Formulation And Characterization Of Palm Oil Esters Based Nano-Cream For Topical Delivery Of Piroxicam: Study Of In Vitro Release And In Vivo Anti-Inflammatory And Analgesic Effects

During recent years, there has been increased interest in the use of topical vehicle systems that could assist drug permeation through the skin. The drugs of interest usually those causing or having problems when given orally, e.g., easily hydrolyzed in the gastro-intestinal tract, poor bioavailability or to cause adverse reactions. One such drug is piroxicam, a highly effective anti-inflammatory, anti-pyretic and analgesic but causes gastro-intestinal ulcers and bleeding. One of the most promising vehicle systems for trans-dermal permeation of drugs is a nano-cream, a semisolid emulsion with droplet size of 20-200 nm. The main purpose of this study is to formulate a novel nano-cream containing piroxicam for topical delivery and to use palm oil esters (POEs) a new derrivetised palm oil as the oil phase. In the initial study, pseudoternary phase diagrams of water, POEs and non-ionic surfactant mixture of several HLB values were constructed and several promising nano-cream formulae were selected. The stability under different temperatures and other properties of the formulations including the rheological behaviour, zeta potential, droplet size and structural characteristics of the formulation and Solubility and partition coeffecient of piroxicam were studied

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-tozein 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 animal

Nanoparticle diffusion within intestinal mucus: Three-dimensional response analysis dissecting the impact of particle surface charge, size and heterogeneity across polyelectrolyte, pegylated and viral particles

Multiple particle tracking (MPT) methodology was used to dissect the impact of nanoparticle surface charge and size upon particle diffusion through freshly harvested porcine jejunum mucus. The mucus was characterised rheologically and by atomic force microscopy. To vary nanoparticle surface charge we used a series of self-assembly polyelectrolyte particles composed of varying ratios of the negatively charged polyacrylic acid polymer and the positively charged chitosan polymer. This series included a neutral or near-neutral particle to correspond to highly charged but near-neutral viral particles that appear to effectively permeate mucus. In order to negate the confounding issue of self-aggregation of such neutral synthetic particles a sonication step effectively reduced particle size (to less than 340 nm) for a sufficient period to conduct the tracking experiments. Across the polyelectrolyte particles a broad and meaningful relationship was observed between particle diffusion in mucus (×1000 difference between slowest and fastest particle types), particle size (104–373 nm) and particle surface charge (−29 mV to +19.5 mV), where the beneficial characteristic promoting diffusion was a neutral or near-neutral charge. The diffusion of the neutral polyelectrolyte particle (0.02887 cm S−1 × 10−9) compared favourably with that of a highly diffusive PEGylated-PLGA particle (0.03182 cm2 S−1 × 10−9), despite the size of the latter (54 nm diameter) accommodating a reduced steric hindrance with the mucin network. Heterogeneity of particle diffusion within a given particle type revealed the most diffusive 10% sub-population for the neutral polyelectrolyte formulation (5.809 cm2 S−1 × 10−9) to be faster than that of the most diffusive 10% sub-populations obtained either for the PEGylated-PLGA particle (4.061 cm2 S−1 × 10−9) or for a capsid adenovirus particle (1.922 cm2 S−1 × 10−9). While this study has used a simple self-assembly polyelectrolyte system it has substantiated the pursuance of other polymer synthesis approaches (such as living free-radical polymerisation) to deliver stable, size-controlled nanoparticles possessing a uniform high density charge distribution and yielding a net neutral surface potential. Such particles will provide an additional strategy to that of PEGylated systems where the interactions of mucosally delivered nanoparticles with the mucus barrier are to be minimised

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 vaccin

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 5 mg/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 152 nm, 112 nm and 191 nm and a zeta potential of − 3.7, − 4.6 and − 5.7 mV, 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− 9 cm2/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

Effect of surfactant and surfactant blends on pseudoternary phase diagram behavior of newly synthesized palm kernel oil esters

Background: The purpose of this study was to select appropriate surfactants or blends of surfactants to study the ternary phase diagram behavior of newly introduced palm kernel oil esters. Methods: Nonionic surfactant blends of Tween® and Tween®/Span® series were screened based on their solubilization capacity with water for palm kernel oil esters. Tween® 80 and five blends of Tween® 80/Span® 80 and Tween® 80/Span® 85 in the hydrophilic-lipophilic balance (HLB) value range of 10.7–14.0 were selected to study the phase diagram behavior of palm kernel oil esters using the water titration method at room temperature. Results: High solubilization capacity was obtained by Tween® 80 compared with other surfactants of Tween® series. High HLB blends of Tween® 80/Span® 85 and Tween® 80/Span® 80 at HLB 13.7 and 13.9, respectively, have better solubilization capacity compared with the lower HLB values of Tween® 80/Span® 80. All the selected blends of surfactants were formed as waterin- oil microemulsions, and other dispersion systems varied in size and geometrical layout in the triangles. The high solubilization capacity and larger areas of the water-in-oil microemulsion systems were due to the structural similarity between the lipophilic tail of Tween® 80 and the oleyl group of the palm kernel oil esters. Conclusion: This study suggests that the phase diagram behavior of palm kernel oil esters, water, and nonionic surfactants is not only affected by the HLB value, but also by the structural similarity between palm kernel oil esters and the surfactant used. The information gathered in this study is useful for researchers and manufacturers interested in using palm kernel oil esters in pharmaceutical and cosmetic preparation. The use of palm kernel oil esters can improve drug delivery and reduce the cost of cosmetics

