rpm screw speed showed the highest solubility enhancement accounting for 50-fold compared to the plain CAR. Physicochemical characterization confirmed the crystalline state of DoE-optimized CAR-SCS. In-vitro dissolution studies indicated a 6.03-fold and 3.40-fold enhancement in the dissolution rate of optimized CAR-SCS in pH 1.2 HCl solution and phosphate buffer pH 6.8, respectively, as compared to the pure CAR. The enhanced efficacy of the optimized CAR-SCS was indicated in the ex vivo and in vivo pharmacokinetic studies wherein the apparent permeability was enhanced 1.84-fold and bioavailability enhanced 1.50-folds compared to the plain CAR. The stability studies showed good stability concerning the drug content., Conclusions: TSP technology could be utilized to enhance the solubility, bioavailability and permeation of poor soluble CAR by preparing the SCS., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Navti PD et al.)

Catechin hydrate is a phytopharmaceutical with promising anticancer effects but poor bioavailability. This study aimed to elaborate catechin loaded chitosan-tethered liposomes (chitosomes) to enhance catechin oral bioavailability. Nanocarriers were optimized via ethanol injection method followed by physicochemical, ex vivo and biological appraisal in male Wistar albino rats. Results demonstrated that chitosomes possessed excellent nanosize of 137 nm, monodispersity (PDI < 0.2) and high Zeta potential of +36.8 mV. Additionally, chitosomes showed significant improvement in digestive stability against bile salt with enhanced ex-vivo intestinal permeation. Pharmacokinetic studies revealed the significant potential of chitosomes to enhance catechin bioavailability (AUC, Cmax) and sustain its effect (Tmax). In conclusion, elaborated chitosomes are promising nanoplatforms to enhance catechin oral efficacy with lower dose, side effects, administration frequency and higher patient compliance. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The transdermal route is a convenient non-invasive way for drug delivery, however, the hydrophobic compact nature of stratum corneum (SC) forms an obstacle hindering the diffusion of drugs particularly hydrophilic ones. Hence, the purpose of this study was to develop novel soft nano-vesicles, entitled Flexosomes, amalgamating two penetration enhancers, ethanol and one edge activator (EA) from various types and different hydrophilic-lipophilic balances. The tailored vesicles were loaded with tropisetron hydrochloride (TRO), a potent highly-soluble anti-emetic, and compared with ethosomes. Aiming to preclude the formation of rigid non-deformable mixed micelles, all critical parameters; EA type, phosphatidylcholine-to-EA molar ratio, and cholesterol concentration, were optimized proving their influences on vesicle-to-micelle transitions. The prepared formulations were characterized in terms of visual inspection, particle size, polydispersity, zeta potential, turbidity measurements, entrapment efficiency, and vesicle morphology. The permeation mechanisms were assessed by differential scanning calorimetry on isolated SC. The modified vesicles, based on ethanol and either vitamin E or PEGylated castor oil derivatives exhibited the highest transdermal fluxes confirmed by a deeply tracking to dermis using confocal laser microscopy. Both vesicles demonstrated higher bioavailability relative to ethosomes, topical and oral aqueous solutions. The findings endorsed the effectiveness of tailored nano-vesicles in boosting TRO skin transport suggesting their applicability with various drug entities for enhanced transdermal delivery. [ABSTRACT FROM AUTHOR]

The pharmacokinetic profile of a drug can be different when delivered as a nanosuspension compared with a true solution, which may in turn affect the therapeutic effect of the drug. The goal of this study was to prepare itraconazole nanosuspensions (ITZ-Nanos) stabilized by an amphipathic polymer, polyethylene glycol-poly (benzyl aspartic acid ester) (PEG-PBLA), by the precipitation-homogenization, and study the pharmacokinetic profile of the ITZ-Nanos. The particle size and morphology of nanosuspensions were determined by Zetasizer and field emission scanning electron microscope (SEM), respectively. The dissolution profile was evaluated using a paddle method according to Chinese Pharmacopoeia 2015. The level of ITZ in plasma and tissues was measured by a HPLC method. The optimized ITZ-Nanos had an average particle size of 268.1 ± 6.5 nm and the particles were in a rectangular form. The dissolution profile of ITZ-Nanos was similar to that of commercial ITZ injections, with nearly 90% ITZ released in the first 5 min. The ITZ-Nanos displayed different pharmacokinetic properties compared with the commercial ITZ injections, including a decreased initial drug concentration, increased plasma half-life and mean residence time (MRT), and increased concentration in the liver, lung, and spleen. The ITZ-Nanos can change the in vivo distribution of ITZ and result in passive targeting to the organs with mononuclear phagocyte systems (MPS).

