Nanostructured Lipid Carriers Can Enhance Oral Absorption of Khellin, a Natural Pleiotropic Molecule.

A novel formulation based on nanostructured lipid carriers (NLCs) was developed to increase solubility and intestinal absorption of khellin. K-NLCs were prepared with stearic acid, hempseed oil, Brij S20, and Labrafil M 1944 CS, using the emulsification-ultrasonication method. Developed nanoparticles were chemically and physically characterized by liquid chromatography, light scattering techniques, and electron microscopy. The size, about 200 nm, was optimal for oral delivery, and the polydispersity index (around 0.26), indicated high sample homogeneity. Additionally, K-NLCs showed a spherical morphology without aggregation by microscopic analysis. The encapsulation efficiency of khellin was about 55%. In vitro release studies were carried out in media with different pH to mimic physiological conditions. K-NLCs were found to be physically stable in the simulated gastric and intestinal fluids, and they preserved about 70% of khellin after 6 h incubation. K-NLCs were also successfully lyophilized testing different lyoprotectants, and obtained freeze-dried K-NLCs demonstrated good shelf life over a month. Lastly, permeability studies on Caco-2 cells were performed to predict khellin passive diffusion across the intestinal epithelium, demonstrating that nanoparticles increased khellin permeability by more than two orders of magnitude. Accordingly, developed NLCs loaded with khellin represent a versatile formulation with good biopharmaceutical properties for oral administration, possibly enhancing khellin's bioavailability and therapeutic effects.

Comparison of the Postprandial Metabolic Fate of U-13C Stearic Acid and U-13C Oleic Acid in Postmenopausal Women.

OBJECTIVE: Compare the postprandial fatty acid metabolism of isotopically labeled stearate (U-13C18:0) and oleate (U-13C18:1). Approach and Results: In conjunction with a randomized-controlled crossover trial, 6 hypercholesterolemic postmenopausal women (≥50 years; body mass index: 25.6±3.0 kg/m2; LDL [low-density lipoprotein]-cholesterol ≥110 mg/dL) consumed isocaloric diets enriched in 18:0 or 18:1 (10%-15% E) for 5 weeks each. On day 1 of week 5, following a 12-hour fast, participants receive their experimental diet divided into 13 hourly meals beginning at 8 am. U-13C18:0 or U-13C18:1 was incorporated into the 1:00 pm meal (1.0 mg/kg body weight). Serial blood and breath samples were collected over 12 hours and fasting samples at 24 and 48 hours. Plasma and lipid subfraction fatty acid profiles were assessed by gas chromatography-flame ionization detector, isotope-enrichment by liquid chromatography time-of-flight mass spectrometry, and fatty acid oxidation rate (expired 13CO2) by isotope ratio mass spectrometry. Both diets resulted in similar plasma LDL-cholesterol concentrations. Kinetic curves showed that U-13C18:0 had a higher plasma area under the curve (66%), lower plasma clearance rate (-46%), and a lower cumulative oxidation rate (-34%) than U-13C18:1. Three labeled plasma metabolites of U-13C18:0 were detected: 13C16:0, 13C16:1, and 13C18:1. No plasma metabolites of U-13C18:1 were detected within the study time-frame. Higher incorporation of 18:0 in cholesteryl ester and triglyceride fractions was observed on the 18:0 compared with the 18:1 diet. CONCLUSIONS: The neutrality of 18:0 on plasma LDL-cholesterol concentrations is not attributable to a single factor. Compared with 18:1, 18:0 had higher plasma area under the curve because of lower clearance and oxidation rates, underwent both a direct and a multistage conversion to 18:1, and was preferentially incorporated into cholesteryl esters and triglycerides.

Deuterated stearic acid uptake and accumulation in lipid droplets of cat oocytes.

