Mixed Pluronic/lecithin micelles formulation for oral bioavailability of candesartan cilexetil drug: in vitro characterization and in vivo pharmacokinetic investigations.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The Increased Dissolution and Oral Absorption of Itraconazole by Nanocrystals with an Endogenous Small-Molecule Surfactant as a Stabilizer.

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.

Paeoniflorin loaded liposomes modified with glycyrrhetinic acid for liver-targeting: preparation, characterization, and pharmacokinetic study.

OBJECTIVE: 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. SIGNIFICANCE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Development of a putative Zn2+-chelating but highly selective MMP-13 inhibitor.

Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn2+ binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC50 = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn2+ ion for chelating the metal ion. Chelating properties of MMP13-inhibitors are often connected with non-selectivity within the enzyme family. Compound 32 demonstrates a rare example where the selectivity can be explained via combinatorial effects of interactions within the S1' loop and a chelating effect of the oxetane moiety. Furthermore, in vivo pharmacokinetic studies were performed demonstrating a concentration of 1.97 µM of 32 within the synovial fluid of the rat knee joint, which makes the compound a promising lead compound for further optimization and development for osteoarthritis.

Evaluation of the Pharmacokinetics of the Pancreastatin Inhibitor PSTi8 Peptide in Rats: Integration of In Vitro and In Vivo Findings.

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.

In Vitro-In Vivo Correlation of Tianeptine Sodium Sustained-Release Dual-Layer Tablets.

Tianeptine tablets are currently marketed to be designed for immediate-release tablets. The tianeptine has a short half-life, making it difficult to design for sustained-release tablets and achieve bioequivalence with the tianeptine immediate-release tablet (Stablon®). We established the in vitro-in vivo correlation (IVIVC) of three formulations of tianeptine sustained-release tablets according to their granule size. To evaluate sustained drug release, in vitro tests were performed in pH 1.2 media for 24 h. In vivo pharmacokinetic analysis was performed following oral administration of reference drug and test drug to beagle dogs. The dissolution profile revealed delayed release as the size of the granules increased. The dissolution results were confirmed in pharmacokinetic analysis, showing that the half-life was delayed as granule size increased. The final formulation and reference drug showed an equivalent area under the curve (AUC). Through this, IVIVC was established according to the size of the tianeptine sodium granules, which is the purpose of this study, and was used to predict in vivo pharmacokinetics from the formulation composition. This approach may be useful for determining optimal formulation compositions to achieve the desired pharmacokinetics when developing new formulations.

Improved uptake and bioavailability of cinnamaldehyde via solid lipid nanoparticles for oral delivery.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: It was concluded that CA-SLNs improved the absorption across Caco-2 cell model and improved the oral administration bioavailability of CA in rats.

Toward simplified oral lipid-based drug delivery using mono-/di-glycerides as single component excipients.

OBJECTIVE: 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. SIGNIFICANCE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Effects of Borneol on the Release of Compound Danshen Colon-Specific Osmotic Pump Capsule In Vitro and Pharmacokinetics Study in Beagle Dogs.

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).

Nano-Co-Delivery of Berberine and Anticancer Drug Using PLGA Nanoparticles: Exploration of Better Anticancer Activity and In Vivo Kinetics.

PURPOSE: Combinatorial approach can be beneficial for cancer treatment with better patient recovery. Co-delivery of natural and synthetic anticancer drug not only valuable to achieve better anticancer effectivity but also to ascertain toxicity. This study was aimed to co-deliver berberine (natural origin) and doxorubicin (synthetic origin) utilizing conjugation/encapsulation strategy through poly (lactic-co-glycolic acid) (PLGA) nanoparticles. METHODS: Doxorubicin was efficiently conjugated to PLGA via carbodiimide chemistry and the PLGA-doxorubicin conjugate (PDC) was used for encapsulation of berberine (PDBNP). RESULTS: Significant anti-proliferative against MDA-MB-231 and T47D breast cancer cell lines were observed with IC50 of 1.94 ± 0.22 and 1.02 ± 0.36 µM, which was significantly better than both the bio-actives (p < 0.05). The ROS study revealed that the PDBNP portrayed the slight increase in the reactive oxygen species (ROS) pattern in MDA-MB-231 cell line in a dose-dependent manner, while in T47D cells, no significant change in ROS was seen. PDBNP exhibits significant alteration (depolarization) in mitochondrial membrane permeability and arrest of cell cycle progression at sub G1 phase while the Annexin V/PI assay followed by confocal microscopy resulted into cell death mode to be because of necrosis against MDA-MB-231 cells. In vivo studies in Sprague Dawley rats revealed almost 14-fold increase in half life and a significant increase in plasma drug concentration. CONCLUSION: The overall approach of PLGA based co-delivery of doxorubicin and berberine witnessed synergetic effect and reduced toxicity as evidenced by preliminary toxicity studies.

