A Window for Enhanced Oral Delivery of Therapeutics via Lipid Nanoparticles.

Oral administration of dosage forms is convenient and beneficial in several respects. Lipid nanoparticulate dosage forms have emerged as a useful carrier system in deploying low solubility drugs systemically, particularly class II, III, and IV drugs of the Biopharmaceutics Classification System. Like other nanoparticulate delivery systems, their low size-to-volume ratio facilitates uptake by phagocytosis. Lipid nanoparticles also provide scope for high drug loading and extended-release capability, ensuring diminished systemic side effects and improved pharmacokinetics. However, rapid gastrointestinal (GI) clearance of particulate delivery systems impedes efficient uptake across the mucosa. Mucoadhesion of dosage forms to the GI mucosa results in longer transit times due to interactions between the former and mucus. Delayed transit times facilitate transfer of the dosage form across the mucosa. In this regard, a balance between mucoadhesion and mucopenetration guarantees optimal systemic transfer. Furthermore, the interplay between GI anatomy and physiology is key to ensuring efficient systemic uptake. This review captures salient anatomical and physiological features of the GI tract and how these can be exploited for maximal systemic delivery of lipid nanoparticles. Materials used to impart mucoadhesion and examples of successful mucoadhesive lipid nanoformulations are highlighted in this review.

Comparisons of in Vitro Models to Evaluate the Membrane Permeability of Amorphous Drug Nanoparticles.

The spontaneous formation of amorphous drug nanoparticles following the release of a drug from a supersaturating formulation is gaining increasing attention due to their potential contribution to increased oral bioavailability. The formation of nanosized drug particles also has considerable implications for the interpretation of in vitro and in vivo data. However, the membrane transport properties of these drug particles remain less well understood. Herein, the membrane permeation of nanosized amorphous drug particles of a model drug atazanavir was evaluated using different artificial membrane-based, cell-based, and animal tissue-based models. Results showed that flux enhancement by particles was different for the various systems used. Generally, good agreement was obtained among experiments performed using the same apparatus with different model membranes, with the exception of the Madin-Darby canine kidney cell monolayer and the Long-Evans rat intestine tissue, which showed lower flux enhancements. Franz cell-based models showed slightly higher flux enhancements by particles compared to Transwell and intestinal tissue sac models. Mass transport analysis suggested that the extent of flux enhancement by particles is dependent on the geometry of the apparatus as well as the properties of the membrane and buffer used, whereas the flux plateau concentration is dependent on the unstirred water later (UWL) asymmetry. These results highlight the complexity in characterizing the permeability advantage of these nonmembrane permeable drug particles and suggest that caution should be used in selecting the appropriate in vitro model to evaluate the overall permeability of colloidal drug particles.

Mechanisms and Extent of Enhanced Passive Permeation by Colloidal Drug Particles.

Formulations containing nanosized drug particles such as nanocrystals and nanosized amorphous drug aggregates recently came into light as promising strategies to improve the bioavailability of poorly soluble drugs. However, the increased solubility due to the reduction in particle size cannot adequately explain the enhanced bioavailability. In this study, the mechanisms and extent of enhanced passive permeation by drug particles were investigated using atazanavir, lopinavir, and clotrimazole as model drugs. Franz diffusion cells with lipid-infused membranes were utilized to evaluate transmembrane flux. The impact of stirring rate, receiver buffer condition, and particle size was investigated, and mass transport analyses were conducted to calculate transmembrane flux. Flux enhancement by particles was found to be dependent on particle size as well as the partitioning behavior of the drug between the receiver solution and the membrane, which is determined by both the drug and buffer used. A flux plateau was observed at high particle concentrations above amorphous solubility, confirming that mass transfer of amorphous drug particles from the aqueous solution to the membrane occurs only through the molecularly dissolved drug. Mass transport models were used to calculate flux enhancement by particles for various drugs at different conditions. Good agreements were obtained between experimental and predicted values. These results should contribute to improved bioavailability prediction of nanosized drug particles and better design of formulations containing colloidal drug particles.

