In-vivo Pharmacokinetics Research Articles

Chitosan/guar gum-based thermoreversible hydrogels loaded with pullulan nanoparticles for enhanced nose-to-brain drug delivery

The biopolymers-based two-fold system could provide a sustained release platform for drug delivery to the brain resisting the mucociliary clearance, enzymatic degradation, bypassing the first-pass hepatic metabolism, and BBB thus providing superior bioavailability through intranasal administration. In this study, poloxamers PF-127/PF-68 grafted chitosan HCl-co-guar gum-based thermoresponsive hydrogel loaded with eletriptan hydrobromide laden pullulan nanoparticles was synthesized and subjected to dynamic light scattering, Fourier transform infrared spectroscopy, thermal analysis, x-ray diffraction, scanning electron microscopy, stability studies, mucoadhesive strength and time, gel strength, cloud point assessment, rheological assessment, ex-vivo permeation, cell viability assay, histology studies, and in-vivo Pharmacokinetics studies, etc. It is quite evident that CSG-EH-NPs T-Hgel has an enhanced sustained release drug profile where approximately 86 % and 84 % of drug released in phosphate buffer saline and simulated nasal fluid respectively throughout 48 h compared to EH-NPs where 99.44 % and 97.53 % of the drug was released in PBS and SNF for 8 h. In-vivo PKa parameters i.e., mean residence time (MRT) of 11.9 ± 0.83 compared to EH-NPs MRT of 10.2 ± 0.92 and area under the curve (AUCtot) of 42,540.5 ± 5314.14 comparing to AUCtot of EH-NPs 38,026 ± 6343.1 also establish the superiority of CSG-EH-NPs T-Hgel.

Vitamin E TPGS-PLGA-based nanoparticles for methotrexate delivery: Promising outcomes from preclinical studies

Methotrexate (MTX) has shown remarkable therapeutic effects against a variety of cancers. However, it is related to various challenges like dose-influenced side effects, compromised bioavailability, and poor tissue penetration. Henceforth, a poly-(lactic-co-glycolic acid) (PLGA)-based d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) conjugated MTX self-assembled nanoparticulate system was developed. The synthesized conjugate (MTX-PLGA-TPGS) was affirmed by FT-IR and NMR spectroscopy, and the developed self-assembled nanoparticles were characterized for particle size, zeta potential, surface charge, drug loading and drug entrapment. The evaluation studies included drug release at the plasma and cancer cell pH, compatibility with erythrocytes, plasma protein binding, in-vitro cytotoxicity on cancer cell lines, confocal laser scanning microscopy, and in-vivo pharmacokinetics. The FT-IR and 1H NMR confirmed the successful conjugation of the two macromolecules. The developed nanoparticulate system offered controlled drug release in a pH-dependent manner, releasing the maximum drug at the pH of cancer cells. The developed systems were not only found to be biocompatible with erythrocytes but also offered substantially enhanced cytotoxicity on MDA-MB-231 cells. The confocal laser scanning microscopy confirmed higher cellular uptake and pharmacokinetics in rodents offered markedly elevated AUC and substantially retarded elimination from the central compartment. The findings vouch for the immense promise of the designed nanosystem in enhancing the efficacy, permeation, safety and reducing the dose and dosing frequency of a well-established BCS class IV drug candidate.

Enhancing the oral bioavailability of asenapine maleate with bio-enhancer: An in-silico assisted in-vivo pharmacokinetic study

The present work is aimed to address the oral bioavailability issue of asenapine maleate with the help of bio-enhancers. Molecular modeling platform by Maestro, Schrödinger was used to screen a list of bio-enhancer molecules. The bio-enhancer with the highest docking score and the best intermolecular interactions was selected for in-vivo pharmacokinetics studies. Of all the bio-enhancer molecules, quercetin showed the highest docking score (−10.6 on CYP1A2 and -9.34 on CYP3A4), induced fit docking score (−989.65 on CYP1A2 and -906.76 on CYP3A4) and greater association with proteins during molecular dynamics run. Animals were divided into five groups and orally administered with asenapine maleate and quercetin suspension at different dose and interval. The plasma was analyzed in high performance liquid chromatography, and various pharmacokinetic parameters were determined using Phoenix WinNonlin version 8.1. The presence of quercetin was found to significantly increase various pharmacokinetic parameters of asenapine maleate, and the groups administered with 25 mg/kg of quercetin showed better pharmacokinetic profile. A 2.5 folds increase in Cmax and 2.17 folds increase in AUC was observed in groups administered with quercetin. The increase in pharmacokinetic parameters could be attributed to the ability of the bio-enhancer to bind to the enzymes responsible for the metabolism of the drug, thereby prolonging the stay of drug in the body.

