Microstructure investigation, Electrical properties, and γ-rays' protection capacity for ZnO doped clay ceramic.

A series of ceramic samples fabricated based on ZnO doped different concentrations of natural clay according to the relation (1-x) ZnO - (x) clay; 5 wt% ≤ x ≤ 20 wt%. The samples were pressed and sintered at 1200 °C. The experimental techniques were used to characterize and measure the chemical composition, density, and current-voltage measurements for the fabricated ceramics samples. The measurements depict an increase in the I-V nonlinearity with raising the clay concentration, where the increase in clay by up to 20 wt% shifts breakdown voltage to a higher value of up to 390 V/cm and decreases leakage current to 55 mA/cm2. The examinations for the gamma-ray shielding capacity for the fabricated composites (utilizing Monte Carlo simulation) demonstrate enrichment of clay concentration between 5 wt% and 20 wt% reduced the linear attenuation coefficient for the fabricated ceramics by 23.15% and 8.66% at γ photon energy of 0.059 MeV and 1.252 MeV, respectively. The half-value thickness and lead's equivalent thickness increased along with a drop in the linear attenuation coefficient, but the radiation protection effectiveness of the fabricated ceramics increased.

Carbopol 934, 940 and Ultrez 10 as viscosity modifiers of palm olein esters based nano-scaled emulsion containing ibuprofen.

Micro-emulsions and sometimes nano-emulsions are well known candidates to deliver drugs locally. However, the poor rheological properties are marginally affecting their acceptance pharmaceutically. This work aimed to modify the poor flow properties of a nano-scaled emulsion comprising palm olein esters as the oil phase and ibuprofen as the active ingredient for topical delivery. Three Carbopol ® resins: 934, 940 and Ultrez 10, were utilized in various concentrations to achieve these goals. Moreover, phosphate buffer and triethanolamine solutions pH 7.4 were used as neutralizing agents to assess their effects on the gel-forming and swelling properties of Carbopol ® 940. The addition of these polymers caused the produced nano-scaled emulsion to show a dramatic droplets enlargement of the dispersed globules, increased intrinsic viscosity, consistent zeta potential and transparent-to-opaque change in appearance. These changes were relatively influenced by the type and the concentration of the resin used. Carbopol ® 940 and triethanolamine appeared to be superior in achieving the proposed tasks compared to other materials. The higher the pH of triethanolamine solution, the stronger the flow-modifying properties of Carbopol ® 940. Transmission electron microscopy confirmed the formation of a well-arranged gel network of Carbopol ® 940, which was the major cause for all realized changes. Later in vitro permeation studies showed a significant decrease in the drug penetration, thus further modification using 10% w/w menthol or limonene as permeation promoters was performed. This resulted in in vitro and in vivo pharmacodynamics properties that are comparably higher than the reference chosen for this study.

Determination of the Attenuation Coefficients of Epoxy Resin with Carbopol Polymer as a Breast Phantom Material at Low Photon Energy Range.

Six different composites of epoxy resin and Carbopol 974p polymer were prepared based on Carbopol 974p polymer concentrations of 0%, 5%, 10%, 15%, 20%, and 25%. The linear and mass attenuation coefficients, Half Value Layer (HVL), and mean free path (MFP) of these composites were determined using single-beam photon transmission in the energy range between 16.65 keV and 25.21 keV. This was carried out by determining the attenuation of ka1 X-ray fluorescent (XRF) photons from niobium, molybdenum, palladium, silver, and tin targets. The results were compared with theoretical values of three types of breast material (Breast 1, Breast 2, Breast 3) and Perspex, which was calculated using a XCOM computer program. The results show that there were no significant differences in the attenuation coefficient values after the consequent Carbopol additions. Moreover, it was found that the mass attenuation coefficients of all tested composites were close to those of Perspex and the values for Breast 3. The HVL and MFP results showed that the E25 sample is closer to the results of the Perspex material with differences of (0.53-1.15%) and (0.51-1.20%), respectively. In addition, the densities of the fabricated samples were in the range of 1.102-1.170 g/cm3, which is in the range of human breast density. A computed tomography (CT) scanner was used to investigate the CT number values for the fabricated samples. The CT numbers of all samples were in the range of human breast tissue (24.53-40.28 HU). Based on these findings, the fabricated epoxy-Carbopol polymer is a good candidate for use as a breast phantom material.

