Proliposome powders for enhanced intestinal absorption and bioavailability of raloxifene hydrochloride: effect of surface charge

The primary goal of the present study was to investigate the combined prospective of proliposomes and surface charge for the improved oral delivery of raloxifene hydrochloride (RXH). Keeping this objective, the present systematic study was focused to formulate proliposomes by varying the ratio of hydrogenated soyphosphatidylcholine and cholesterol. Furthermore, to assess the role of surface charge on improved absorption of RXH, anionic and cationic vesicles were prepared using dicetyl phosphate and stearylamine, respectively. The formulations were characterized for size, zeta potential and entrapment efficiency. The improved dissolution characteristics assessed from dissolution efficiency, mean dissolution rate were higher for proliposome formulations. The solid state characterization studies indicate the transformation of native crystalline form of the drug to amorphous and/or molecular state. The higher effective permeability coefficient and fraction absorbed in humans extrapolated from in situ single-pass intestinal absorption study data in rats provide an insight on the potential of proliposomes and cationic surface charge for augment in absorption across gastro intestinal barrier. To draw the conclusions, in vivo pharmacokinetic study carried out in rats indicate a threefold enhancement in the rate and extent of absorption of RXH from cationic proliposome formulation which unfurl the potential of proliposomes and role of cationic charge for improved oral delivery of RXH.     

Bortezomib-loaded solid lipid nanoparticles: preparation,characterization, and intestinal permeability investigation

Bortezomib (BTZ), a proteasome inhibitor, is clinically used for the treatment of multiple myeloma and mantle cell lymphoma via intravenous or subcutaneous administration. Since BTZ has limited intestinal permeability, in this study, solid lipid nanoparticles (SLNs) were selected as lipid carrier to improve the intestinal permeability of BTZ. The nanoparticles were prepared by hot oil-in-water emulsification method and characterized for physicochemical properties. Moreover, in situ single-pass intestinal perfusion technique was used for intestinal permeability studies. Mean particle size of the BTZ-loaded solid lipid nanoparticles (BTZ-SLNs) was 94.6?±?0.66?nm with a negative surface charge of –18?±?11?mV. The entrapment efficiency of the BTZ-SLNs was 68.3?±?3.7% with a drug loading value of 0.8?±?0.05%. Cumulative drug release (%) over 48?h, indicated a slow release pattern for nanoparticles. Moreover, the SEM image showed a spherical shape and uniform size distribution for nanoparticles. Also, FTIR analysis indicated that BTZ was successfully loaded in the SLNs. The results of the intestinal perfusion studies revealed an improved effective permeability for BTZ-SLNs with a P_eff value of about threefold higher than plain BTZ solution.     

Enhanced oral bioavailability of isradipine via proniosomal systems

The objective of the present research was to develop a proniosomal formulation of isradipine and to evaluate the influence of proniosomal systems on the oral bioavailability of the drug in albino Wistar rats. Proniosomes were prepared by film deposition on carrier’s method using various molar ratios of nonionic surfactants such as span20, span40, span60, and span80 with cholesterol as membrane stabilizing agent and dicetylphosphate as a charge inducer. The formation of niosomes and surface morphology of proniosome formulations were studied by optical and scanning electron microscopy (SEM), respectively. The prepared proniosomes have shown higher dissolution of isradipine compared with pure drug powder. Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffractometry studies were performed to understand the solid state properties of the drug. Ex vivo permeation enhancement assessed from flux, permeability coefficient, and enhancement ratio were significantly higher for proniosomes compared with control. The pharmacokinetic parameters were evaluated in male albino Wistar rats and a significant enhancement in the bioavailability (2.3-fold) was observed from optimized proniosome formulation compared with control (oral suspension). The stability study reveals that the proniosome formulations are stable when stored at 4°C.     