Thiolated Chitosan Microneedle Patch of Levosulpiride from Fabrication, Characterization to Bioavailability Enhancement Approach.

In this study, a first attempt has been made to deliver levosulpiride transdermally through a thiolated chitosan microneedle patch (TC-MNP). Levosulpiride is slowly and weakly absorbed from the gastrointestinal tract with an oral bioavailability of less than 25% and short half-life of about 6 h. In order to enhance its bioavailability, levosulpiride-loaded thiolated chitosan microneedle patches (LS-TC-MNPs) were fabricated. Firstly, thiolated chitosan was synthesized and characterized by nuclear magnetic resonance (1HNMR) spectroscopy, attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Thiolated chitosan has been used in different drug delivery systems; herein, thiolated chitosan has been used for the transdermal delivery of LS. LS-TC-MNPs were fabricated from different concentrations of thiolated chitosan solution. Furthermore, the levosulpiride-loaded thiolated chitosan microneedle patch (LS-TC-MNP) was characterized by FTIR spectroscopic analysis, scanning electron microscopy (SEM) study, penetration ability, tensile strength, moisture content, patch thickness, and elongation test. LS-TC-MNP fabricated with 3% thiolated chitosan solution was found to have the best tensile strength, moisture content, patch thickness, elongation, drug-loading efficiency, and drug content. Thiolated chitosan is biodegradable, nontoxic and has good absorption and swelling in the skin. LS-TC-MNP-3 consists of 100 needles in 10 rows each with 10 needles. The length of each microneedle was 575 μm; they were pyramidal in shape, with sharp pointed ends and a base diameter of 200 µm. The microneedle patch (LS-TC-MNP-3) resulted in-vitro drug release of 65% up to 48 h, ex vivo permeation of 63.6%, with good skin biocompatibility and enhanced in-vivo pharmacokinetics (AUC = 986 µg/mL·h, Cmax = 24.5 µg/mL) as compared to oral LS dispersion (AUC = 3.2 µg/mL·h, Cmax = 0.5 µg/mL). Based on the above results, LS-TC-MNP-3 seems to be a promising strategy for enhancing the bioavailability of levosulpiride.

Fabrication of thiolated chitosan based biodegradable nanoparticles of ticagrelor and their pharmacokinetics

The current study was aimed to design a thiolated chitosan (TC) based mucoadhesive nanoparticle (NP) formulation for enhancing the oral bioavailability of an anti-coagulant, Ticagrelor (TG). Nanoparticles (NPs) containing naturally occurring biodegradable polymers have been revealed as promising carriers for the controlled delivery of various therapeutic agents through the oral route. Ionic gelation technique was adopted to prepare thiolated chitosan nanoparticles of TG (TCNPs/TG) and chitosan (CH) nanoparticles of TG (CHNPs/TG) by varying the concentration of polymers with respect to TG and cross-linker i.e. tripolyphosphate (TPP). The prepared CHNPs/TG and TCNPs/TG were subjected to assessment for their particle size, the zeta potential, shape and morphology along with loading capacity (LC) and entrapment efficiency (EE). Formed TCNPs/TG showed a particle size of 190.3 nm, zeta potential of 16 mv along with the polydispersity index (PDI) of 0.375 as compared to CHNPs/TG, displaying particle size of 147.3 nm, zeta potential of 22.6 mv and PDI of 0.364. Likewise, during Fourier transform infrared spectroscopy (FTIR) analysis, the emergence of a characteristic peak at 2495 cm−1 in TC, has confirmed the successful modification of CH. Moreover, in-vitro drug release studies have disclosed a good sustained release behavior of the drug, both from CHNPs/TG and TCNPs/TG. However, the in-vivo pharmacokinetics have illustrated the superiority ( p < .05) of the TCNPs/TG (494.96 ng/mL) over the CHNPs/TG (438.73 ng/mL) in terms of bioavailability. Ultimately, the findings have indicated that TCNPs/TG might help to improve the oral bioavailability of TG and hence, its therapeutic effects.