Study of surface activity of piroxicam at the interface of palm oil esters and various aqueous phases.

The surface activity of some non-steroidal anti-inflammatory agents like ibuprofen was investigated extensively. This fact has attracted the researchers to extend this behavior to other agents like piroxicam. Piroxicam molecules are expected to orient at the interface of oil and aqueous phase. The aim of this study was, firstly, to assess the surface and interfacial tension behaviour of newly synthesised palm oil esters and various pH phosphate buffers. Furthermore, the surface and interfacial tension activity of piroxicam was studied. All the measurements of surface and interfacial tension were made using the tensiometer. The study revealed that piroxicam has no effect on surface tension values of all pH phosphate buffers and palm oil esters. Similarly, various concentrations of piroxicam did not affect the interfacial tensions between the oil phase and the buffer phases. Accordingly, the interfacial tension values of all mixtures of oil and phosphate buffers were considerably high which indicates the immiscibility. It could be concluded that piroxicam has no surface activity. Additionally, there is no surface pressure activity of piroxicam at the interface of plam oil esters and phosphate buffers in the presence of Tweens and Spans.

Topical, immunomodulatory epoxy-tiglianes induce biofilm disruption and healing in acute and chronic skin wounds.

The management of antibiotic-resistant, bacterial biofilm infections in chronic skin wounds is an increasing clinical challenge. Despite advances in diagnosis, many patients do not derive benefit from current anti-infective/antibiotic therapies. Here, we report a novel class of naturally occurring and semisynthetic epoxy-tiglianes, derived from the Queensland blushwood tree (Fontainea picrosperma), and demonstrate their antimicrobial activity (modifying bacterial growth and inducing biofilm disruption), with structure/activity relationships established against important human pathogens. In vitro, the lead candidate EBC-1013 stimulated protein kinase C (PKC)-dependent neutrophil reactive oxygen species (ROS) induction and NETosis and increased expression of wound healing-associated cytokines, chemokines, and antimicrobial peptides in keratinocytes and fibroblasts. In vivo, topical EBC-1013 induced rapid resolution of infection with increased matrix remodeling in acute thermal injuries in calves. In chronically infected diabetic mouse wounds, treatment induced cytokine/chemokine production, inflammatory cell recruitment, and complete healing (in six of seven wounds) with ordered keratinocyte differentiation. These results highlight a nonantibiotic approach involving contrasting, orthogonal mechanisms of action combining targeted biofilm disruption and innate immune induction in the treatment of chronic wounds.

Renal sympathetic nervous system hyperactivity in early streptozotocin-induced diabetic kidney disease.

AIM: We assessed the role of renal sympathetic nervous system in the deterioration of renal hemodynamic and excretory functions in rats with streptozotocin (STZ)-induced diabetic kidney disease (DKD). METHODS: Male Sprague-Dawley (SD) rats were induced with diabetes mellitus (DM) using STZ (55 mg/kg, i.p.). The acute studies were conducted on denervated anesthetized rats 7 days after STZ administration. Two sets of experiments were performed: clearance experiments in which six 20-min urine and plasma collections were carried out to measure kidney function parameters, and hemodynamic experiments in which the renal nerves were electrically stimulated and responses in renal vascular resistance (RVR) and renal blood flow (RBF) were recorded. RESULTS: Renal denervation in STZ-induced diabetic rats produced higher fractional excretion of sodium (FE(Na) ) but lower plasma sodium (P(Na) ), glomerular filtration rate (GFR), and plasma creatinine (P(Cr) ) (all P<0.05 vs. innervated diabetic rats). In innervated diabetic rats, renal nerve stimulation (RNS) caused significant attenuation in the renal vasoconstrictor responses (all P<0.05 vs. innervated control). Renal denervation in diabetic rats significantly blunted these responses (all P<0.05 vs. innervated diabetic rats); however, they were significantly higher (all P<0.05) while compared to denervated control counterparts. CONCLUSIONS: The data demonstrate an early role for the renal sympathetic innervation in the pathogenesis of DKD. If the kidney is prevented from renal sympathetic nerve action renal functional parameters are markedly improved. The data further suggest an early enhancement in renal sensitivity to intrarenal norepinephrine (NE) upon the removal of renal sympathetic tone in STZ-induced diabetic rats.