Concentrations of Cefuroxime in Brain Tissue of Neurointensive Care Patients.

Effective concentrations of antibiotics in brain tissue are essential for antimicrobial therapy of brain infections. However, data concerning cerebral penetration properties of antibiotics for treatment or prophylaxis of central nervous system infections are rare. Six patients suffering subarachnoid hemorrhage and requiring cerebral microdialysis for neurochemical monitoring were included in this study. Free interstitial concentrations of cefuroxime after intravenous application of 1,500 mg were measured by microdialysis in brain tissue, as well as in plasma at steady-state (n = 6) or after single-dose administration (n = 1). At steady state, free area under the concentration-time curve from 0 to 24 h (AUC0-24) values of 389.0 ± 210.3 mg/liter·h and 131.4 ± 72.8 mg/liter·h were achieved for plasma and brain, respectively, resulting in a brain tissue penetration ratio (AUC0-24 brain/AUC0-24 free plasma) of 0.33 ± 0.1. Plasma and brain tissue concentrations at individual time points correlated well (R = 0.59, P = 0.001). At steady-state time over MIC (t>MIC) values of >40% of dosing interval were achieved up to an MIC of 16 mg/liter for plasma and 4 mg/liter for brain tissue. Although MIC90 values could not be achieved in brain tissue for relevant bacteria, current dosing strategies of cefuroxime might be sufficient to treat pathogens with MIC values up to 4 mg/liter. The activity of cefuroxime in brain tissue might be overestimated when relying exclusively on plasma levels. Although currently insufficient data after single dose administration exist, lower brain-plasma ratios observed after the first dose might warrant a loading dose for treatment and perioperative prophylaxis.

Development of matrix metalloproteinase-13 inhibitors - A structure-activity/structure-property relationship study.

A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhibitor 2, compound 31 was identified which exhibited microsomal half-life higher than 20 min, kinetic solubility higher than 20 µM, and a permeability coefficient greater than 20 × 10-6 cm/s. Compound 31 also showed excellent in vivo PK properties after IV dosing (Cmax = 56.8 µM, T1/2 (plasma) = 3.0 h, Cl = 0.23 mL/min/kg) and thus is a suitable candidate for in vivo efficacy studies in an OA animal model.

Pharmacokinetics of Cefuroxime in Synovial Fluid.

Cefuroxime is frequently used as preoperative antibiotic prophylaxis and may be used for the treatment of septic arthritis. A prerequisite for successful treatment of septic arthritis is the ability of an antibiotic agent to penetrate into the target site. Therefore, the concentration of cefuroxime in synovial fluid was evaluated. Ten patients who underwent elective knee arthroscopy were included in this study. Patients were treated with a single dose of 1,500 mg cefuroxime intravenously, and subsequently, the concentrations in plasma, the interstitial fluid of muscle tissue, and synovial fluid were measured by using microdialysis. Pharmacokinetic/pharmacodynamic calculations to predict bacterial killing were performed using the epidemiologically defined MIC90 for clinical isolates and CLSI breakpoints. Cefuroxime penetrated excellently into muscle tissue (ratio of the area under the concentration-time curve [AUC] for muscle tissue/AUC for free plasma, 1.79) and synovial fluid (ratio of the AUC for synovial fluid/AUC for free plasma, 1.94). The cefuroxime concentration was greater than the MIC90 for Staphylococcus aureus and S. epidermidis strains (≤2 mg/liter) over the complete dosing interval (the percentage of the dosing interval during which the free cefuroxime concentration exceeded the MIC for the pathogen [fTMIC]). CLSI defines staphylococci with MICs of ≤8 mg/liter to be susceptible to cefuroxime. For staphylococci with MICs of ≤8 mg/liter, the fTMIC in plasma was 52.5%, while the fTMIC in muscle tissue and synovial fluid was 93.6% and 96.3%, respectively. Cefuroxime may be used to treat septic arthritis caused by susceptible bacterial strains (MIC ≤ 8 mg/liter). The activity of cefuroxime in septic arthritis might be underestimated when relying exclusively on plasma concentrations.