Surface solid dispersion: A novel method for improving in-vitro dissolution and in-vivo pharmacokinetics of Meclizine hydrochloride

Surface solid dispersion: A novel method for improving in-vitro dissolution and in-vivo pharmacokinetics of Meclizine hydrochloride

Biodegradable nanoparticles from prosopisylated cellulose as a platform for enhanced oral bioavailability of poorly water-soluble drugs

Bio-inspired nanotechnology-based strategies are potential platforms for enhanced dissolution and oral biovailability of poorly water-soluble drugs. In this study, a recently patented green biopolymer (Prosopis africana gum, PG) was compatibilized with microcrystalline cellulose (MCC), a conventional polysaccharide, via thermo-regulated coacervation to obtain PG-MCC (1:0, 1:1, 1:2, 2:1, and 0:1) rational blends and the nanoparticles developed with optimized (1:1) biocomposites (termed “prosopisylated cellulose”) by combined homogenization-nanoprecipitation technique was engineered as a high circulating system for improved oral bioavailability of griseofulvin (GF), a model Biopharmaceutics Classification System (BCS) Class-II drug. The effects of biopolymer interaction on morphological and microstructural properties of drug-free biocomposites obtained were investigated by Fourier transform infra-red spectroscopy, scanning electron microscopy and x-ray diffractometry, while the physicochemical properties and in-vivo pharmacokinetics of GF-loaded nanoparticles were also ascertained. Optimized biocomposites revealed inter-molecular and intra-molecular hydrogen bonding between the hydroxyl group of MCC and polar components of PG, as well as reduction in crystallinity of MCC. Griseofulvin-loaded nanoparticles were stable, displayed particles with relatively smooth surfaces and average size of 26.18 ± 0.94 . nm, with zeta potential and polydispersity index of 32.1 ± 0.57 mV and 0.173 ± 0.06, respectively. Additionally, the nanoparticles showed good entrapment efficiency (86.51 ± 0.93 %), and marked improvement in griseofulvin dissolution when compared to free drug, with significantly (p < 0.05) higher GF release in basic than acidic PEG-reinforced simulated bio-microenvironments. Besides, x-ray diffractogram of GF-loaded nanoparticles showed amorphization with few characteristic peaks of GF while infra-red spectrum indicated broader principal peaks of GF and components compatibility. Furthermore, GF-loaded nanoparticles showed low plasma clearance with three-fold increase in systemic bioavailability of griseofulvin compared with free drug. These results showed that prosopisylated cellulose nanoparticles would be a facile approach to improve oral bioavailability of BCS class-II drugs and can be pursued as a new versatile drug delivery platform.

Hydrogel-based matrices for controlled drug delivery of etamsylate: Prediction of in-vivo plasma profiles

ObjectivesTo design oral controlled release (CR) hydrogel matrix tablets of etamsylate using various hydrophilic polymers. Additionally, to predict plasma concentration-time profiles of etamsylate released from different CR matrices. MethodsCharacterization of the in-vitro release rate was performed by various model dependent and model independent approaches. A simple numerical convolution strategy was adopted to predict the in-vivo performance of all matrices from their in-vitro percent released data. The statistical analysis was conducted utilizing a student t-test and ANOVA. ResultsThe release of etamsylate from all matrices showed a deviation from Fickian transport mechanism except; F2 followed Case II release whereas, F9 and F11 obeyed Fickian diffusion. CR hydrogel based-matrices (F4 and F11) demonstrated the maximum drug retardation and satisfied the USP release limits. Concentration–time profiles of etamsylate were predicted successfully from the in-vitro release data of all prepared matrices. Pharmacokinetic parameters of etamsylate CR hydrogel matrices were significantly changed with comparison to reference product except F1. ConclusionThe designed (F2-F11) matrices had the capability to extend the plasma level of etamsylate for an adequate time. However, F4 and F11 were considered the most ideal formulations for once daily application of etamsylate. The prediction of in-vivo pharmacokinetics of etamsylate was very useful to assess the rationality of the designed matrices for the practical application in humans.