Development of a stepping force analgesic meter for a rat arthritic model.

Behavioural assessment of experimental pain is an essential method for analysing and measuring pain levels. Rodent models, which are widely used in behavioural tests, are often subject to external forces and stressful manipulations that cause variability of the parameters measured during the experiment. Therefore, these parameters may be inappropriate as indicators of pain. In this article, a stepping-force analgesimeter was designed to investigate the variations in the stepping force of rats in response to pain induction. The proposed apparatus incorporates new features, namely an infrared charge-coupled device (CCD) camera and a data acquisition system. The camera was able to capture the locomotion of the rats and synchronise the stepping force concurrently so that each step could be identified. Inter-day and intra-day precision and accuracy of each channel (there were a total of eight channels in the analgesimeter and each channel was connected to one load cell and one amplifier) were studied using different standard load weights. The validation studies for each channel also showed convincing results whereby intra-day and inter-day precision were less than 1% and accuracy was 99.36-100.36%. Consequently, an in vivo test was carried out using 16 rats (eight females and eight males). The rats were allowed to randomly walk across the sensor tunnel (the area that contained eight channels) and the stepping force and locomotion were recorded. A non-expert, but from a related research domain, was asked to differentiate the peaks of the front and hind paw, respectively. The results showed that of the total movement generated by the rats, 50.27 ± 3.90% in the case of the male rats and 62.20 ± 6.12% in that of the female rats had more than two peaks, a finding which does not substantiate the assumptions made in previous studies. This study also showed that there was a need to use the video display frame to distinguish between the front and hind paws in the case of 48.80 ± 4.01% of the male rats and 66.76 ± 5.35% of the female rats. Evidently the assumption held by current researchers regarding stepping force measurement is not realistic in terms of application, and as this study has shown, the use of a video display frame is essential for the identification of the front and hind paws through the peak signals.

Preparation and in vitro evaluation of mebeverine HCl colon-targeted drug delivery system.

Mebeverine HCl is a water soluble drug commonly used to treat irritable bowel syndrome by acting directly on the smooth muscles of the colon. This work was aimed at the formulation and in vitro evaluation of a colon-targeted drug delivery system containing mebeverine HCl. Matrix tablets were prepared using ethyl cellulose (EC), Eudragit RL 100 either solely or in combination by wet granulation technique. Dissolution was carried out in 0.1 N HCl for 2?h followed by pH 6.8 phosphate buffer for eight hours. Uncoated forms released more than 5% drug in 0.1 N HCl therefore, Eudragit L100 was used as a coat. The results indicated very slow release profile. As a result, single retardant was used to prepare the matrix and coated by Eudragit L 100. The matrix containing 7% Eudragit RL 100 and 6% of binder was subjected to further studies to assess the effect of different coats (Eudragit L 100-55 and cellulose acetate phthalate) and different binders (pectin and sodium alginate) on the release profile. Eudragit L 100 and pectin were the best coating agent and binder, respectively. The final formula was stable and it can be concluded that the prepared system has the potential to deliver mebeverine HCl in vivo to the colon.

Intestinal permeability studies of sulpiride incorporated into self-microemulsifying drug delivery system (SMEDDS).

The objective of the present study was to determine the intestinal absorption of sulpiride incorporated into SMEDDS by means of single-pass intestinal perfusion method (SPIP) in rat and to compare the effective permeability coefficient obtained with that of drug solution and micellar solution. The prepared SMEDDS and micelles formulations were investigated for droplets size. SPIP experiment was performed using the three formulations in three of the secluded regions of the small intestine (duodenum, jejunum, and ileum). The amount of the drug in the samples was estimated by HPLC and the effective permeability coefficients in rats were calculated. The human intestinal permeability was predicted based on rat effective permeability coefficient value. The dilution stability of the formulations was also determined. The average droplet size of SMEDDS and micelles was 9.27 nm and 7.20 nm respectively. The effective permeability coefficient of sulpiride was appreciably lower in the ileum weighed against jejunum and duodenum when administered as a solution (P<0.05). The estimated human absorption of sulpiride for the SMEDDS dilutions was superior to that from solution (P<0.05) and similar to micellar solution. The micellar dilutions were unstable whereas the SMEDDS dilutions were stable. Based on the above results, SMEDDS can be a potential candidate for improving the peroral absorption of the sulpiride.