Fatty acid uptake and accumulation in lipid droplets are essential processes of lipid metabolism. Oocyte in vitro culture in media enriched with fatty acid is used to modify the lipid content and composition, aiming to study the consequences of obesity and enhance cell cryotolerance. We applied Raman spectroscopy and deuterium labeling approach to quantify stearic acid uptake and investigate its incorporation within oocytes. Our data suggest that deuterium labeling does not affect oocyte maturation rates. The efficiency of deuterated stearic acid (dSA) uptake was shown to decrease with the increase of its concentration in culture medium and the duration of in vitro culture. The molar ratio between dSA and bovine serum albumin has no significant effect on the dSA uptake for 200 µM but modifies concentration dependence of the lipid uptake. dSA accumulates in all the lipid droplets inside oocytes. Different lipid droplets within the same oocyte exhibit different concentrations of dSA. The scatter in the dSA concentration in lipid droplets decreases with the culture time. Using dSA as an example, we provide a comprehensive description of how fatty acid concentration, its molar ratio versus bovine serum albumin, and culture time affect the uptake of the fatty acids in oocytes. Raman microspectroscopy of deuterium-labeled fatty acids is a nondestructive tool providing information about fatty acid uptake and heterogeneity of their accumulation between lipid droplets within the single oocyte.

Biopharmaceutical implications of excipient variability on drug dissolution from immediate release products.

Elucidating the impact of excipient variability on oral product performance in a biopharmaceutical perspective would be beneficial and allow excipient implementation on Quality by Design (QbD) approaches. The current study investigated the impact of varying viscosity of binders (hypromellose (HPMC)) and superdisintegrants (sodium starch glycolate (SSG)) and particle size distribution of lubricants (magnesium stearate (MgSt)) on the in vitro dissolution of a highly and a poorly soluble drug from immediate release formulations. Compendial (pharmacopoeia buffers) and biorelevant (media simulating the gastrointestinal fluids) media and the USP 2 and USP 4 apparatuses were used to assess the exerted excipient effects on drug dissolution. Real-time dissolution UV imaging provided mechanistic insights into disintegration and dissolution of the immediate release formulations. Varying the viscosity type of HPMC or SSG did not significantly affect drug dissolution irrespective of the compound used. Faster drug dissolution was observed when decreasing the particle size of MgSt for the highly soluble drug. The use of real-time dissolution UV Imaging revealed the influential role of excipient variability on tablet disintegration, as for the highly soluble drug, tablets containing high viscosity HPMC or low particle size MgSt disintegrated faster as compared to the control tablets while for the poorly soluble drug, slower tablet disintegration was observed when increasing the viscosity of the HPMC as compared to the control tablets. Changes in drug dissolution when varying excipients may be anticipated if the excipient change has previously affected drug solubility. The use of multivariate data analysis revealed the influential biopharmaceutical factors such as critical excipient types/properties, drug aqueous solubility, medium/hydrodynamic characteristics affecting the impact of excipient variability on in vitro drug dissolution.

Impact of Magnesium Stearate Presence and Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties.

Excipients are major components of oral solid dosage forms, and changes in their critical material attributes (excipient variability) and/or amount (excipient variation) in pharmaceutical formulations may present a challenge for product performance. Understanding the biopharmaceutical factors affecting excipient performance is recommended for the successful implementation of excipient variability on Quality by Design (QbD) approaches. The current study investigated the impact of magnesium stearate (MgSt) variability on the apparent solubility of drugs with a wide range of physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility). Compendial and biorelevant media were used to assess the role of gastrointestinal (GI) conditions on the excipient effects on drug apparent solubility. The lipophilic nature of MgSt decreased the apparent solubility of most compounds. The reduction in drug apparent solubility was more pronounced for highly soluble and/or highly ionized drugs and in presence of more highly crystalline or smaller particle size MgSt. The use of multivariate data analysis revealed the critical physicochemical and biopharmaceutical factors and the complex nature of excipient variability on the reduction in drug apparent solubility. The construction of a roadmap combining drug, excipient and medium characteristics allowed the identification of the cases where the presence of excipient or excipient variability may present risks for oral drug performance.

l-Carnitine conjugated chitosan-stearic acid polymeric micelles for improving the oral bioavailability of paclitaxel.

A delivery system based on l-carnitine (LC) conjugated chitosan (CS)-stearic acid polymeric micelles has been developed for improving the oral bioavailability of paclitaxel (PTX) through targeting intestinal organic cation/carnitine transporter 2 (OCTN2). Stearic acid grafted chitosan (CS-SA), as micelle skeleton material, was synthesized by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-mediated coupling reaction. The PTX-loaded micelles were prepared by solvent evaporation-hydration method, and the ligand LC was conjugated onto the micelle surface by anchoring its derivative stearoyl group to the lipophilic core of micelle. The modified polymeric micelles showed regular spherical shapes with small particle size of 157.1 ± 5.2 nm and high drug loading capacity of 15.96 ± 0.20 wt%, and the micelle stability in water was supported by low critical micelle concentration of 14.31 ± 0.21 µg/ml. The drug-loaded micelles presented a slow and incomplete in vitro release, and the pharmacokinetic studies indicated the micelle carriers increased the relative bioavailability of PTX to 165.8% against the commercial formulation. The enhancement effect on intestinal absorption was also confirmed by the intracellular uptake of Caco-2 cells. The proposed micelle carrier system manifested a prospective tool for oral drug delivery.

pH-responsive stearic acid-O-carboxymethyl chitosan assemblies as carriers delivering small molecular drug for chemotherapy.