Biodistribution, pharmacokinetics and toxicity evaluation of mannosylated gelatin nanoparticles of linezolid for anti-tubercular therapy

ABSTRACT The present study explores the therapeutic potential of gelatin nanoparticles as a carrier for the delivery of linezolid, a repurposed drug for the treatment of Mycobactrium tuberculosis. However, it has significant issues of large dose and toxicity. To overcome this problem, linezolid loaded mannosylated gelatin nanoparticles were prepared for specific targeting to alveolar macrophages. The system was characterised for in-vitro , ex-vivo and in-vivo pharmacokinetics, biodistribution and toxicity studies to evaluate the safety and efficacy of the formulation. The method resulted in small-sized (197–298 nm) nanoparticles with a low polydispersity index (0.127–0.148) and higher drug entrapment (51–56%). The formulation was capable of sustained drug release with a significant increase in mean residence time and the half-life. The system is capable of reducing the dose, dosing frequency, and toxic adverse effects, which ultimately improves patient compliance and, therefore, a promising approach for the effective management of tuberculosis.

Biopharmaceutical characterization of rebamipide: The role of mucus binding in regional-dependent intestinal permeability

In this study, we aimed to elucidate biopharmaceutical characteristics of the anti-ulcer drug rebamipide, with special emphasis on the influence of gastrointestinal (GI) mucus on rebamipide segmental-dependent permeability and absorption. Experimental studies and physiologically-based pharmacokinetic (GastroPlusTM) simulations were used to elucidate segmental-dependent absorption and pharmacokinetic (PK) profile, accounting for various drug properties, including solubility/dissolution limitations, regional-dependent drug affinity to mucus and membrane permeability, as well as physiological factors such as regional-pH differences along the intestine, thickness and types of mucus, transit time and surface areas. Low permeability and extensive binding to GI mucus were the key modeling features, and accounting for these resulted in good fitting between the predicted and in-vivo PK profiles, validating the ability of the model to pinpoint the underlying mechanisms of rebamipide limited oral bioavailability. Furthermore, the simulations indicated regional-dependent intestinal permeability of rebamipide, with absorption rank order of jejunum>ileum>duodenum>colon, mainly attributable to segmental mucus differences. Food effect simulations indicated somewhat decreased rebamipide absorption in the fed state, in corroboration with previous reports. Since this anti-ulcer drug is currently examined for additional indications, this work provides important input for future development of rebamipide.

QbD aided development of ibrutinib-loaded nanostructured lipid carriers aimed for lymphatic targeting: evaluation using chylomicron flow blocking approach.

Ibrutinib (IBR) is the choice of drug for the treatment of chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). IBR has low oral bioavailability of 2.9% owing to its high first pass metabolism. Present study was aimed to develop the nanostructured lipid carriers (NLC) using glyceryl monostearate (GMS) as solid lipid and Capryol™ PGMC as liquid lipid. Plackett-Burman design (PBD) was applied to screen the significant factors; furthermore, these significant factors were subjected to optimisation using Central Composite design (CCD). The size, poly dispersity index (PDI) and entrapment efficiency (E.E.) of the developed NLC were 106.4 ± 8.66nm, 0.272 ± 0.005 and 70.54 ± 5.52% respectively. Morphological evaluation using transmission electron microscope (TEM) and field emission scanning electron microscope (FESEM) revealed spherical particles. Furthermore, differential scanning calorimetry (DSC) indicates the formation of molecular dispersion of drug in the melted lipid matrix while Powder X-Ray Diffraction (PXRD) studies reveal the absence of crystalline drug peaks in the formulation diffractogram. In-vivo pharmacokinetics of NLC displayed an increase in Cmax (2.89-fold), AUC0-t (5.32-fold) and mean residence time (MRT) (1.82-fold) compared with free drug. Furthermore, lymphatic uptake was evaluated by chylomicron flow blocking approach using cycloheximide (CXI). The pharmacokinetic parameters Cmax, AUC0-t and MRT of NLC without CXI were 2.75, 3.57 and 1.30 folds higher compared with NLC with CXI. The difference in PK parameters without CXI indicates significant lymphatic uptake of the formulation. Hence, NLC can be a promising approach to enhance the oral bioavailability of drugs with high first-pass metabolism. Graphical abstract.