Preparation and characterization of camptothecin solid lipid nanoparticles

Camptothecin (CA), an antitumor drug, was incorporated into solid lipid nanoparticles (SLNs) prepared by high-pressure homogenization. A Taguchi orthogonal experimental design was used to study the influence of four different variables, with each variable having three value levels on nanoparticle size. Analysis of variance (ANOVA) has been used to evaluate the preparation of CA-SLNs and perform product optimization. The optimized CA-SLNs suspension was lyophilized using mannitol and glucose as cryoprotectants. The physicochemical characteristics of CA-SLNs were evaluated using transmission electron microscopy (TEM), electrophoresis, and differential scanning calorimetry (DSC). The release of camptothecin from CA-SLNs in various media was evaluated using a high-performance liquid chromatography (HPLC) method. The results showed that the concentration of emulsifier and the homogenization pressure had a significant influence on the particle size. The optimized CA-SLNs had an average diameter of about 200 nm, exhibited monodispersity with Dw/Dn of 1.06, and carried a negative charge. The optimal cryoprotectants consisted of 10% mannitol and 5% glucose in nanoparticle suspension. Lyophilized product was reconstituted in distilled water within 0.5 min without change of nanoparticle size. Camptothecin might exist in an amorphous state in SLNs. In vitro results showed that drug release was achieved for up to one week, and the released camptothecin quickly changed to open carboxylate form in the biological pH phosphate buffer. The results indicate that SLNs might be good potential sustained-release delivery vehicles for camptothecin or other lipophilic drugs.     

Functionalized solid lipid nanoparticles for transendothelial delivery

The objectives of this study were to synthesize and characterize functionalized solid lipid nanoparticles (fSLN) to investigate their interaction with endothelial cell monolayers and to evaluate their transendothelial transport capabilities. fSLN bearing tetramethylrhodamine-isothiocyanate-labeled bovine serum albumin (TRITC-BSA) and Coumarin 6 were prepared using a single-step phase-inversion process that afforded concurrent surface modification with a variety of macromolecules such as polystyrene sulfonate (PSS), poly-L-lysine (PLL), heparin (Hep), polyacrylic acid (PAA), polyvinyl alcohol, and polyethylene glycol (PEG). TRITC-BSA/Coumarin 6 encapsulated in fSLN with composite surface functionality (PSS-PLL and PSS-PLL-Hep) were also investigated. Size and surface charge of fSLN were analyzed using dynamic light scattering and transmission electron microscopy. Transport across bovine aortic endothelial cell (BAEC) monolayers was assessed spectrophotometrically using a transwell assay, and fSLN localization at the level of the cell and permeable support was analyzed using fluorescence microscopy. fSLN with tunable size and surface functionality were successfully produced, and had significant effects on cell localization and transport. Specifically, fSLN with PSS-PLL-Hep composite surface functionalization was capable of translocating 53.2 +/- 8.7 mug of TRITC-BSA within 4 h, with fSLN-PEG, fSLN-PAA, and fSLN-PSS exhibiting near-complete apical, paracellular, and cytosolic localization, respectively. Coumarin 6 was released by fSLN as indicated by dye labeling of BAEC membranes. We have developed a rapid process for the production of fSLN bearing low- and high-molecular-weight payloads of varying physicochemical properties. These findings have impications for drug delivery and bioimaging applications, since due to tunable surface chemistry, fSLN internalization and/or translocation across intact endothelial cell monolayers is possible.     

Transport characteristics of wheat germ agglutinin-modified insulin-liposomes and solid lipid nanoparticles in a perfused rat intestinal model

Wheat germ agglutinin (WGA) modified liposomes and solid lipid nanoparticles (SLNs) were evaluated for improving intestinal absorption of insulin. In an in situ local intestinal perfusion experiment, formulations containing 100 IU/kg insulin were administered to the duodenum, jejunum, and ileum of fasted rats. As hypothesized, ileum was the best intestinal location for the absorption of insulin-containing liposomes. Serum insulin concentrations decreased for the various formulations in different absorption sites according to the following trends: Duodenum > ileum > jejunum for WGA-modified insulin-containing liposomes; duodenum > jejunum > ileum for WGA-modified insulin-containing SLNs; ileum > jejunum > duodenum for insulin-containing liposomes; ileum > duodenum > jejunum for insulin-containing SLNs; and duodenum > or = ileum > jejunum for aqueous solution of insulin. These results imply that the nanoparticle type and delivery site were important factors with respect to increasing the bioavailability of insulin following oral administration. The proteolytic degradation as well as the epithelial permeability were primary determinants influcing insulin mucosal absorption.     