Quantifying the effects of antibiotic treatment on the extracellular polymer network of antimicrobial resistant and sensitive biofilms using multiple particle tracking.

Novel therapeutics designed to target the polymeric matrix of biofilms requires innovative techniques to accurately assess their efficacy. Here, multiple particle tracking (MPT) was developed to characterize the physical and mechanical properties of antimicrobial resistant (AMR) bacterial biofilms and to quantify the effects of antibiotic treatment. Studies employed nanoparticles (NPs) of varying charge and size (40-500 nm) in Pseudomonas aeruginosa PAO1 and methicillin-resistant Staphylococcus aureus (MRSA) biofilms and also in polymyxin B (PMB) treated Escherichia coli biofilms of PMB-sensitive (PMBSens) IR57 and PMB-resistant (PMBR) PN47 strains. NP size-dependent and strain-related differences in the diffusion coefficient values of biofilms were evident between PAO1 and MRSA. Dose-dependent treatment effects induced by PMB in PMBSens E. coli biofilms included increases in diffusion and creep compliance (P < 0.05), not evident in PMB treatment of PMBR E. coli biofilms. Our results highlight the ability of MPT to quantify the diffusion and mechanical effects of antibiotic therapies within the AMR biofilm matrix, offering a valuable tool for the pre-clinical screening of anti-biofilm therapies.

Zwitterionic self-assembled nanoparticles as carriers for Plasmodium targeting in malaria oral treatment.

The current decline in antimalarial drug efficacy due to the evolution of resistant Plasmodium strains calls for new strategies capable of improving the bioavailability of antimalarials, especially of those whose lipophilic character imparts them a low solubility in biological fluids. Here we have designed, synthesized and characterized amphiphilic zwitterionic block copolymers forming nanoparticles capable of penetrating the intestinal epithelium that can be used for oral administration. Poly(butyl methacrylate-co-morpholinoethyl sulfobetaine methacrylate) (PBMA-MESBMA)-based nanoparticles exhibited a specific targeting to Plasmodium falciparum-infected vs. parasite-free red blood cells (74.8%/0.8% respectively), which was maintained upon encapsulation of the lipophilic antimalarial drug curcumin (82.6%/0.3%). The in vitro efficacy of curcumin upon encapsulation was maintained relative to the free compound, with an IC50 around 5 µM. In vivo assays indicated a significantly increased curcumin concentration in the blood of mice one hour after being orally fed PBMA-MESBMA-curcumin in comparison to the administration of free drug (18.7 vs. 2.1 ng/ml, respectively). At longer times, however, plasma curcumin concentration equaled between free and encapsulated drug, which was reflected in similar in vivo antimalarial activities in Plasmodium yoelii yoelii-infected mice. Microscopic analysis in blood samples of fluorescently labeled PBMA-MESBMA revealed the presence of the polymer inside P. yoelii yoelii-parasitized erythrocytes one hour after oral administration to infected animals.

HPLC and anti-inflammatory studies of the flavonoid rich chloroform extract fraction of Orthosiphon stamineus leaves.

The aim of the present study was to verify the anti-inflammatory activity of Orthosiphon stamineus leaf extracts and to identify the active compound(s) contributing to its anti-inflammatory activity using a developed HPLC method. Active chloroform extract of O. stamineus was fractionated into three fractions using a dry flash column chromatography method. These three fractions were investigated for anti-peritoneal capillary permeability, in vitro nitric oxide scavenging activity, anti-inflammatory and nitric oxide (NO) inhibition using carrageenan-induced hind paw edema method. The flavonoid rich chloroform extract fraction (CF2) [containing sinensetin (2.86% w/w), eupatorin (5.05% w/w) and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (1.101% w/w)], significantly reduced rat hind paw edema, NO and decreased dye leakage to peritoneal cavity at p < 0.05. IC(50) of in vitro NO scavenging of CF2 was 0.3 mg/mL. These results suggest that the anti-inflammatory properties of these CF2 may possibly be due to the presence of flavonoid compounds capable of affecting the NO pathway.