Recently, chemotherapy is still widely exploited to treat the residual, infiltrative tumor cells after surgical resection. However, many anticancer drugs are limited in clinical application due to their poor water-solubility (hydrophibic) and stability, low bioavailability, and unfavorable pharmacokinetics. Herein, an amphiphilic stearic acid-O-carboxymethyl chitosan (SA-CMC) conjugate was synthesized by amide linkage of SA to the backbone of CMC polymer and then self-assembled into nanoparticles (SA-CMC NPs) with the hydrodynamic particle size of ~100 nm. Subsequently, Paclitaxel (PTX) as a potent and broad-spectrum anticancer drug was loaded into SA-CMC NPs by a probe sonication combined with dialysis method. Owing to the multi-hydrophobic inner cores, the prepared PTX-SA-CMC NPs showed a considerable drug-loading capacity of ~19 wt% and a biphasic release behavior with an accumulative release amount in the range of 70-90% within 72 h. PTX-SA-CMC NPs remarkably enhanced the accumulation at the tumor sites by passive targeting followed by cellular endocytosis. Upon the stimuli of acid, PTX-SA-CMC NPs showed exceptional instability by pH change, thereby triggering the rapid disassembly and accelerated drug release. Consequently, compared with Cremophor EL-based free PTX treatment, PTX-SA-CMC NPs under pH-stimuli accomplished highly efficient apoptosis in cancer cells and effectively suppression of tumors by chemotherapy. Overall, PTX-SA-CMC NPs integrating imaging capacity might be a simple yet feasible PTX nanosystem for tumor-targeted delivery and cancer therapy.

Multifunctional carbamazepine loaded nanostructured lipid carrier (NLC) formulation.

Carbamazepine is a valuable pharmacological agent prescribed in treatment of epilepsy and trigeminal neuralgia. Poor bioavailability, successive dose adjustments and reported long term toxic effects are the main hurdles associated with carbamazepine oral administration. Bees wax containing NLC formulations were developed using high shear homogenization/sonication technique to overcome drug limitations. Formulations were successfully produced and evaluated for both in vitro and in vivo assessments. Results showed particles in nanometric range with negative surface charge and satisfying encapsulation efficiencies (from 93.1 ±â€¯7.6 to 95.7 ±â€¯5.6%). In vitro release studies revealed biphasic pattern and faster release was accompanied with higher bees wax concentration. Interaction between drug and NLC components was assessed using infrared and thermal analysis. Using validated chromatographic analytical method, selected formulation showed good pharmacokinetic profile depriving from plasma fluctuation with 2.27-fold and 1.83-fold improved bioavailability compared to conventional drug suspension and Tegretol™ suspension respectively. It also showed stronger anticonvulsant activity, with respect to conventional drug suspension, in terms of seizure latency, frequency and duration. Toxicity studies revealed undetectable liver or testicular toxicity in biochemical, histological and immunohistochemical investigations verifying its superiority above other investigated formulations. Collectively, results indicate potential suitability of NLC system to effectively and safely deliver carbamazepine orally.

The role of organic anion-transporting polypeptides and formulation in the clearance and distribution of a novel Nav 1.7 channel blocker.

PF-06456384 is an extremely potent and selective blocker of the Nav 1.7 sodium channel designed as a potential intravenous (i.v.) analgesic targeting high potency and rapid clearance to minimize the potential for residual effects following the end of infusion. In our previous experience targeting oral molecules, the requirement to obtain potent, Nav 1.7 selective molecules led to a focus on acidic, amphipilic compounds cleared primarily by organic anion-transporting polypeptide mediated hepatic uptake and subsequent biliary excretion. However, the physicochemical properties of the i.v. lead matter were substantially different, moving from acidic, amphiphilic chemical space to zwitterions as well as substantially increasing molecular weight. This report describes the continued relevance of organic anion-transporting polypeptide driven hepatic uptake in this physicochemical space and highlights an apparent impact of the formulation excipient Solutol on the clearance and distribution of PF-06456384.