Flibanserin (FLB) is a nonhormonal medicine approved by the Food and Drug Administration (FDA) to treat the hypoactive sexual appetite disorder in females. However, the peroral administration of the medicine is greatly affected by its poor bioavailability as a result of its extensive first-pass effect and poor solubility. Aiming at circumventing these drawbacks, this work involves the formulation of optimized FLB transfersome (TRF) loaded intranasal hydrogel. Box–Behnken design was utilized for the improvement of FLB TRFs with decreased size. The FLB-to-phospholipid molar ratio, the edge activator hydrophilic lipophilic balance, and the pH of the hydration medium all exhibited significant effects on the TRF size. The optimized/developed TRFs were unilamellar in shape. Hydroxypropyl methyl cellulose based hydrogel filled with the optimized FLB TRFs exhibited an improved ex vivo permeation when compared with the control FLB-loaded hydrogel. In addition, the optimized TRF-loaded hydrogel exhibited higher bioavailability and enhanced brain delivery relative to the control hydrogel following intranasal administration in Wistar rats. The results foreshadow the possible potential application of the proposed intranasal optimized FLB-TRF-loaded hydrogel to increase the bioavailability and nose-to-brain delivery of the drug.

The pharmacokinetic profile of a drug can be different when delivered as a nanosuspension compared with a true solution, which may in turn affect the therapeutic effect of the drug. The goal of this study was to prepare itraconazole nanosuspensions (ITZ-Nanos) stabilized by an amphipathic polymer, polyethylene glycol-poly (benzyl aspartic acid ester) (PEG-PBLA), by the precipitation-homogenization, and study the pharmacokinetic profile of the ITZ-Nanos. The particle size and morphology of nanosuspensions were determined by Zetasizer and field emission scanning electron microscope (SEM), respectively. The dissolution profile was evaluated using a paddle method according to Chinese Pharmacopoeia 2015. The level of ITZ in plasma and tissues was measured by a HPLC method. The optimized ITZ-Nanos had an average particle size of 268.1 ± 6.5 nm and the particles were in a rectangular form. The dissolution profile of ITZ-Nanos was similar to that of commercial ITZ injections, with nearly 90% ITZ released in the first 5 min. The ITZ-Nanos displayed different pharmacokinetic properties compared with the commercial ITZ injections, including a decreased initial drug concentration, increased plasma half-life and mean residence time (MRT), and increased concentration in the liver, lung, and spleen. The ITZ-Nanos can change the in vivo distribution of ITZ and result in passive targeting to the organs with mononuclear phagocyte systems (MPS). [ABSTRACT FROM AUTHOR]

Felbamate, an antiepileptic drug is administered multiple times a day to obtain proper restorative action against seizures in childhood onset epilepsy (Lennox-Gastaut syndrome), which usually result in poor therapeutic efficacy because of fluctuating plasma levels and low patient compliance. Hence, controlled release hydroxypropyl methylcellulose matrix tablets of felbamate were formulated to overcome these drawbacks. The results of pre-formulation studies such as differential scanning calorimetry and Fourier-transform infrared spectroscopy showed compatibility of drug with the selected excipients. The formulation variables were optimized using D-optimal design, which can elucidate the effect of all variables simultaneously during formulation optimization. In vitro drug release at the end of 2, 8 and 20 h were taken as the response parameters for the optimization study by D-optimal design. The results enabled selection of the formulation with the desired drug release pattern approaching to zero order. The optimized batch was subjected to in vivo pharmacokinetic studies in rabbits, which showed extended release of drug up to 24 h. Thus, the felbamate controlled release tablets optimized by D-optimal design have potential to reduce the dose and dosing frequency, improve therapy and patient compliance. [ABSTRACT FROM AUTHOR]

