Sponge like microparticles for drug delivery and cosmeto-textile use: Formulation and human skin penetration.

This unique work is targeted to achieve three main goals: i) to enhance the aqueous solubility of three specifically selected hydrophobic active agents, ii) to prepare such polymeric biodegradable microparticles which can encapsulate actives-cyclodextrin complexes and iii) to functionalize a polyamide base textile with active loaded microparticles and active-cyclodextrin loaded microparticles. To achieve this objective, biodegradable cationic microparticles were prepared via double emulsion solvent evaporation process and were loaded with hydroxypropyl-beta-cyclodextrin based complexes of Indomethacin, α-tocopheroland Lauryl Isoquinolinium Bromide during the formulation process. Inclusion complex based particles were evaluated for their morphology, size distribution, zeta potential, skin penetration aptitude and adsorption onto a selected textile. It was observed that active-cyclodextrin complex encapsulation do not affect the morphology, size and zeta potential of the microparticles as well as adsorption of the microparticles onto textile remains unaltered. However such active-cyclodextrin complex encapsulated particles provided the enhancement in the aqueous solubility of hydrophobic agents and also provided prolonged release formulations.

Orodispersible films based on amorphous solid dispersions of tetrabenazine.

In this work, the formation and stability of amorphous solid dispersions (SDs) as orodispersible films (ODF) were investigated using tetrabenazine (TBZ) as a poorly water soluble drug. The influence of polymer nature and pH-modifier incorporation to form and maintain SDs was investigated. TBZ-loaded ODF were formulated using 4 different polymers (HPMC, PVP, Pullulan, and HEC). Binary systems (BS) were obtained mixing the drug with different polymers, while ternary (TS) systems were also obtained by adding citric acid to solubilize TBZ in the mixture. Drug dissolution studies, thermal analysis and X-ray diffraction were carried out to characterize the physical state of API in ODF. ODF made of TS allowed a major improvement of TBZ dissolution profile in buccal conditions compared to a pure drug or BS. DSC and X-ray diffraction revealed that API was in amorphous state in TS while remained crystalline in BS. Following 6 months of storage, TBZ recrystallization occurred for PVP-TS and HEC-TS which induced a decrease of drug release in saliva conditions. HPMC and PUL-TS maintained API in amorphous state during 6 months. Briefly, amorphous SDs were obtained by the pre-dissolution of the drug in acidified water and incorporation in polymeric films. The miscibility and potential interaction between TBZ and polymers have been identified as important factor to explain stability differences.

Elaboration of ammonio methacrylate copolymer based spongy cationic particles via double emulsion solvent evaporation process.

The aim of present work is to investigate systematic study of the preparation of biodegradable particles via double emulsion solvent evaporation technique. The used formation is based on cationic ammonium methacrylate copolymer Eudragit® RS 100, without the use of any stabilizer. The effect of process parameters like ultra turrax® stirring speed and stirring time, ultrasonication time, polymer amount, and volume of outer aqueous phases on the colloidal properties of particles was investigated. All prepared dispersions were characterized in terms of size, size distribution, and electrokinetic properties, and surface morphology was investigated.

Antimicrobial films containing microparticles for the enhancement of long-term sustained release.

Coated packagings with thin films containing antimicrobial agents are an alternative technology to ensure the protection of products against microbial contaminations. Indeed, they allow lowering the antimicrobial concentration in the bulk of the product while meeting the safety requirements and the growing consumer demand for low preservative concentrations. Microencapsulation is a suitable way for controlling active agent release and providing a long-term activity. This work aims at combining both technical solutions with coatings containing antimicrobial microparticles for the achievement of long-term sustained release. Polyethylene surfaces were functionalized with microparticles of poly(methyl methacrylate) (PMMA) loaded with phenylethyl alcohol (PEA) as antimicrobial agent by the dip coating process using a polyurethane binder. The release of PEA into water from coated polyethylene surfaces and from PMMA microparticles was investigated to assess the sustained release and its mechanisms. Films with various thicknesses of 400-1000 µm containing antimicrobial microparticles demonstrated unusual long-term release longer than 3 months. The diffusion of the antimicrobial agent through PMMA was the rate limiting step of the sustained release. PEA release increased as the contact area of the protruding microparticles with the external medium increased and the thickness of the film decreased. Such antimicrobial agents encapsulated inside thin coatings are promising with regards to antimicrobial preservation of products along their full shelf-life.