[Effects of caprylic acid, capric acid or stearic acid on exogenous cholesterol absorption in intestine of ApoE~(-/-) mice].

OBJECTIVE: To investigate caprylic acid( C8 ∶ 0), capric acid( C10 ∶ 0)or stearic acid( C18∶ 0) on the absorption of exogenous cholesterol in mice. METHODS: ApoE-/-mice were randomly divided into 3 groups: 2% caprylic acid( C8 ∶ 0), capric acid( C10∶ 0) or stearic acid( C18∶ 0) were fed with high cholesterol diet for 16 weeks. Serum lipids and lipoproteins were measured at the beginning of the experiment, the 8 th week and the 16 th week. At 16 th weeks of intervention, 1 h and 4 h after ~3H-cholesterol intragastric administration, the contents of ~3H-cholesterol in the jejunum, ileum and colon contents of mice were intragastric measured. Also the levels of ~3H-cholesterol in blood of0. 5 h, 1 h, 2 h and 4 h after administration were measured. RESULTS: Serum TC and LDL-c in the C8∶ 0 group were significantly lower than those in the C18: 0 group at the 8 th week of intervention( P < 0. 01). Serum TC and LDL-c levels of the both C8∶ 0 group and C10∶ 0 group were significantly lower than those in the C18 ∶ 0 group at the 16 th week( P < 0. 01). The contents of ~3H-cholesterol in the jejunum of mice in C8 ∶ 0 group were significantly lower than those in C18 ∶ 0 group after 1 h of ~3H-cholesterol intragastric administration( P < 0. 05). The contents of ~3H-cholesterol in the colon contents of mice in C8∶ 0 group were significantly higher than those in C18∶ 0 group after 1 h( P < 0. 05) and4 h( P < 0. 01) of ~3H-cholesterol intragastric administration. The ~3H-cholesterol content in blood in C8∶ 0 group were significantly lower than those in C18∶ 0 group after 0. 5 h and 2 h of intragastric administration( P < 0. 01). And the area under the curve( AUC) of ~3H-cholesterol in blood after 4 h of intragastric administration in C8∶ 0 group were significantly lower than those in C18 ∶ 0 group( P < 0. 05). CONCLUSION: Caprylic acid could reduce the absorption of exogenous cholesterol in the intestinal tract and improve blood cholesterol metabolism of mice.

Preparation and characterization of adefovir dipivoxil-stearic acid cocrystal with enhanced physicochemical properties.

The objectives of this study were to prepare cocrystal composed of adefovir dipivoxil (AD) and stearic acid (SA) and to investigate the enhanced properties of the cocrystal. The cocrystal was prepared by antisolvent precipitation and characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC). The enhanced properties were evaluated by dissolution testing, permeability studies, and powder rheology analysis. The AD raw material has a cuboid-like crystal and the cocrystal has a needle shape. In the FT-IR study, there were bathochromic shifts caused by the hydrogen bonding. The melting point of the cocrystal was 52.9 °C, which was lower than that of AD. The XRPD pattern also had distinct differences, supporting the formation of a new crystalline form. The cocrystal showed changes in the lattice energy and the solvation strength, which caused an enhanced dissolution. The permeability was increased due to the SA, which acts as a P-gp inhibitor. The tabletability was enhanced due to the altered crystal habit. In conclusion, cocrystal containing AD and SA was successfully prepared, presenting advantages such as enhanced solubility, tabletability, and permeability. The use of the cocrystal is a desirable approach for the improved physicochemical properties.

Thermosensitive Gel-Based Formulation for Intratumoral Delivery of Toll-Like Receptor 7/8 Dual Agonist, MEDI9197.

