Development of polymeric films embedded with liquid nanodomains.

Modified microemulsions (MEs), termed by us nanodomains (NDs), seem to be suitable vehicles for dermal drug delivery due to their high surface area and the interface enriched with membrane recognizing agents, penetration enhancers, and other components. However, liquid nanodomains do not provide a controlled release of the bioactive through the skin. Therefore, the main goal of our present study is to develop a film polymeric platform embedded with liquid nanovehicles for the controlled release of drugs. This study provides a fundamental understanding of the main challenges of the preparation of special films capable of embedding nanodomains without destroying them. We describe film formation from "nanodomains destructive polymers" causing coalescence of the nanodroplets followed by structural failure compared to the formation from "constructive polymer" leading to the homogeneous, transparent films with a high loading capacity of nanodomains (up to 90 wt%). Using various fundamental structural techniques, we found that the film-forming process and its redissolution suggest the reconstitution of nanodomains with original structure and similar droplet size diameter ca. 12 nm. Additionally, thermal behavior studies demonstrated that the film does not have "free" or "bulk" water compared to well-defined free water peaks in liquid nanodomains systems. The embedded film with drug-loaded nanodomains offers a significant advantage as a drug delivery platform for controlled release long-term therapy.

Incorporation of curcumin in liquid nanodomains embedded into polymeric films for dermal application.

Liquid nanovehicles are gaining interest in drug delivery because of the high solubilization capacity of bioactives at their interface and enhanced permeation of compounds across physiological membranes. However, the dermal application of liquid nanovehicles is still limited. The goal of this research is to develop a dermal delivery system based on embedding of liquid nanovehicles into polymeric films, which will allow controlled release of the nanodroplets with the solubilized drug. In this study, we describe the incorporation of empty and curcumin-loaded nanodomains into polymeric film. The novel technology results in formation of homogeneous, transparent and elastic films with high (up to 85 wt%) loading capacity of nanodomains. The fundamental structural characterizations show that nanodomain structures embedded in the dry film are spontaneously reformed during the dermal application with similar droplets size of 10 nm. Ex-vivo release studies were performed on Franz diffusion cells and demonstrated a significant permeation of curcumin through the pig skin. This novel film technology can serve as a "solid platform reservoir" for liquid nanovehicles which enables controlled release of nanodroplets with solubilized bioactive.

Structural Characterization of Reconstituted Bioactive-Loaded Nanodomains after Embedding in Films Using Electron Paramagnetic Resonance and Self-Diffusion Nuclear Magnetic Resonance Techniques.

Pharmaceutical applications of microemulsions (MEs) as drug delivery vehicles are recently gaining scientific and practical interests. Most MEs are able to solubilize bioactive molecules, but, at present, they cannot guarantee either controlled release of the drugs or significant advantage in the bioavailability of the bioactives. This study proposes to incorporate the modified ME structures, or nanodomains, into a natural polymeric film, to be used as a stable and capacious reservoir of drug-loaded nanodomains. These nanodomain-loaded films may release the nanodroplets along with the drug molecules in a slow and controlled way. Gellan gum, an anionic polysaccharide, was used in aqueous solution as the film former, and curcumin, hydrophobic polyphenol, served as the guest molecule in the loaded systems. Films were prepared by using empty and curcumin-loaded MEs. It is imperative to verify the persistence of the ME structure upon the dissolution of the film mimicking its behavior when in contact with a human physiological aqueous environment via reaching the cell membranes. For this purpose, the films were dissolved, and the reconstituted ME structure was compared with the ME structure before film formation. Characterization of these structures, before and after dissolution, was achieved using electron paramagnetic resonance (EPR) and self-diffusion nuclear magnetic resonance (SD-NMR) techniques. Specific spin probes were inserted in the system, and a computer-aided analysis of the EPR spectra was performed to provide information on nanodomain microstructure assemblies. In addition, the SD-NMR profile of each component was analyzed to extract information on the diffusivity of the ME components before film formation and after ME reconstitution. The EPR and SD-NMR results were in good agreement to each other. The most important finding was that, after film dissolution, the ME nanodomains were reversibly and spontaneously reformed. It was also found that the film did not perturb the ME-nanodomain structure embedded in it. The film remained transparent and the bioactive curcumin was easily solubilized into the ME-droplet/water interface even after film dissolution. The combined techniques confirmed that the film constituted by bioactive-loaded MEs can serve as novel drug delivery vehicles.

Cellular mechanism of oral absorption of solidified polymer micelles.

Oral delivery of poorly soluble and permeable drugs represents a significant challenge in drug development. The oral delivery of drugs remains to be the ultimate route of any drugs. However, in many cases, drugs are not absorbed well in the gastrointestinal tract, or they lose their activity. Polymer micelles were recognized as an effective carrier system for drug encapsulation, and are now studied as a vehicle for oral delivery of insoluble compounds. We characterized the properties of monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles, and visualized their internalization in mouse small intestine. Using Caco-2 cells as a cellular model, we studied the kinetics of particle uptake, their transport, and the molecular mechanism of their intestinal absorption. Moreover, by inhibiting specific endocytosis pathways, pharmacologically and genetically, we found that mPEG-PLA nanoparticle endocytosis is mediated by clathrin in an energy-dependent manner, and that the low-density lipoprotein receptor is involved. FROM THE CLINICAL EDITOR: Many current drugs used are non-water soluble and indeed, the ability to deliver these drugs via the gastrointestinal tract remains the holy grail for many researchers. The authors in this paper developed monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles as a drug nanocarrier, and studied the mechanism of uptake across intestinal cells. The findings should improve our current understanding and point to the development of more nanocarriers.