Self-emulsifying drug delivery system: Mucus permeation and innovative quantification technologies.

Mucus is a dynamic barrier which covers and protects the underlying mucosal epithelial membrane against bacteria and foreign particles. This protection mechanism extends to include therapeutic macromolecules and nanoparticles (NPs) through trapping of these particles. Mucus is not only a physical barrier that limiting particles movements based on their sizes but it selectively binds with particles through both hydrophilic and lipophilic interactions. Therefore, nano-carriers for mucosal delivery should be designed to eliminate entrapment by the mucus barrier. For this reason, different strategies have been approached for both solid nano-carriers and liquid core nano-carriers to synthesise muco-diffusive nano-carrier. Among these nano-strategies, Self-Emulsifying Drug Delivery System (SEDDS) was recognised as very promising nano-carrier for mucus delivery. The system was introduced to enhance the dissolution and bioavailability of orally administered insoluble drugs. SEDDS has shown high stability against intestinal enzymatic activity and more importantly, relatively rapid permeation characteristics across mucus barrier. The high diffusivity of SEDDS has been tested using various in vitro measurement techniques including both bulk and individual measurement of droplets diffusion within mucus. The selection and processing of an optimum in vitro technique is of great importance to avoid misinterpretation of the diffusivity of SEDDS through mucus barrier. In conclusion, SEDDS is a system with high capacity to diffuse through intestinal mucus even though this system has not been studied to the same extent as solid nano-carriers.

Modulation of the fate of zein nanoparticles by their coating with a Gantrez® AN-thiamine polymer conjugate.

The aim of this work was to evaluate the mucus-permeating properties of nanocarriers using zein nanoparticles (NPZ) coated with a Gantrez® AN-thiamine conjugate (GT). NPZ were coated by incubation at different GT-to-zein ratios: 2.5% coating with GT (GT-NPZ1), 5% (GT-NPZ2) and 10% (GT-NPZ3). During the process, the GT conjugate formed a polymer layer around the surface of zein nanoparticles. For GT-NPZ2, the thickness of this corona was estimated between 15 and 20 nm. These nanocarriers displayed a more negative zeta potential than uncoated NPZ. The diffusivity of nanoparticles was evaluated in pig intestinal mucus by multiple particle tracking analysis. GT-NPZ2 displayed a 28-fold higher diffusion coefficient within the mucus layer than NPZ particles. These results align with in vivo biodistribution studies in which NPZ displayed a localisation restricted to the mucus layer, whereas GT-NPZ2 were capable of reaching the intestinal epithelium. The gastro-intestinal transit of mucoadhesive (NPZ) and mucus-permeating nanoparticles (GT-NPZ2) was also found to be different. Thus, mucoadhesive nanoparticles displayed a significant accumulation in the stomach of animals, whereas mucus-penetrating nanoparticles appeared to exit the stomach more rapidly to access the small intestine of animals.

Mannosylated Nanoparticles for Oral Immunotherapy in a Murine Model of Peanut Allergy.

Peanut allergy is one of the most prevalent and severe of food allergies with no available cure. The aim of this work was to evaluate the potential of an oral immunotherapy based on the use of a roasted peanut extract encapsulated in nanoparticles with immunoadjuvant properties. For this, a polymer conjugate formed by the covalent binding of mannosamine to the copolymer of methyl vinyl ether and maleic anhydride was first synthetized and characterized. Then, the conjugate was used to prepare nanoparticles with an important capability to diffuse through the mucus layer and reach, in a large extent, the intestinal epithelium, including Peyer's patches. Their immunotherapeutic potential was evaluated in a model of presensitized CD1 mice to peanut. After completing therapy, mice underwent an intraperitoneal challenge with peanut extract. Nanoparticle-treatment was associated with both less serious anaphylaxis symptoms and higher survival rates than control, confirming the protective effect of this formulation against the challenge.

Oral Immunogenicity in Mice and Sows of Enterotoxigenic Escherichia Coli Outer-Membrane Vesicles Incorporated into Zein-Based Nanoparticles.