Preparation and pharmacokinetic evaluation of Tashinone IIA solid lipid nanoparticles

Tashinone IIA loaded solid lipid nanoparticles (TA-SLN) coated with poloxamer 188 was prepared by emulsification/evaporation. The TA-SLN was characterized by transmission electron microscope and dynamic light scattering (DLS). The results showed that the TA-SLN had an average diameter of 98.7 nm with a zeta potential of - 31.6 mv and the drug loading of 4.6% and entrapment efficiency of 87.7%. In vitro release experiment showed that the release of Tashinone IIA from TA-SLN was in accordance with the Weibull equation. The best model fitting experimental data was a two-compartment open model with first-order. The area under curve of plasma concentration-time (AUC) and mean residence time (MRT) of TA-SLN were much higher than those of Tashinone IIA control solution (TA-SOL). The results of pharmacokinetic studies in rabbits indicated that the formulation of TA-SLN was successful in providing a delivery of slow release of Tashinone IIA.     

Enhanced oral bioavailability and intestinal lymphatic transport of a hydrophilic drug using liposomes

A liposome system was evaluated for oral delivery of a poorly bioavailable hydrophilic drug. The system was prepared from proliposome, which consisted of negatively charged phosphatidylcholine, whereas cefotaxime was chosen as the model drug. An in vivo study was carried out on nine rats according to a three-way crossover design to compare the oral bioavailability of cefotaxime from the liposomal formulation with that of an aqueous drug solution and a physical mixture of cefotaxime with blank liposomes. The results indicated that the extent of bioavailability of cefotaxime was increased approximately 2.7 and 2.3 times compared with that of the aqueous solution and the physical mixture, respectively. In a separate study, simultaneous determination of cefotaxime in intestinal lymph (collected from the mesenteric lymph duct) and in plasma (collected from the tail vein) revealed that its concentration was consistently higher in the lymph than in the plasma when administered via the liposomal formulation, whereas the reverse was observed with the aqueous solution. Thus, the results indicated that the liposomes system has the potential of increasing the oral bioavailability of poorly bioavailable hydrophilic drugs and also promote their lymphatic transport in the intestinal lymph.     

Enhanced in vivo absorption of CB-1 antagonist in rats via solid solutions prepared by hot-melt extrusion

The aim of the present work was to investigate in vitro dissolution properties of three binary solid solutions prepared by a hot-melt extrusion (HME) process with vinyl pirrolidone--vinyl acetate copolymer (Kollidon VA 64), ethyl acrylate, methyl methacrylate polymer (Eudragit E) polyetilenglicol 8000 (PEG 8000) with a cannabinoid type 1 (CB-1) antagonist. Hansen solubility parameters were calculated from the chemical structures of the drug and the individual polymers in order to predict miscibility. Solid state characterizations of drug substance, physical blends and HME formulations were performed with differential scanning calorimetry. The dissolution testing conducted under sink conditions revealed that the dissolution rate of HME formulations improved around 1.8-fold vs drug substance. Supersaturation dissolution study demonstrated that HME formulations composed by Eudragit E and Kollidon VA64 increased drug solubility between 30- and 35-fold, respectively comparing to the drug substance. Physical and chemical stability of formulations were studied at 40°C/75%HR with open dish during 15 days. The formulation composed by the drug and Eudragit E at 10:90 was evaluated for in vivo drug absorption in male Wistar-Hannover rats and it was found to increase CB-1 absorption threefold greater than pure drug oral suspension.     

Mannosylated solid lipid nanoparticles for lung-targeted delivery of Paclitaxel

Objective: The present study discusses paclitaxel (PTX)-loaded mannosylated-DSPE (Distearoyl-phosphatidyl-ethanolamine) solid lipid nanoparticles (M-SLNs) using mannose as a lectin receptor ligand conjugate for lung cancer targeting and to increase the anticancer activity of PTX against A549 lung’s epithelial cancer cells.