Development of mebendazole loaded nanostructured lipid carriers for lymphatic targeting: Optimization, characterization, in-vitro and in-vivo evaluation

The basic objective of research work was to develop, optimize and evaluate MBZ loaded NLCs to overcome the issues of poor solubility and bioavailability of the drug. The nanoformulation was prepared by melt-emulsification ultrasonication technique and optimizes the formulation parameters by Box–Behnken design. The optimized MBZ loaded NLCs were evaluated for its particle size, drug content and encapsulation efficiency. Characterization was done by DSC, XRD, and TEM. Further, in-vitro release study, stability study, and in-vivo pharmacokinetics and biodistribution studies were also performed. The optimized MBZ loaded NLCs composed of using Compritol 888 ATO, Miglyol 812 and Poloxamer 407 as a solid lipid, liquid lipid, and surfactant respectively. The particle size, zeta potential, drug loading and entrapment efficiency of optimized NLCs were found to be 117.4 nm, −25.3 mV, 90.1% and 3.17% respectively. In-vitro drug release studies show biphasic release pattern from NLCs. Stability study indicated that the optimized nanoformulation was significantly stable at refrigerator temperature as compared to room temperature. Lymphatic uptake of the drug was achieved by prepared nanoformulation. It was concluded from the data obtained that MBZ loaded NLCs could be regarded as a potential carrier for sustained delivery of MBZ and efficient carrier for lymphatic targeting. Highlights MBZ loaded NLCs showed high drug entrapment efficiency and bioavailability. Box–Behnken design was used to optimize the formulation parameters. In-vitro release showed the biphasic sustained behavior from nanoformulation. Lymphatic uptake of MBZ through nanoformulation was observed. Improved pharmacokinetic and biodistribution were observed.

COMPARATIVE STUDY OF HERBAL BIOENHANCER CONTAINING NANO FORMULATION FOR ORAL DELIVERY OF PACLITAXEL: PHARMACOKINETIC AND CYTOTOXICITY ANALYSIS

Objective: The main objective of this study was to develop novel formulation containing herbal bioenhancer to increase the bioavailability of poorly water-soluble anticancer drug. Material and methods: Paclitaxel (PTX) loaded bioenhancer nanoparticle prepared by Emulsification solvent evaporation method by using Eudragit RLPO as a polymer and to evaluate its in-vivo pharmacokinetics (PK) and cytotoxicity studies The result is reduced oral bioavailability, which limits the use of paclitaxel, a crucial anticancer medication, when taken orally. Though multiple formulation approaches have been taken to fight this low absorption profile but consequence of different herbal bioenhancer, happening CYP3A and P-gp inhibitor on augmentation of paclitaxel plasma. Result: The prepared nanoparticles were evaluated for in vitro cell cytotoxicity study by MTT assay on lung cancer cell line and pharmacokinetic profile. The result revealed good in vitro properties with bioenhancer. Conclusion: The goal of the present work is to asses any modification in oral pharmacokinetics of paclitaxel. Therefore, it can be concluded that addition of bioenhancer with antitumor drug can enhance its prolifertive effect. However, further in vivo studies are recommended to establish the fact.

Modulating the site-specific oral delivery of sorafenib using sugar-grafted nanoparticles for hepatocellular carcinoma treatment

Globally, one in six deaths is reported due to cancer suggesting the critical need for development of advanced treatment regimens. In this study, solid lipid nanoparticles (SLN) were prepared and appended with polyethylene glycol (PEGylated) galactose and a multikinase inhibitor sorafenib (SRFB) was used as chemotherapeutic drug, for treating hepatocellular carcinoma (HCC). The nanoparticles were evaluated for in-vitro and in-vivo performances to showcase the targeting efficiency and therapeutic benefits of the sorafenib loaded ligand conjugated nanoparticles (GAL-SSLN). When compared with SRFB or Sorafenib loaded SLN, GAL-SSLN showed superior cytotoxicity and apoptosis in HepG2 (human hepatocellular carcinoma cells). In addition, in-vivo pharmacokinetics and real time biodistribution studies in BALB/c mice showed that the surface conjugation of nanoparticles with galactose resulted in better pharmacokinetic performance and targeted delivery of the nanoparticles to liver. Results indicated that GAL-SSLN showed promising attributes in terms of targeting sorafenib to liver and therapeutic efficacy.

Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity

Over the last decade, various new therapies have been developed to promote anti-tumor immunity. Despite interesting clinical results in hematological malignancies, the development of bispecific killer-cell-engager antibody formats directed against tumor cells and stimulating anti-tumor Tcell immunity has proved challenging, mostly due to toxicity problems. We report here the generation of trifunctional natural killer (NK) cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. Trifunctional NKCEs were more potent invitro than clinical therapeutic antibodies targeting the same tumor antigen. They had similar invivo pharmacokinetics to full IgG antibodies and no off-target effects and efficiently controlled tumor growth in mouse models of solid and invasive tumors. Trifunctional NKCEs thus constitute a new generation of molecules for fighting cancer. VIDEO ABSTRACT.

O05 Physiologically based pharmacokinetic modelling to characterize acetaminophen pharmacokinetics and NAPQI formation in non-pregnant and pregnant women

BackgroundLittle is known about the pharmacokinetics (PK) of acetaminophen during different stages of pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen PK throughout pregnancy.MethodsPBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen PK were considered. The models were evaluated using goodness-of-fit-plots and through comparison of predicted PK profiles with in-vivo PK data. Predictions were performed to illustrate the concentrations at steady state (Css-mean), used as indicator for efficacy of acetaminophen achieved following 1000 mg q6h. Furthermore, as measurement for potential hepatotoxicity, the molar dose fraction of acetaminophen converted to NAPQI was estimated.ResultsPBPK models successfully predicted the PK of acetaminophen and its metabolites in populations of non-pregnant and pregnant women. Predictions resulted in lowest Css-mean in the third trimester (4.5 mg/L), while Css-mean was 6.7, 5.6 and 4.9 mg/L in non-pregnant, first and second trimester populations, respectively. Assuming a constant increased activity of CYP2E1 throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first (11.0%), followed by second (9.0%) and third trimester (8.2%), compared to non-pregnant women (7.1%).ConclusionRisk for drug related hepatotoxicity in pregnant women might be increased as more NAPQI is produced during pregnancy compared to non-pregnant women, especially during the first trimester. However, lack of information on the detoxifying capacity precludes any strong conclusions.Disclosure(s)Paola Mian received a Short term Minor (STM-2017) grant from the Stichting Sophia Kinderziekenhuis fonds to conduct this research.

Preparation, In-Vitro Characterization and Pharmacokinetic Evaluation of Brij Decorated Doxorubicin Liposomes as a Potential Nanocarrier for Cancer Therapy.

The aim of current study was to investigate the effect of Brij decoration of liposomes on in-vitro and in-vivo characteristics of the nanocarriers. Two hydrophilic Brij surfactants (Brij 35 and Brij 78) with almost similar molecular weight but differing in acyl chain were incorporated into liposomal bilayers at two percentages (5% and 10%). Conventional liposomes (CL) containing egg phosphatidylcholine and cholesterol as well as Brij-enriched liposomal dispersions were prepared and characterized. In-vivo pharmacokinetics of various liposomal formulations and drug solution (six groups) was studied after intravenous administration to rats. Conventional and Brij enriched doxorubicin (DOX) liposomes had small size within 82-97 nm and showed homogenous distribution (PDI < 0.1). Drug encapsulation was higher than 97% in all liposomes. The drug release profiles proved sustained DOX release from various formulations. Based on the results of in-vivo studies, all five liposomes increased drug exposure and plasma concentration in comparison to free drug. However, DOX liposomes enriched with 5% of either Brij 35 or Brij 78 showed higher AUC values and lower clearance. Overall, Brij surfactants (5% of bilayer lipids) could be potentially used to improve liposomal pharmacokinetic parameters.