Enterotoxigenic Escherichia coli (ETEC) strains are a major cause of illness and death in neonatal and recently weaned pigs. The immune protection of the piglets derives from maternal colostrum, since this species does not receive maternal antibodies through the placenta. In the present study, outer membrane vesicles (OMVs) obtained from main ETEC strains involved in piglet infection (F4 and F18 serotypes), encapsulated into zein nanoparticles coated with Gantrez®® AN-mannosamine conjugate, were used to orally immunize mice and pregnant sows. Loaded nanoparticles were homogeneous and spherical in a shape, with a size of 220-280 nm. The diffusion of nanoparticles through porcine intestinal mucus barrier was assessed by a Multiple Particle Tracking technique, showing that these particles were able to diffuse efficiently (1.3% diffusion coefficient), validating their oral use. BALB/c mice were either orally immunized with free OMVs or encapsulated into nanoparticles (100 µg OMVs/mouse). Results indicated that a single dose of loaded nanoparticles was able to elicit higher levels of serum specific IgG1, IgG2a and IgA, as well as intestinal IgA, with respect to the free antigens. In addition, nanoparticles induced an increase in levels of IL-2, IL-4 and IFN-γ with respect to the administration of free OMVs. Orally immunized pregnant sows with the same formulation elicited colostrum-, serum- (IgG, IgA or IgM) and fecal- (IgA) specific antibodies and, what is most relevant, offspring suckling piglets presented specific IgG in serum. Further studies are needed to determine the infection protective capacity of this new oral subunit vaccine.

In vivo evaluation of an oral self-emulsifying drug delivery system (SEDDS) for exenatide.

BACKGROUND: The aim of the study was to develop an oral self-emulsifying drug delivery system (SEDDS) for exenatide and to evaluate its in vivo efficacy. METHODS: Exenatide was lipidised via hydrophobic ion pairing with sodium docusate (DOC) and incorporated in SEDDS consisting of 35% Cremophor EL, 25% Labrafil 1944, 30% Capmul-PG 8 and 10% propylene glycol. Exenatide/DOC was characterized in terms of lipophilicity evaluating the octanol/water phase distribution (logP). Exenatide/DOC SEDDS were characterized via droplet size analysis, drug release characteristics (log DSEDDS/release medium determination) and mucus permeation studies. Furthermore, the impact of orally administered exenatide/DOC SEDDS on blood glucose level was investigated in vivo on healthy male Sprague-Dawley rats. RESULTS: Hydrophobic ion pairing in a molar ratio of 1:4 (exenatide:DOC) increased the effective logP of exenatide from -1.1 to 2.1. SEDDS with a payload of 1% exenatide/DOC had a mean droplet size of 45.87 ±â€¯2.9 nm and a Log DSEDDS/release medium of 1.9 ±â€¯0.05. Permeation experiments revealed 2.7-fold improved mucus diffusion for exenatide/DOC SEDDS compared to exenatide in solution. Orally administered exenatide/DOC SEDDS showed a relative bioavailability (versus s.c.) of 14.62% ±â€¯3.07% and caused a significant (p < .05) 20.6% decrease in AUC values of blood glucose levels. CONCLUSION: According to these results, hydrophobic ion pairing in combination with SEDDS represents a promising tool for oral peptide delivery.

Impact of different hydrophobic ion pairs of octreotide on its oral bioavailability in pigs.

The objective of this study was to investigate the impact of different hydrophobic ion pairs (HIP) on the oral bioavailability of the model drug octreotide in pigs. Octreotide was ion paired with the anionic surfactants deoxycholate, decanoate and docusate differing in lipophilicity. These hydrophobic ion pairs were incorporated in self-emulsifying drug delivery systems (SEDDS) based on BrijO10, octyldodecanol, propylene glycol and ethanol in a concentration of 5mg/ml. SEDDS were characterized regarding size distribution, zeta potential, stability towards lipase, log DSEDDS/release medium and mucus diffusion behavior. The oral bioavailability of octreotide was evaluated in pigs via LC-MS/MS analyses. Most efficient ion pairing was achieved at a molar ratio of 1:3 (peptide: surfactant). SEDDS containing the octreotide-deoxycholate, -decanoate and -docusate ion pair exhibited a mean droplet size of 152nm, 112nm and 191nm and a zeta potential of -3.7, -4.6 and -5.7mV, respectively. They were completely stable towards degradation by lipase and showed a log DSEDDS/release medium of 1.7, 1.8 and 2.7, respectively. The diffusion coefficient of these SEDDS was in the range of 0.03, 0.11 and 0.17×10-9cm2/s, respectively. In vivo studies with these HIPs showed no improvement in the oral bioavailability in case of octreotide-decanoate. In contrast, octreotide-deoxycholate and octreotide-docusate SEDDS resulted in a 17.9-fold and 4.2-fold higher bioavailability vs. CONTROL: According to these results, hydrophobic ion pairing could be identified as a key parameter for SEDDS to achieve high oral bioavailability.