Formulation and in vitro release evaluation of newly synthesized palm kernel oil esters-based nanoemulsion delivery system for 30% ethanolic dried extract derived from local Phyllanthus urinaria for skin antiaging

Elrashid Saleh Mahdi1, Azmin Mohd Noor1, Mohamed Hameem Sakeena1, Ghassan Z Abdullah1, Muthanna F Abdulkarim1, Munavvar Abdul Sattar2 1Department of Pharmaceutical Technology, 2Department of Physiology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia Background: Recently there has been a remarkable surge of interest about natural products and their applications in the cosmetic industry. Topical delivery of antioxidants from natural sources is one of the approaches used to reverse signs of skin aging. The aim of this research was to develop a nanoemulsion cream for topical delivery of 30% ethanolic extract derived from local Phyllanthus urinaria (P. urinaria) for skin antiaging. Methods: Palm kernel oil esters (PKOEs)-based nanoemulsions were loaded with P. urinaria extract using a spontaneous method and characterized with respect to particle size, zeta potential, and rheological properties. The release profile of the extract was evaluated using in vitro Franz diffusion cells from an artificial membrane and the antioxidant activity of the extract released was evaluated using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) method. Results: Formulation F12 consisted of wt/wt, 0.05% P. urinaria extract, 1% cetyl alcohol, 0.5% glyceryl monostearate, 12% PKOEs, and 27% Tween® 80/Span® 80 (9/1) with a hydrophilic lipophilic balance of 13.9, and a 59.5% phosphate buffer system at pH 7.4. Formulation F36 was comprised of 0.05% P. urinaria extract, 1% cetyl alcohol, 1% glyceryl monostearate, 14% PKOEs, 28% Tween® 80/Span® 80 (9/1) with a hydrophilic lipophilic balance of 13.9, and 56% phosphate buffer system at pH 7.4 with shear thinning and thixotropy. The droplet size of F12 and F36 was 30.74 nm and 35.71 nm, respectively, and their nanosizes were confirmed by transmission electron microscopy images. Thereafter, 51.30% and 51.02% of the loaded extract was released from F12 and F36 through an artificial cellulose membrane, scavenging 29.89% and 30.05% of DPPH radical activity, respectively. Conclusion: The P. urinaria extract was successfully incorporated into a PKOEs-based nanoemulsion delivery system. In vitro release of the extract from the formulations showed DPPH radical scavenging activity. These formulations can neutralize reactive oxygen species and counteract oxidative injury induced by ultraviolet radiation and thereby ameliorate skin aging. Keywords: nanoemulsions, Phyllanthus urinaria, skin antiaging, palm kernel oil ester

Effect of surfactant and surfactant blends on pseudoternary phase diagram behavior of newly synthesized palm kernel oil esters

Elrashid Saleh Mahdi1, Mohamed HF Sakeena1, Muthanna F Abdulkarim1, Ghassan Z Abdullah1,3, Munavvar Abdul Sattar2, Azmin Mohd Noor11Department of Pharmaceutical Technology, 2Department of Physiology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Penang, Malaysia; 3Department of Pharmaceutical Technology, International Medical University, Bukit Jalil, Kuala Lumpur, MalaysiaBackground: The purpose of this study was to select appropriate surfactants or blends of surfactants to study the ternary phase diagram behavior of newly introduced palm kernel oil esters.Methods: Nonionic surfactant blends of Tween® and Tween®/Span® series were screened based on their solubilization capacity with water for palm kernel oil esters. Tween® 80 and five blends of Tween® 80/Span® 80 and Tween® 80/Span® 85 in the hydrophilic-lipophilic balance (HLB) value range of 10.7–14.0 were selected to study the phase diagram behavior of palm kernel oil esters using the water titration method at room temperature.Results: High solubilization capacity was obtained by Tween® 80 compared with other surfactants of Tween® series. High HLB blends of Tween® 80/Span® 85 and Tween® 80/Span® 80 at HLB 13.7 and 13.9, respectively, have better solubilization capacity compared with the lower HLB values of Tween® 80/Span® 80. All the selected blends of surfactants were formed as water-in-oil microemulsions, and other dispersion systems varied in size and geometrical layout in the triangles. The high solubilization capacity and larger areas of the water-in-oil microemulsion systems were due to the structural similarity between the lipophilic tail of Tween® 80 and the oleyl group of the palm kernel oil esters.Conclusion: This study suggests that the phase diagram behavior of palm kernel oil esters, water, and nonionic surfactants is not only affected by the HLB value, but also by the structural similarity between palm kernel oil esters and the surfactant used. The information gathered in this study is useful for researchers and manufacturers interested in using palm kernel oil esters in pharmaceutical and cosmetic preparation. The use of palm kernel oil esters can improve drug delivery and reduce the cost of cosmetics.Keywords: phase diagram, palm kernel oil esters, nonionic surfactants, microemulsion

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 (PE) encapsulated in nanoparticles with immunoadjuvant properties. For this, a polymer conjugate formed by the covalent binding of mannosamine to the copolymer of methylvinyl ether and maleic anhydride was firstly 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 pre-sensitized CD1 mice to peanut. After completing therapy, mice underwent an intraperitoneal challenge with PE. 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