Skin delivery by block copolymer nanoparticles (block copolymer micelles).

Block copolymer nanoparticles often referred to as "block copolymer micelles" have been assessed as carriers for skin delivery of hydrophobic drugs. Such carriers are based on organic biocompatible and biodegradable materials loaded with hydrophobic drugs: poly(lactide)-block-poly(ethylene glycol) copolymer (PLA-b-PEG) nanoparticles that have a solid hydrophobic core made of glassy poly(d,l-lactide), and poly(caprolactone)-block-poly(ethylene glycol) copolymer (PCL-b-PEG) nanoparticles having a liquid core of polycaprolactone. In vitro skin absorption of all-trans retinol showed a large accumulation of retinol in stratum corneum from both block copolymer nanoparticles, higher by a factor 20 than Polysorbate 80 surfactant micelles and by a factor 80 than oil solution. Additionally, skin absorption from PLA-b-PEG nanoparticles was higher by one order of magnitude than PCL-b-PEG, although their sizes (65nm) and external surface (water-swollen PEG layer) were identical as revealed by detailed structural characterizations. Fluorescence microscopy of histological skin sections provided a non-destructive picture of the storage of Nile Red inside stratum corneum, epidermis and dermis. Though particle cores had a different physical states (solid or liquid as measured by (1)H NMR), the ability of nanoparticles for solubilization of the drug assessed from their Hildebrand solubility parameters appeared the parameter of best relevance regarding skin absorption.

The parameters influencing the morphology of poly(ɛ-caprolactone) microspheres and the resulting release of encapsulated drugs.

Polymer microparticles used for drug encapsulation and delivery have various surface morphologies depending on the type of formulation ingredients and parameters of the manufacture process. This works aims at investigating the critical parameters governing the morphology of microparticles and to underline the influence of their surface state on the drug release. The classical fabrication process by the "emulsion-solvent evaporation" is addressed using poly(ɛ-caprolactone) as the polymer and methylene chloride as the volatile organic solvent. The typical surfactants poly(vinyl alcohol) and polysorbate 80 have been considered. Scanning electron microscopy observations showed the various surface morphologies mainly depending on the stirring rate, the viscosity of the oil phase and by the presence of inappropriate surfactants. Because of arrested coalescence during solvent evaporation, the evaporation of the organic solvent causing particles hardening is the most important parameter that controls the morphology. Indeed, slow evaporation allows partial coalescence of the soft particles swollen by the organic solvent, whereas the particles morphology is frozen rapidly upon fast evaporation, thus preventing damaged surface states. Moreover, an effective stabilizing system for the primary emulsion is also a determining factor to control the final morphology. The morphology of the particles has a definite influence on the drug delivery of cholecalciferol. The surface morphology should be taken into consideration in the design of polymer microparticles because it allows a control over the drug release kinetics.

Encapsulation of a pressure-sensitive adhesive by spray-drying: microparticles preparation and evaluation of their crushing strength.

An industrial pressure-sensitive adhesive was microencapsulated by spray-drying using an aqueous colloidal ethylcellulose dispersion (Aquacoat® ECD) plasticised by triacetin to form the wall material. Unloaded (0:100) and adhesive-loaded (25:75) particles were produced in a Büchi B-191 mini spray-dryer with product yields of 62% and 57%, respectively. Microparticles were spherical and narrow sized with mean D3,2 diameters of 3.165 ± 0.001 and 5.544 ± 0.105 µm, respectively. The microparticles were found to redisperse well in water and exhibit enough stability in neutral and alkaline aqueous media to be further used in a coating slip. Crush tests on single microparticles with diameters ranging from 2 to 12 µm were performed using a nanoindenter. They revealed that the crushing force of both kinds of microparticles increased linearly with their diameter and that the adhesive loading reduced the mechanical strength of the prepared microparticles.

Microemulsion microstructure influences the skin delivery of an hydrophilic drug.