Nano-vesicular delivery system loaded by Bifonazole: Preparation, optimization, and assessment of pharmacokinetic and antifungal activity

Bifonazole (BF) is a highly lipophilic antifungal drug that has limited absorption. A self-nano-emulsifying drug delivery system (SNEDDS) not only aids solubility, but it also enhances the absorption. The aim was to formulate BF-SNEDDS for topical delivery using the mixture design and to evaluate the antifungal activity, permeability, and in-vivo pharmacokinetics. Solubility of BF in different oils, surfactants, and cosurfactants was evaluated. A mixture design was used to optimize the formulation variables, X1 (Peceol% as oil), X2 (Kolliphore % as a surfactant), and X3 (Plurol Oleique% as cosurfactant), to evaluate their effects on the globule size. Antifungal activity against Candida albicans, and ex-vivo permeability across rat abdominal membrane were evaluated. The in-vivo pharmacokinetics was also assessed. Results of mixture design indicated that the optimum levels for SNEDDs components were X1(15%), X2(65%), and X3(20%). The globule size, the zone of inhibition, and permeability coefficient for the optimized formula were 36 ± 3 nm, 26 ± 3 mm, and 7.3 × 10−4 cm/min, respectively. This results indicated that, the optimum formula enhances the antifungal activity, ex vivo permeability, and in vivo bioavailability by 1.85-fold, 2.179-fold, and 6-fold, respectively, compared to aqueous suspension. In conclusion, BF-SNEDDS had enhanced anti-fungal pharmacotherapy and acts as a promising medium for transdermal delivery.

Enhanced oral bioavailability and brain uptake of Darunavir using lipid nanoemulsion formulation.

The present work aimed to formulate Darunavir loaded lipid nanoemulsion to increase its oral bioavailability and enhance brain uptake. Various batches of lipid nanoemulsion of Darunavir were prepared by high pressure homogenization using soya bean oil, egg lecithin and Tween 80. The optimized batch DNE-3 had globule size of 109.5 nm, zeta potential of -41.1 mV, entrapment efficiency 93% and creaming volume 98%. The batch remained stable at 4 °C for 1 month with an insignificant change in globule size and zeta potential (P > 0.05). In-vivo pharmacokinetics male wistar rats indicated 223% bioavailability of Darunavir relative to drug suspension. Cmax of DNE-3 was twofold higher than suspension form. The organ biodistribution study indicated 2.65 fold higher brain uptake for DNE-3 than that for suspension. The higher bioavailability of Darunavir from nanoemulsion could lessen the dose related side effects. Moreover, high organ distribution results in passive uptake of Darunavir to HIV reservoir organs.

In vitro and preclinical assessment of factorial design based nanoethosomal transdermal film formulation of mefenamic acid to overcome barriers to its use in relieving pain and inflammation

Mefenamic acid (MA) is a non-steroidal anti-inflammatory drug with analgesic activity. Marketed MA tablets or capsules often result in gastrointestinal disorders, such as upset and bleeding. MA also has poor solubility and short half-life (2 h), which requires frequent dosing, leading to higher incidence of side effects. The objective was to develop a statistically optimized nanoethosome (NE) formulation of MA loaded into transdermal films, as an alternative to oral delivery, to offer an extended release behavior. Box-Behnken design was used to analyze the effect of phospholipid concentration, ethanol concentration, and ultrasonication time. On three variables, particle size, entrapment efficiency, and steady state flux. Optimized MA-loaded nanoethosome formulation was prepared using a thin layer evaporation technique. Further, the nanoethosomal-loaded transdermal film was evaluated for in-vitro release, ex-vivo permeation, and in-vivo pharmacokinetics studies. The optimized formula indicated particle size of 97 nm with 80% of entrapment efficiency. Enhanced skin permeation of MA was more than 3.4 folds higher for nanoethosomes loaded films in comparison to pure drug transdermal films The estimated steady state flux was 2 and 15 mcg/cm2 min. The bioavailability studies indicated that mean AUC0-48 increased by 4-folds after transdermal delivery of optimized nanoethosomal film with no side effects.