Toll-like receptor (TLR) agonists TLR 7/8, MEDI9197, is a imidazoquinoline analogue that can be used for cancer immunotherapy based on its efficacy toward a variety of tumors. Systemic administration of TLR agonists results in stimulation of the immune system throughout the entire body causing undesirable side effects. To minimize these adverse events, local administration of TLR agonists including intratumoral (IT) delivery has been introduced. Here, a poloxamer 407 thermogel formulation for IT delivery of a TLR 7/8 dual agonist, MEDI9197, is described in which the combination of the aqueous thermogel and the ethanolic TLR 7/8 dual agonist, MEDI9197, solution leads to precipitated drug particles within the gel. The in vitro release profile showed an initial burst followed by sustained release. A B16-OVA mouse tumor model was used to assess the in vivo pharmacokinetics, efficacy, and systemic cytokine and chemokine (cytokine) production of the poloxamer 407-based thermogel formulation. The pharmacokinetic evaluation showed that the agonist level within the tumor was reduced by ∼70% over 14 days while serum agonist levels indicated an initial burst at the 6-h time point followed by a drop in serum drug levels over the 14 days of the experiment. The tumor growth inhibition, survival, and serum cytokines for post-IT injection of the poloxamer 407 formulation showed that it slowly released TLR 7/8 agonist, MEDI9197, resulting in more efficacious tumor growth inhibition compared with control groups. In addition, the cytokine levels in circulation indicated that a dose increase led to a decrease in the serum inflammatory and interferon-inducible cytokines levels. This observation could be due to a reduction of drug diffusion and escape from the tumor site due to the precipitation of the drug inside the tumor leading to sustained release. IT delivery of TLR 7/8 dual agonist, MEDI9197, via a thermosensitive gel-based formulation was efficacious and could offer an alternate method of local drug delivery.

Ciprofloxacin Controlled-Solid Lipid Nanoparticles: Characterization, In Vitro Release, and Antibacterial Activity Assessment.

The objective of this research was to formulate ciprofloxacin (CIP) in solid lipid nanoparticles (SLNs) in an attempt to develop a controlled drug delivery system. An ultrasonic melt-emulsification method was used for preparing CIP-loaded SLNs. Key findings included that SLNs were successfully produced with average particle sizes ranging from 165 to 320 nm and polydispersity index in the range of 0.18-0.33. High entrapment efficiency values were reported in all formulations. The atomic force scanning microscopic images showed spherical shape with the size range closer to those found by the particle size analyzer. CIP release exhibited controlled-release behavior with various lipids. Ciprofloxacin solid lipid nanoparticles formula containing stearic acid (CIPSTE) displayed the strongest burst effect and the most rapid release rate. The release data revealed a better fit to the Higuchi diffusion model. After storing the CIPSTE formula at room temperature for 120 days, no significant difference in particle size and zeta potential was found. CIP-loaded SLNs exhibited superior antibacterial activity. Incorporation of CIP into SLNs leads to controlled release and a superior antibacterial effect of CIP.

The molecular assembly of the ionic liquid/aliphatic carboxylic acid/aliphatic amine as effective and safety transdermal permeation enhancers.

In spite of numerous advantages, transdermal drug delivery systems are unfeasible for most drugs because of the barrier effect of the stratum corneum. Ionic liquids were recently used to enhance transdermal drug delivery by improving drug solubility. In the present study, safe and effective ionic liquids for transdermal absorption were obtained as salts generated by a neutralization reaction between highly biocompatible aliphatic carboxylic acids (octanoic acid or isostearic acid) and aliphatic amines (diisopropanolamine or triisopropanolamine) (Medrx Co., Ltd., 2009). The mechanism of skin permeability enhancement by ionic liquids was investigated by hydrophilic phenol red and hydrophobic tulobuterol. Further, the skin permeation enhancing effect was remarkably superior in the acid excess state rather than the neutralization state. Infrared absorption spectrum analysis confirmed that ionic liquids/aliphatic carboxylic acid/aliphatic amine are coexisting at all mixing states. In the acid excess state, ionic liquids interact with aliphatic carboxylic acids via hydrogen bonds. Thus, the skin permeation enhancing effect is not caused by the ionic liquid alone. The "liquid salt mixture," referred to as a complex of ingredients coexisting with ionic liquids, forms a molecular assembly incorporating hydrophilic drug. This molecular assembly was considered an effective and safety enhancer of transdermal drug permeation.

Nanovesicles of nitrendipine with lipid complex for transdermal delivery: pharmacokinetic and pharmacodynamic studies.