Highlights • Application of acrylamide grafted pullulan as one of the component for controlled release drug delivery system. • Detailed thermal kinetic profile of microsphere using isoconversional model. • In vitro enzymatic degradation of microsphere. • Biocompatibility assessment of microsphere in human hepatocellular carcinoma cell line. • Comparative in vivo pharmacokinetic study of optimized formulation with marketed product. Abstract The aim of present study was to develop controlled release formulation of pirfenidone using acrylamide grafted pullulan. Interpenetrating polymer network (IPN) microspheres were prepared using acrylamide grafted pullulan and PVA utilizing glutaraldehyde assisted water-in-oil emulsion crosslinking method. IPN microspheres were characterized by FTIR, solid state 13C NMR and XRD spectroscopy. In vitro enzymatic degradation study showed 34.30% degradation after 24 h with degradation rate constant of 0.0088 min−1. In vitro biocompatibility test showed no changes in cellular morphology and cell adherence to microspheres, indicating its biocompatible nature. The release exponent value of all formulations was less than 0.45, indicating the release mechanism to be Fickian diffusion. Finally, in vivo pharmacokinetic study showed longer T max (1.16 h) and greater AUC value (10037.76 ng h/mL,) as compared to Pirfenex® (T max = 0.5 h; AUC = 4310.45 ng h/mL,). The results indicated that the prepared formulation could successfully control the drug release for prolonged time period. [ABSTRACT FROM AUTHOR]

Abstract This study aimed to investigate the potential of lecithin-based nanoemulsions costabilized by sucrose esters, with and without skin pretreatment with stainless steel microneedles, to improve delivery of aceclofenac, as a model drug, into/across the skin. The characterization revealed favorable droplet size (about 180 nm), narrow size distribution (<0.15), high surface charge (about −40 mV) and satisfying long-term stability (one year at 4 ± 1 °C) of the formulation costabilized by sucrose palmitate, demonstrating a similar trend observed for the reference stabilized by widely used lecithin/polysorbate 80 combination. In vitro release/permeation testing and differential stripping on the porcine ear proved the superiority of the sucrose ester- over polysorbate-based nanoemulsion. However, in vitro findings were not fully indicative of the in vivo performances – no significant differences were observed between investigated formulations in pharmacokinetic profile and total amount of aceclofenac deposited in the rat skin 24 h after dosing, simultaneously pointing to delayed aceclofenac delivery into the systemic circulation. In addition, the ratio of plasma concentrations of aceclofenac and its major metabolite in rats, diclofenac, was remarkably changed after topical application of tested nanoemulsions compared to intravenous administration of aceclofenac solution. Finally, skin pretreatment with microneedles improved aceclofenac delivery into/across the rat skin from tested formulations, resulting in 1.4–2.1-fold increased bioavailability and 1.2–1.7-fold enhanced level of aceclofenac retained in the skin, as measured 24 h after administration. Moreover, the plasma concentrations of aceclofenac 24 h after application of tested formulations (lecithin/sucrose palmitate vs. lecithin/polysorbate 80) combined with microneedles (173.37 ± 40.50 ng/ml vs. 259.23 ± 73.18 ng/ml) were significantly higher than those obtained through intact skin (105.69 ± 19.53 ng/ml vs. 88.38 ± 14.46 ng/ml). However, obtained results suggest that combination of microneedles and sucrose palmitate-costabilized nanoemulsion could be useful to attain higher skin concentration, while combination of microneedles with polysorbate 80-costabilized nanoemulsion could be a preferable option for enhancing drug delivery into the bloodstream. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract In this study, a physiologically based pharmacokinetic (PBPK) model was established for valacyclovir based on absolute expression quantity of hPEPT1 along the entire length of the human intestine and other reliable in vitro , in vivo observed data. The PBPK model-3 defined acyclovir as metabolite of valacyclovir and simulated the plasma concentration-time profiles of valacyclovir and acyclovir simultaneously. It was validated strictly by a series of observed plasma concentration-time profiles. The average fold error (AFE) and absolute average fold error (AAFE) values were all smaller than 2. Then, it was used to quantitatively evaluate the effect of hPEPT1, luminal degradation rate, drug release rate and gastric residence time on the oral absorption of valacyclovir and acyclovir. The PBPK model-3 suggests that mainly 75% of valacyclovir was absorbed by active transport of hPEPT1. The luminal degradation of valacyclovir in the upper intestinal lumen cannot be considered the only reason for its incomplete bioavailability. The plasma concentration-time profiles of valacyclovir and its metabolite acyclovir were not sensitive to dissolution rate faster than T 85% = 120 min. Prolonged gastric residence time of sustained release tablet can improve the oral absorption of valacyclovir. All in all, the PBPK model-3 in this study is reliable and accurate. It is useful for the research of clinical application and dosage forms design of valacyclovir. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract Small series of acylguanidine and acylthiourea derivatives were synthesized in gram-scale and assayed for their ability to modulate the Hh signalling pathway. In vitro studies showed a low micromolar inhibitory activity toward tumor cell lines, while the oral administration revealed an excellent ADME profile in vivo. Compound 5 emerged as the most active and safe inhibitor of colon cancer cells both in vitro and in a xenograft mouse model. Based on these data, 5 could be prioritized to further development with the perspective of clinical studies. Graphical abstract Image 1 Highlights • Gram-scale synthesis of Hedgehog inhibitors with an Heck coupling. • Cell-based evaluation and ADME profiling with vismodegib as reference. • The phenetyl analogue 5 is a safe inhibitor of a LS180 colon cancer xenograft. [ABSTRACT FROM AUTHOR]