Materials and methods: The PTX-SLNs were prepared by solvent injection method and mannose was conjugated to the free amine group of stearylamine. The M-SLNs obtained were characterized for their particle size, polydispersity index, zeta potential and morphology by transmission electron microscope.

Results: The M-SLNs were spherical in shape with 254?±?2.3?nm average size, positive zeta potential (3.27?mV), 79.4?±?1.6 drug entrapment efficiency and showed the lower extent of drug release 40% over 48?h in vitro. Cytotoxicity study on A549 cell lines and biodistrubtion study of drug revealed that M-SLNs deliver a higher concentration of PTX as compared to PTX-SLNs in an alveolar cell site.

Discussion and conclusion: These results suggested that mannosylated M-SLNs are safe and potential vector for lung cancer targeting.     

Dissolution and bioavailability enhancement of alpha-asarone by solid dispersions via oral administration

Alpha (α)-asarone (1-propenyl-2,4,5-methoxybenzol) (ARE) has been extensively used to treat chronic obstructive pulmonary diseases (COPD), bronchial asthma, pneumonia, and epilepsy. Due to its poor solubility and bioavailability, ARE was clinically administered via intravenous injection. However, severe allergies were often reported due to the presence of solublizers in the injection formulation. In our study, we sought to explore the biopharmaceutical classification of ARE, elucidate the mechanisms behind ARE absorption, and to develop a viable formulation to improve the oral bioavailability of ARE. ARE was not a P-glycoprotein substrate, which was absorbed in the passive mode without site specificity in the gastrointestinal tract. Solid dispersions prepared using hydrophilic matrix materials such as Pluronic F68, and polyethylene glycol (PEG) of varying molecular weights (PEG4K, PEG10K, and PEG20K) were proven to significantly improve the dissolution of ARE in vitro and the oral bioavailability of ARE in rats, which represent a promising strategy for the oral administration of ARE and other BCS II compounds.     

Evaporative drying of aqueous dispersions of solid lipid nanoparticles.

Solid lipid nanoparticles (SLNs) have been proposed as alternative colloidal drug carriers. SLNs are obtained by dispersing warm oil-in-water microemulsions into cold water. The aim of this research was to investigate an evaporative drying process for aqueous dispersions of SLNs. For this purpose, a special apparatus, namely a thermostatic minidesiccator having alumina as the drying medium, was designed to carry out the evaporative drying at a controlled temperature. Besides the water removal kinetics, the mean particle size and the size distribution of SLNs were measured during the during with the aim of detecting the highest temperature at which the drying process can be carried out without significantly affecting the SLN average diameter. The SLN dispersions were evaluated with and without a hydrophilic excipient, commonly used as a cryoprotector (trehalose). The drying temperature of 10 degrees C was found to be the most suitable for obtaining SLNs as a powder, maintaining almost the same size as that of the SLNs in dispersion.     

Physicochemical characterization techniques for solid lipid nanoparticles: principles and limitations

Solid lipid nanoparticles (SLNs) are gaining importance due to numerous advantages they offer as a drug delivery system. SLN incorporate poorly soluble drugs, proteins, biologicals, etc. SLN are prepared by techniques like high-pressure homogenization, sonication and employs a wide range of lipids and surfactants. Physicochemical characterization techniques include particle size analysis, zeta potential and determination of crystallinity/polymorphism. Furthermore, drug loading and drug entrapment efficiency are common parameters used to test the efficiency of SLN. Most importantly, the functionality assay of SLN is essential to predict the activity and performance in vivo. The review presented discusses the importance of SLN in drug delivery with emphasis on principles and limitations associated with their physicochemical characterization.     

Enhanced dissolution and bioavailability of grapefruit flavonoid Naringenin by solid dispersion utilizing fourth generation carrier

Context: Naringenin (NRG), the aglycone flavonoid present in grapefruits, possesses anti-inflammatory, anti-carcinogenic, anti-lipid peroxidation and hepato-protective effects. However, it is poorly soluble in water and exhibits slow dissolution after oral ingestion, thus restricting its therapeutic efficacy.