CONTEXT: Vesicular transdermal delivery can enhance the bioavailability of a drug especially affected by first-pass metabolism, e.g. nitrendipine. However effective transdermal delivery employs permeation enhancer, e.g oleic acid (OA) with ceramide 2, stearic acid, behenic acid, and cholesteryl sulfate lipid complex. OBJECTIVE: This study investigated the preparation, characterization of physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential in rats, of nitrendipine-loaded nanovesicles of ceramide 2, stearic acid, behenic acid and cholesteryl sulfate containing oleic acid gel (NOVG). MATERIALS AND METHODS: The nanovesicles were made using film hydration method and characterized for physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential. RESULTS: Nitrendipine-loaded nanovesicles of ceramide-2 containing oleic acid (NOV-5) have shown fluxes in the range of 4.88-24.72 µg/cm(2)/h nitrendipine oral suspension (NOS) at equal dose. NOVG-5 has shown almost 33% reduction in blood pressure in the first hour and a further decrease of 25% in the second hour to restore the normal pressure. DISCUSSION: The permeation increases with increase in OA content. OA gets integrated in vesicle wall and enhances its permeability, whereas ceramide content makes sure that skin does not become damaged even after permeation. CONCLUSION: NOVG-5 has shown the most favorable physicochemical properties and good permeation through skin providing good management of hypertension during crucial initial hours.

Formulation and evaluation of gemcitabine-loaded solid lipid nanoparticles.

Gemcitabine-loaded solid lipid nanoparticles (SLNs) were produced by double emulsification technique using stearic acid as lipid, soy lecithin as surfactant and sodium taurocholate as cosurfactant. Prepared nanoparticles are characterized for particle size and surface morphology using scanning electron microscopy (SEM). Particle yield, entrapment efficiency and zeta potential were also determined. In-vitro release studies were performed in phosphate-buffered saline (PBS) pH 7.4 using metabolic shaker. The formulation F6 with maximum entrapment efficiency 72.42% and satisfactory in-vitro release was selected. In-vivo tissue distribution to liver, spleen, lung, heart and kidneys of optimized formulation followed by stability study under specific conditions were also determined. This investigation has shown preferential drug targeting to liver followed by spleen, lungs, kidneys and heart. Stability studies showed no significant change in the particle size followed with very slight decrease in entrapment efficiency at 25 ± 2 °C/60 ± 5% RH over a period of three months.

TNYL peptide functional chitosan-g-stearate conjugate micelles for tumor specific targeting.

Nowadays, a real challenge in cancer therapy is to design drug delivery systems that can achieve high concentrations of drugs at the target site for improved therapeutic effect with reduced side effects. In this research, we designed and synthesized a homing peptide-(TNYLFSPNGPIA, TNYL) modified chitosan-g-stearate (CS) polymer micelle (named T-CS) for targeting delivery. The peptide displayed specific binding affinity to EphB4 which is a member of the Eph family of receptor tyrosine protein kinases. The amphiphilic polymer T-CS can gather into micelles by themselves in an aqueous environment with a low critical micelle concentration value (91.2 µg/L) and nano-scaled size (82.1 ± 2.8 nm). The drug encapsulation efficiency reached 86.43% after loading the hydrophobic drug doxorubicin (DOX). The cytotoxicity of T-CS/DOX against SKOV3 cells was enhanced by approximately 2.3-fold when compared with CS/DOX. The quantitative and qualitative analysis for cellular uptake indicated that TNYL modification can markedly increase cellular internalization in the EphB4-overexpressing SKOV3 cell line, especially with a short incubation time. It is interesting that relatively higher uptake of the T-CS/DOX micelles by SKOV3 cells (positive-EphB4) than A549 cells (negative-EphB4) was observed when the two cells were co-incubated. Furthermore, in vivo distribution experiment using a bilateral-tumor model showed that there was more fluorescence accumulation in the SKOV3 tumor than in the A549 tumor over the whole experiment. These results suggest that TNYL-modified CS micelles may be promising drug carriers as targeting therapy for the EphB4-overexpressing tumor.

A hybrid design to optimize preparation of lopinavir loaded solid lipid nanoparticles and comparative pharmacokinetic evaluation with marketed lopinavir/ritonavir coformulation.