In Silico Absorption Analysis of Valacyclovir in Wildtype and Pept1 Knockout Mice Following Oral Dose Escalation.

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.

Dendrimer nanocarriers for transport modulation across models of the pulmonary epithelium.

The purpose of this study was to determine the effect of PEGylation on the interaction of poly(amidoamine) (PAMAM) dendrimer nanocarriers (DNCs) with in vitro and in vivo models of the pulmonary epithelium. Generation-3 PAMAM dendrimers with varying surface densities of PEG 1000 Da were synthesized and characterized. The results revealed that the apical to basolateral transport of DNCs across polarized Calu-3 monolayers increases with an increase in PEG surface density. DNC having the greatest number of PEG groups (n = 25) on their surface traversed at a rate 10-fold greater than its non-PEGylated counterpart, in spite of their larger size. This behavior was attributed to a significant reduction in charge density upon PEGylation. We also observed that PEGylation can be used to modulate cellular internalization. The total uptake of PEG-free DNC into polarized Calu-3 monolayers was 12% (w/w) vs 2% (w/w) for that with 25 PEGs. Polarization is also shown to be of great relevance in studying this in vitro model of the lung epithelium. The rate of absorption of DNCs administered to mice lungs increased dramatically when conjugated with 25 PEG groups, thus supporting the in vitro results. The exposure obtained for the DNC with 25PEG was determined to be very high, with peak plasma concentrations reaching 5 µg·mL(-1) within 3 h. The combined in vitro and in vivo results shown here demonstrate that PEGylation can be potentially used to modulate the internalization and transport of DNCs across the pulmonary epithelium. Modified dendrimers thereby may serve as a valuable platform that can be tailored to target the lung tissue for treating local diseases, or the circulation, using the lung as pathway to the bloodstream, for systemic delivery.

Hemocompatible and biocompatible hybrid nanocarriers for enhanced oral bioavailability of paclitaxel: in vivo evaluation.

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 (AUC0-∞, AUMC0-∞, t1/2, and MRT0-∞) 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.

A Self-Skin Permeable Doxorubicin Loaded Nanogel Composite as a Transdermal Device for Breast Cancer 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 ß-cyclodextrin-based nanogels can enhance the loading capacity of poorly soluble drugs and promote a sustained drug release. The ß-cyclodextrin-grafted methacrylic acid conjugated hyaluronic acid composite nanogel was successfully synthesized. ß-Cyclodextrin was first grafted onto methacrylic acid. The composite nanogel-based drug carrier was prepared by controlled radical polymerization (CRP) of ß-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.

Design and evaluation of oseltamivir phosphate dual-phase extended-release tablets for the treatment of influenza.

In this study, once-daily extended-release tablets with dual-phase release of oseltamivir phosphate were developed for the treatment of influenza. The goal was to improve patient adherence and offer more therapeutic choices. The tablets were manufactured using wet granulation, bilayer tablet compression, and enteric membrane-controlled coating processes. Various polymers, such as hydroxypropyl methylcellulose (HPMC K100MCR, K15MCR, K4MCR, K100LV), enteric polymers (HPMC AS-LF, Eudragit L100-55) and membrane-controlled polymers (OPADRY® CA), were used either individually or in combination with other common excipients. The formulations include enteric-coated extended-release tablet (F1), hydrophilic matrix extended-release tablet (F2), semipermeable membrane-controlled release tablet (F3) and a combination extended-release tablet containing both enteric and hydrophilic matrix (F4). The in vitro drug release profile of each formulation was fitted to the first-order model, and the Ritger-Peppas model suggested that Fickian diffusion was the primary mechanism for drug release. Comparative bioequivalence studies with Tamiflu® (oseltamivir phosphate) capsules revealed that formulations F1, F2, and F3 did not achieve bioequivalence. However, under fed conditions, formulation F4 achieved bioequivalence with a relative bioavailability of 95.30% (90% CI, 88.83%-102.15%). This suggests that the formulation F4 tablet could potentially be a new treatment option for patients with influenza.

A Visual Raman Nano-Delivery System Based on Thiophene Polymer for Microtumor Detection.

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.

In Vitro Release and In Vivo Pharmacokinetics of Praziquantel Loaded in Different Polymer Particles.

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.