Objective: With the aim to enhance the dissolution rate and oral bioavailability of NRG, solid dispersion technique has been applied using Soluplus® as carrier.

Methods: Solid dispersions of NRG were prepared by solvent evaporation and kneading methods using various ratios (1:4, 3:7, 2:3 and 1:1) of NRG:Carrier. Characterization of the optimized formulations was performed using Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. The in vivo behavior of the optimized formulations was also investigated in Wistar Albino rats.

Results: NRG solid dispersion showed a significantly higher solubility and drug dissolution rate than pure NRG (p?Conclusion: Based on these results, it was concluded that solid dispersion technique markedly enhances the in vitro drug release and in vivo behavior of the grapefruit flavonoid NRG.     

Characterization and body distribution of beta-elemene solid lipid nanoparticles (SLN)

Solid lipid nanoparticles (SLN) containing β-elemene, a volatile oil used for the treatment of cancer, were prepared by the method combining probe sonication and membrane extrusion. Effects of the formulations and procedures on the characteristics of SLN were investigated. Body distribution of β-elemene SLN in rats after intravenous administration was compared with that of the commercial emulsion. The results showed that dispersing the surfactant in the melted lipid matrix could obtain smaller particles than that dispersing in the water phase. Increasing the ratio of monostearin in the lipid matrix or the concentration of surfactant reduced the mean volume size of the SLN. Optimized formulation was composed of monostearin and precirol ATO 5 at a mass ratio of 3:7, which was quite stable for 8 months at room temperature. In vitro release of β-elemene from the SLN was slow and stable without obvious burst release and was found to follow the Higuich equation. After intravenous administration, the β-elemene levels after 5 min injection of SLN formulation were 1.5, 2.9, and 1.4 times higher than those of β-elemene emulsion in liver, spleen, and kidney, respectively, while the concentrations of β-elemene were decreased 30% in heart and lung. Therefore, the SLN containing β-elemene might be an attractive candidate for the treatment of liver cancer.     

Anionic solid lipid nanoparticles supported on protamine/DNA complexes

The objective of this study was to design novel anionic ternary nanoparticles for gene delivery. These ternary nanoparticles were equipped with protamine/DNA binary complexes (150-200?nm) as the support, and the anionic formation was achieved by absorption of anionic solid lipid nanoparticles (≤20?nm) onto the surface of the binary complexes. The small solid lipid nanoparticles (SLNs) were prepared by a modified film dispersion-ultrasonication method, and adsorption of the anionic SLNs onto the binary complexes was typically carried out in water via electrostatic interaction. The formulated ternary nanoparticles were found to be relatively uniform in size (257.7 ± 10.6?nm) with a 'bumpy' surface, and the surface charge inversion from 19.28 ± 1.14?mV to -17.16 ± 1.92?mV could be considered as evidence of the formation of the ternary nanoparticles. The fluorescence intensity measurements from three batches of the ternary nanoparticles gave a mean adsorption efficiency of 96.75 ± 1.13%. Circular dichroism spectra analysis showed that the protamine/DNA complexes had been coated by small SLNs, and that the anionic ternary nanoparticles formed did not disturb the construction of the binary complexes. SYBR Green I analysis suggested that the ternary nanoparticles could protect the DNA from nuclease degradation, and cell viability assay results showed that they exhibit lower cytotoxicity to A549 cells compared with the binary complexes and lipofectamine. The transfection efficiency of the ternary nanoparticles was better than that of naked DNA and the binary complexes, and almost equal to that of lipofectamine/DNA complexes, as revealed by inversion fluorescence microscope observation. These results indicated that the anionic ternary nanoparticles could facilitate gene transfer in cultured cells, and might alleviate the drawbacks of the conventional cationic vector/DNA complexes for gene delivery in vivo.     