OBJECTIVES: To prepare stearic acid-based lopinavir (LPV) loaded solid lipid nanoparticles (SLNs) using a hybrid design and compare in-vivo performance of optimized formulation with marketed LPV/ritonavir (RTV) coformulation. METHODS: LPV SLNs were prepared by hot melt emulsion technique and optimized using Plackett-Burman design and Box-Behnken design. Physical characterization studies were conducted for the optimized SLNs. Comparative oral pharmacokinetic studies and tissue distribution studies of optimized SLNs and LPV/RTV coformulation were done in Wistar rats. In-vitro metabolic stability and intestinal permeability studies for LPV SLNs were undertaken to elucidate the mechanism involved in the pharmacokinetic improvement of LPV. KEY FINDINGS: Optimized SLNs exhibited nanometeric size (223 nm) with high entrapment efficiency (83%). In-vitro drug release study of SLNs showed biphasic sustained release behaviour. Significant increase in oral bioavailability of LPV from LPV SLNs (5 folds) and LPV/RTV coformulation (3.7 folds) was observed as compared with free LPV. LPV SLNs showed better tissue distribution of LPV in HIV reservoirs than LPV/RTV coformulation. In-vitro studies demonstrated that SLNs provided metabolic protection of LPV and were endocytosized during absorption. CONCLUSIONS: SLNs enhanced oral bioavailability and improved distribution profile of LPV to HIV reservoirs and hence could be better alternative to LPV/RTV coformulation.

A propofol microemulsion with low free propofol in the aqueous phase: formulation, physicochemical characterization, stability and pharmacokinetics.

The purpose of this study was to develop a propofol microemulsion with a low concentration of free propofol in the aqueous phase. Propofol microemulsions were prepared based on single-factor experiments and orthogonal design. The optimal microemulsion was evaluated for pH, osmolarity, particle size, zeta potential, morphology, free propofol in the aqueous phase, stability, and pharmacokinetics in beagle dogs, and comparisons made with the commercial emulsion, Diprivan(®). The pH and osmolarity of the microemulsion were similar to those of Diprivan(®). The average particle size was 22.6±0.2 nm, and TEM imaging indicated that the microemulsion particles were spherical in appearance. The concentration of free propofol in the microemulsion was 21.3% lower than that of Diprivan(®). Storage stability tests suggested that the microemulsion was stable long-term under room temperature conditions. The pharmacokinetic profile for the microemulsion showed rapid distribution and elimination compared to Diprivan(®). We conclude that the prepared microemulsion may be clinically useful as a potential carrier for propofol delivery.

Brain-targeting study of stearic acid-grafted chitosan micelle drug-delivery system.

PURPOSE: Therapy for central nervous system disease is mainly restricted by the blood-brain barrier. A drug-delivery system is an effective approach to overcome this barrier. In this research, the potential of polymeric micelles for brain-targeting drug delivery was studied. METHODS: Stearic acid-grafted chitosan (CS-SA) was synthesized by hydrophobic modification of chitosan with stearic acid. The physicochemical characteristics of CS-SA micelles were investigated. bEnd.3 cells were chosen as model cells to evaluate the internalization ability and cytotoxicity of CS-SA micelles in vitro. Doxorubicin (DOX), as a model drug, was physically encapsulated in CS-SA micelles. The in vivo brain-targeting ability of CS-SA micelles was qualitatively and quantitatively studied by in vivo imaging and high-performance liquid chromatography analysis, respectively. The therapeutic effect of DOX-loaded micelles in vitro was performed on glioma C6 cells. RESULTS: The critical micelle concentration of CS-SA micelles with 26.9% ± 1.08% amino substitute degree was 65 µg/mL. The diameter and surface potential of synthesized CS-SA micelles in aqueous solution was 22 ± 0.98 nm and 36.4 ± 0.71 mV, respectively. CS-SA micelles presented excellent cellular uptake ability on bEnd.3 cells, the IC(50) of which was 237.6 ± 6.61 µg/mL. DOX-loaded micelles exhibited slow drug-release behavior, with a cumulative release up to 72% within 48 hours in vitro. The cytotoxicity of DOX-loaded CS-SA micelles against C6 was 2.664 ± 0.036 µg/mL, compared with 0.181 ± 0.066 µg/mL of DOX · HCl. In vivo imaging results indicated that CS-SA was able to transport rapidly across the blood-brain barrier and into the brain. A maximum DOX distribution in brain of 1.01%/g was observed 15 minutes after administration and maintained above 0.45%/g within 1 hour. Meanwhile, free DOX · HCl was not detected in brain. In other major tissues, DOX-loaded micelles were mainly distributed into lung, liver, and spleen, with a reduction of DOX accumulation in heart. CONCLUSION: The CS-SA micelles were able to be used as a promising carrier for a braintargeting drug delivery system.