Sunitinib is an oral FDA/EMEA approved multi-targeted tyrosine kinase inhibitor. It possesses anti-angiogenic and antitumor activity against a variety of advanced solid tumors. However, its chemical core does not allow a potential linkage to tumor-homing elements that could eventually enhance its potency. Therefore, a novel linkable sunitinib derivative, designated SB1, was rationally designed and synthesized. The pharmaceutical profile of SB1 was explored both in vitro and in vivo . Mass spectrometry and NMR spectroscopy were utilized for characterization, while MTT assays and LC-MS/MS validated protocols were used to explore its antiproliferative effect and stability, respectively. Cytotoxicity evaluation in three glioma cells showed that SB1 preserved the antiproliferative effect of sunitinib. SB1 was stable in vitro after 24 h incubation in mouse plasma, while both agents exhibited bioequivalent pharmacokinetic characteristics after i.v. administration in Balb/c mice. To evaluate the levels of SB1 in mouse plasma, a novel analytical method was developed and validated in accordance to the US FDA and the EU EMA guidelines. We formulated a novel linkable sunitinib analog exhibiting similar antiproliferative and apoptotic properties with native sunitinib in glioma cell lines. Both SB1 and native sunitinib showed identical in vitro stability in mouse plasma and pharmacokinetics after i.v. administration in Balb/c mice. [ABSTRACT FROM AUTHOR]

Nanosuspensions technique is an important tool to enhance the saturation solubility and dissolution velocity of poorly soluble drugs. Trans-resveratrol (t-Res) with extensive pharmacological effects was severely restricted by poor solubility and short biological half-life. In this study, anti-solvent precipitation was employed to development trans-resveratrol nanosuspensions (t-Res NS) with PVPK30 as stabilizer. The physicochemical properties, in vitro release and in vivo pharmacokinetics of t-Res NS were investigated. The mean particle size, zeta potential, encapsulation efficiency and drug loading of t-Res NS prepared by the optimal prescription were 96.9 nm, −20.4mV, 78% and 28.1%, respectively. The morphology of t-Res nanoparticles was spherical indicated by SEM with amorphous phase verified by XRD and DSC. The t-Res NS present a good physical stability as well as enhanced chemical stability. Compared to crude drug, the in vitro dissolution rate of t-Res NS was increased with fitting Higuchi equation ( Q = 0.3215 t 1 / 2 + 0.0070 ). The in vivo pharmacokinetic test in rats showed that the AUC 0 ∼ t of t-Res NS (559.4 μg/mL·min) was about 3.6-fold higher than that of t-Res solution. Meanwhile, the MRT of t-Res nanosuspensions was longer than that of t-Res solution. These results suggested that NS may be a potentially nanocarrier for clinical delivery of t-Res. [ABSTRACT FROM AUTHOR]

Purpose: We developed simulation and modeling methods to predict the in vivo pharmacokinetic profiles of acyclovir, following escalating oral doses of valacyclovir, in wildtype and Pept1 knockout mice. We also quantitated the contribution of specific intestinal segments in the absorption of valacyclovir in these mice. Methods: Simulations were conducted using a mechanistic advanced compartmental absorption and transit (ACAT) model implemented in GastroPlus™. Simulations were performed for 3 h post-dose in wildtype and Pept1 knockout mice following single oral doses of 10, 25, 50 and 100 nmol/g valacyclovir, and compared to experimentally observed plasma concentration-time profiles of acyclovir. Results: Good fits were obtained in wildtype and Pept1 knockout mice. Valacyclovir was primarily absorbed from duodenum (42%) and jejunum (24%) of wildtype mice, with reduced uptake from ileum (3%) and caecum/colon (1%), for a total of 70% absorption. In contrast, the absorption of valacyclovir in Pept1 knockout mice was slow and sustained throughout the entire intestinal tract in which duodenum (4%), jejunum (14%), ileum (10%) and caecum/colon (12%) accounted for a total of 40% absorption. Conclusion: The ACAT model bridged the gap between in situ and in vivo experimental findings, and facilitated our understanding of the complicated intestinal absorption processes of valacyclovir. [ABSTRACT FROM AUTHOR]