Evaluation of nanoparticles as oral vehicles for immunotherapy against experimental peanut allergy.

The aim of this work was to evaluate the potential application of an original oral immunotherapy, based on the use of nanoparticles, against an experimentally induced peanut allergy. In this context, a roasted peanut extract, containing the main allergenic proteins, were encapsulated into poly(anhydride) nanoparticles. The resulting peanut-loaded nanoparticles (PE-NP) displayed a mean size of about 150nm and a significantly lower surface hydrophobicity than empty nanoparticles (NP). This low hydrophobicity correlated well with a higher in vitro diffusion in pig intestinal mucus than NP and an important in vivo capability to reach the intestinal epithelium and Peyer's patches. The immunotherapeutic capability of PE-NP was evaluated in a model of pre-sensitized CDI mice to peanut. After completing therapy of three doses of peanut extract, either free or encapsulated into nanoparticles, mice underwent an intraperitoneal challenge. Anaphylaxis was evaluated by means of assessment of symptom scores and mouse mast cell protease-1 levels (mMCPT-1). PE-NP treatment was associated with significant lower levels of mMCPT-1, and a significant survival rate after challenge, confirming the protective effect of this formulation against the challenge. In summary, this nanoparticle-based formulation might be a valuable strategy for peanut-specific immunotherapy.

Mucus permeating thiolated self-emulsifying drug delivery systems.

CONTEXT: Mucus represents a critical obstacle for self-emulsifying drug delivery systems (SEDDS) targeting the epithelial membrane site. OBJECTIVE: The aim of the study was the development of a novel SEDDS to overcome the mucus barrier. MATERIALS AND METHODS: Two novel conjugates N-dodecyl-4-mercaptobutanimidamide (thiobutylamidine-dodecylamine, TBA-D) and 2-mercapto-N-octylacetamide (thioglycolicacid-octylamine, TGA-O) were synthesized, incorporated into SEDDS and analyzed for stability, cytotoxicity and physico-chemical characteristics using dynamic light scattering. Mucus interaction studies were performed using in vitro assays based on multiple particle tracking, rotational silicone tubes and rheology. RESULTS AND DISCUSSION: TBA-D was synthesized using dodecylamine and iminothiolane as thiol precursor (yield=55 ± 5%). TGA-O was obtained via crosslinking of octylamine with SATA ((2,5-dioxopyrrolidin-1-yl) 2-acetylsulfanylacetate) (yield=70 ± 6%). The chemical structure of target compounds was confirmed via NMR analysis. The thiol-conjugates were incorporated in an amount of 3% (m/m) into SEDDS (Cremophor EL 30%, Capmul MCM 30%, Captex 355 30% and propylene glycol 10%), namely thiolated SEDDS leading to a droplet size around 50 nm and zeta potential close to 0 mV. Thiolated SEDDS with an effective diffusion coefficient 〈Deff〉 of up to 0.871 ± 0.122 cm(2) s(-1) × 10(-9) were obtained. Rotational silicone studies show increased permeation of the thiolated SEDDS A in comparison with unthiolated control. Rheological studies confirmed the mucolytic activity of the thiol-conjugates which differed only by 3% from DTT (dithiothreitol) serving as positive control. CONCLUSION: Low molecular weight thiol-conjugates were identified to improve the mucus permeation, leading to highly efficient mucus permeating SEDDS, which were superior to conventional SEDDS and might thus be a new carrier for lipophilic drug delivery.