PURPOSE: We aimed to investigate the influence of microemulsion nanoscale organization as either oil-in-water droplets, water-in-oil droplets, or bicontinuous structures on skin delivery of drugs assisted by microemulsions. METHODS: Three microemulsions of different microstructure, o/w, w/o, and bicontinuous at the skin temperature (32°C), having the same oil and water contents and containing the same ingredients were selected using the Kahlweit fish phase diagrams method. The microemulsions are quaternary mixtures of the Polysorbate 21 (Tween®21) and Sorbitan monolaurate (Span®20) surfactants, isononyl isononanoate oil and water. The microemulsion nanostructure was characterized by electrical conductivity, Pulsed Field Gradient Spin-Echo NMR and Small-Angle Neutron Scattering measurements. The Franz cell method was used to monitor skin absorption of caffeine loaded in microemulsions over 24 h exposure to excised pig skin. RESULTS: Three microemulsions with the three structures were selected, keeping the same composition but the Tween®21/Span®20 ratio. The transdermal flux of caffeine was in the order aqueous solution ≈ w/o < bicontinuous < o/w microemulsion. The o/w microemulsion allows the permeation of 50% of the applied dose within 24 h. CONCLUSIONS: The structure of microemulsions is of relevance for skin absorption. The water-continuous structures allow faster transport of hydrophilic drugs.

Topical delivery of lipophilic drugs from o/w Pickering emulsions.

Surfactant-free emulsions stabilized by solid particles (Pickering emulsions) have been evaluated in the terms of skin absorption of lipophilic drugs. The behavior of three formulations: a surfactant-based emulsion, a Pickering emulsion stabilized by silica particles and a solution in triglyceride oil, were compared in order to assess the effect of the surface coating of Pickering emulsions as new dosage forms for topical application. Such comparative investigation was performed in vitro on excised pig skin in Franz diffusion cells with all-trans retinol as model lipophilic drug. Surfactant-based (classical, CE) and Pickering (PE) oil-in-water emulsions containing retinol were prepared with the same chemical composition (except the stabilizing agent: surfactant or silica particles), the same droplet size and the same viscosity. No permeation through the skin sample was observed after 24h exposure because of the high lipophilic character of retinol. Penetration of retinol was 5-fold larger for both CE and PE than for the solution in triglyceride. The distribution of retinol inside the skin layers depended significantly on the emulsions type: the classical emulsion allowed easy diffusion through the stratum corneum, so that large amounts reached the viable epidermis and dermis. Conversely, high storage of retinol inside the stratum corneum was favored by the Pickering emulsion. The retinol content in stratum corneum evaluated by skin stripping, demonstrated the increased retinol accumulation from PE. Therefore Pickering emulsions are new drug penetration vehicles with specific behavior; they are well-suited either for targeting the stratum corneum or aimed at slow release of drug from stratum corneum used as a reservoir to the deeper layers of skin.

Pickering w/o emulsions: drug release and topical delivery.

The skin absorption from Pickering emulsions as a new dosage form was investigated for the first time. Pickering emulsions are stabilized by adsorbed solid particles instead of emulsifier molecules. They are promising dosage forms that significantly differ from classical emulsions within several features. The skin permeation of a hydrophilic model penetrant (caffeine) was investigated from a w/o Pickering emulsion and compared to a w/o classical emulsion stabilized with an emulsifier. Both emulsions had the same composition and physicochemical properties in order to focus on the effect of the interfacial layer on the drug release and skin absorption processes. The highest permeation rates were obtained from the Pickering emulsion with a pseudo-steady state flux of 25 microg cm(-2)h(-1), threefold higher than from a classical emulsion (9.7 microg cm(-2)h(-1)). After 24h exposure, caffeine was mostly in the receptor fluid and in the dermis; cumulated amounts of caffeine were higher for the Pickering emulsion. Several physicochemical phenomena were investigated for clearing up the mechanisms of enhanced permeation from the Pickering emulsion. Among them, higher adhesion of Pickering emulsion droplets to skin surface was disclosed. The transport of caffeine adsorbed on silica particles was also considered relevant since skin stripping showed that aggregates of silica particles entered deeply the stratum corneum.