Prospects of Curcumin Nanoformulations in Cancer Management.

There is increasing interest in the use of natural compounds with beneficial pharmacological effects for managing diseases. Curcumin (CUR) is a phytochemical that is reportedly effective against some cancers through its ability to regulate signaling pathways and protein expression in cancer development and progression. Unfortunately, its use is limited due to its hydrophobicity, low bioavailability, chemical instability, photodegradation, and fast metabolism. Nanoparticles (NPs) are drug delivery systems that can increase the bioavailability of hydrophobic drugs and improve drug targeting to cancer cells via different mechanisms and formulation techniques. In this review, we have discussed various CUR-NPs that have been evaluated for their potential use in treating cancers. Formulations reviewed include lipid, gold, zinc oxide, magnetic, polymeric, and silica NPs, as well as micelles, dendrimers, nanogels, cyclodextrin complexes, and liposomes, with an emphasis on their formulation and characteristics. CUR incorporation into the NPs enhanced its pharmaceutical and therapeutic significance with respect to solubility, absorption, bioavailability, stability, plasma half-life, targeted delivery, and anticancer effect. Our review shows that several CUR-NPs have promising anticancer activity; however, clinical reports on them are limited. We believe that clinical trials must be conducted on CUR-NPs to ensure their effective translation into clinical applications.

Cetuximab-conjugated chitosan-pectinate (modified) composite nanoparticles for targeting colon cancer.

In the present study, we successfully developed a cetuximab-conjugated modified citrus pectin-chitosan nanoparticles for targeted delivery of curcumin (Cet-MCPCNPs) for the treatment of colorectal cancer. In vitro analyses revealed that nanoparticles were spherical with size of 249.33 ±â€¯5.15 nm, a decent encapsulation efficiency (68.43 ±â€¯2.4%) and a 'smart' drug release profile. 61.37 ±â€¯0.70% of cetuximab was adsorbed to the surface of the nanoparticles. Cellular uptake studies displayed enhanced internalization of Cet-MCPCNPs in Caco-2 (EGFR +ve) cells, which ultimately resulted in a significant reduction in cancer cell propagation. The cell cycle analysis indicated that Cet- MCPCNPs induced cell death in enhanced percentage of Caco-2 cells by undergoing cell cycle arrest in the G2/M phase. These data suggest that Cet-MCPCNPs represent a new and promising targeting approach for the treatment of colorectal cancer.

Assessment of toxic metals and phthalates in children's toys and clays.

Toxic metals and phthalates are introduced in the manufacturing of plastic toys and modeling clays. In Lebanon, inexpensive plastic toys and modeling clays (sold in dollar stores) are affordable and popular, and there is no legislation to monitor or regulate such toys. This study aimed to assess the quality of inexpensive plastic toys and modeling clays imported in Lebanon. Metal concentrations in toys, namely, zinc [not detectable (ND) to 3,708 µg/g], copper (ND to 140), chromium (ND to 75 µg/g), tin (ND to 39 µg/g), and cadmium (Cd) (ND to 20 µg/g), were lower than the European Union (EU) Directive limits, whereas lead (ND to 258 µg/g) in 10% of samples and antimony (Sb) (ND to 195 µg/g) in 5% of samples were greater than the EU limits. In modeling clays, most of the metals were lower than the EU Directive limits except for Cd and arsenic (As). Cd was detected in 83% of samples, with a mean level of 9.1 µg/g, which is far greater than the EU Directive limit (1.9 µg/g). The As mean level of 4.5 µg/g was greater than the EU limit (4.0 µg/g) and was detected in 9% of samples. Phthalic acid esters (PAEs) were found in 60% of children's toys and 77% of modeling clays. Phthalic acid butyl ester had the highest-level PAE encountered and was ≤59.1 % in one type of clay. However, among children's toys, di(4-octyl) ester terephthalic acid was the highest encountered phthalate at a concentration of 25.7%. The community survey indicated that 82% of households purchase their toys from inexpensive shops and that only 17% of parents were aware of the health hazard of such toys. Consequently, an intervention plan was proposed for the provision of safe toys to children.