Enhancing effects of chitosan and chitosan hydrochloride on intestinal absorption of berberine in rats

Berberine chloride (BBR) is a plant alkaloid that has been used for centuries for treatment of inflammation, dysentery, and liver diseases. It is poorly absorbed from the gastrointestinal (GI) tract and its various clinical uses are limited because of its poor bioavailability. The object of the present study was to investigate the absorption enhancing effect of chitosan on BBR. Mixtures of BBR and chitosan were prepared and the absorption enhancement was investigated in rats. The results showed a dose-dependent absorption enhancement produced by chitosan. Formulations containing 0.5%, 1.5%, and 3.0% chitosan resulted in improvement of AUC(0-36 h) values by 1.9, 2.2, 2.5 times. The absorption enhancing ability of chitosan may be due to its ability to improve the BBR paracellular pathway in the intestinal tract. Chitosan hydrochloride, a salt of chitosan, was also investigated in this study. However, the addition of 2.0% and 3.3% chitosan hydrochloride to BBR solution did not produce any increase in either C(max) or AUC(0-36 h) of BBR. Subsequent solubility studies suggested that the reduced berberine chloride solubility in chitosan hydrochloride may limit the enhancement ability. This study showed that the optimum formulation producing the highest BBR absorption is the BBR solution containing 3.0% chitosan.     

Enhanced optical absorption in semiconductor nanoparticles enabled by nearfield dielectric scattering

The optical absorption of semiconducfing AgBr nanocubes is significantly increased by up to 5 times in the measured spectral range when they are bonded to the surface of dielectric SiO2 nanospheres through electrostatic interaction.The absorption enhancement factor depends on the wavelength and the size of the SiO2 nanoparticles (NPs).Finite-difference time-domain calculations provide the nearfield intensity mapping of a heterostructure that is composed of a AgBr nanocube in close contact with a SiO2 nanosphere.The electric-field distributions indicate the field enhancement near the SiOdAgBr interface due to light scattering and absorption enhancement in the AgBr nanocube,implying that the enhanced scattering nearfield increases the absorption cross section of the AgBr nanocube.The absorption cross-section spectra calculated using Mie theory agree with the experimental observations.This discovery sheds light on the utilization of dielectric spherical particles to increase the absorption in semiconductor NPs,thus improving the light-harvesting efficiency for solar-energy conversion.     

Enhancing effects of chitosan and chitosan hydrochloride on intestinal absorption of berberine in rats

Berberine chloride (BBR) is a plant alkaloid that has been used for centuries for treatment of inflammation, dysentery, and liver diseases. It is poorly absorbed from the gastrointestinal (GI) tract and its various clinical uses are limited because of its poor bioavailability. The object of the present study was to investigate the absorption enhancing effect of chitosan on BBR. Mixtures of BBR and chitosan were prepared and the absorption enhancement was investigated in rats. The results showed a dose-dependent absorption enhancement produced by chitosan. Formulations containing 0.5%, 1.5%, and 3.0% chitosan resulted in improvement of AUC_{0–36 h} values by 1.9, 2.2, 2.5 times. The absorption enhancing ability of chitosan may be due to its ability to improve the BBR paracellular pathway in the intestinal tract. Chitosan hydrochloride, a salt of chitosan, was also investigated in this study. However, the addition of 2.0% and 3.3% chitosan hydrochloride to BBR solution did not produce any increase in either C_max or AUC_{0–36 h} of BBR. Subsequent solubility studies suggested that the reduced berberine chloride solubility in chitosan hydrochloride may limit the enhancement ability. This study showed that the optimum formulation producing the highest BBR absorption is the BBR solution containing 3.0% chitosan.     

In situ intestinal absorption of cyclosporine A solid dispersion in rats

Effects of concentration of Polyoxyethylene (40) stearate, Na(+) and P-gp inhibitor on cyclosporin A (CyA-SD) absorption were investigated by in situ circulation method. The results showed that the absorption of CyA increased linearly with its concentration, indicating a passive diffusion process was dominated. CyA absorption decreased with the carrier concentration. The concentration of Na(+) didn't influence the drug absorbed (P > 0.05). The P-gp inhibitor enhanced the CyA absorption significantly (P < 0.05). The passive diffusion process during the intestinal absorption indicated that the solubility enhancement of CyA is one of the mechanisms for the absorption of this water insoluble drug.