Stéphanie Briançon

Determination of poly(ɛ-caprolactone) solubility parameters: Application to solvent substitution in a microencapsulation process

The evolution of regulation on chemical substances (i.e. REACH regulation) calls for the progressive substitution of toxic chemicals in formulations when suitable alternatives have been identified. In this context, the method of Hansen solubility parameters was applied to identify an alternative solvent less toxic than methylene chloride used in a microencapsulation process. During the process based on a multiple emulsion (W/O/W) with solvent evaporation/extraction method, the solvent has to dissolve a polymer, poly(epsilon-caprolactone) (PCL), which forms a polymeric matrix encapsulating or entrapping a therapeutic protein as the solvent is extracted. Therefore the three partial solubility parameters of PCL have been determined by a group contribution method, swelling experiments and turbidimetric titration. The results obtained allowed us to find a solvent, anisole, able to solubilize PCL and to form a multiple emulsion with aqueous solutions. A feasibility test was conducted under standard operating conditions and allowed the production of PCL microspheres.

Nanocapsules of biodegradable polymers: preparation and characterization by direct high resolution electron microscopy

Abstract In the field of pharmaceutical applications relying on encapsulation of drug by polymer coating, capsules based on biodegradable polymers with mean size of about 500 nm have been obtained by a patented emulsion–diffusion method. The morphology, size and structure of the nanocapsules (NC) control their pharmaceutical properties, especially release of the drug. Here is reported a decisive contribution of transmission electron microscopy (TEM) in revealing the controlled form and size of the NC: mean size values measured by TEM do agree with data obtained by laser granulometry. Moreover, the TEM magnification allows an estimation of the membrane thickness.

Effect of Freeze-Drying Process Conditions on the Stability of Nanoparticles

Abstract The purpose of this study was to optimize the freeze-drying processes of nanoparticles in order to improve their end-used properties and their stability. Polycaprolactone (PCL) nanoparticles were prepared by the emulsification-diffusion method and then were frozen at different freezing rates. Finally, the nanoparticles were freeze-dried under different operating conditions by using a laboratory-made freeze-dryer. Then, the average particle size was analyzed by using a Coulter® LS 230 apparatus firstly after the freezing step and finally after the sublimation step. The surface morphology and the thermophysical characteristics of the nanoparticles were determined by SEM and by DSC, respectively. It was observed that, the freezing process can break the nanoparticles and cause the leakage of their contents during the freeze-drying step. The higher the freezing rate, the larger the size of nanoparticles during the freezing process. From the results DSC data, it could be assumed that the nanoparticles in the nanosuspensions may have been broken not by water crystallization in the external phase, but by the solidification of the oil (miglyol) in the internal phase.

Percutaneous release of caffeine from microemulsion, emulsion and gel dosage forms

The transport of caffeine to the hypodermis by an alcohol-free o/w microemulsion was investigated and compared with an aqueous gel and an o/w emulsion. The microemulsion was well characterized and in vitro diffusion measurements through pig skin having the hypodermis either kept or removed were performed in static Franz cells. The microemulsion allowed delivery of a large fraction of the caffeine in the hypodermis: 23% of caffeine reached the hypodermis after 24h diffusion, 1.3-fold larger than from the emulsion and gel dosage forms. Half this amount was stored in the hypodermis, the other half continuing its diffusion to the receptor compartment of the Franz cell.

Topical delivery of cosmetics and drugs. Molecular aspects of percutaneous absorption and delivery

Percutaneous penetration/permeation is a useful tool for obtaining qualitative and/or quantitative information on the amount of a drug, a cosmetic substance, or any chemical that may enter a skin compartment or the systemic circulation of the human body for pharmaceutical or cosmetic purposes, or for toxicological studies. In the latter case, the extent entering can then be taken into consideration in order to calculate the margin of safety using the NOAEL (No Observed Adverse Effect Level) of an appropriate repeated dose toxicity study with the respective substance. This paper is a short overview of various aspects of skin penetration/permeation of drugs or cosmetic agents. The literature reports numerous studies on skin structure and skin properties influencing drug/cosmetic agent permeation profiles and kinetic parameters. The extensive research concerning the skin structure for determining the key parameters of the penetration/permeation process is therefore described first. Mathematical models of the skin absorption process for a drug are then discussed. Finally new developments in pharmaceutical and cosmetic fields to enhance drug permeation or to modify the stratum corneum structure are considered.

Nanoparticles through the skin: managing conflicting results of inorganic and organic particles in cosmetics and pharmaceutics.

Toxicity of nanoparticles is a current scientific issue because of the enhanced reactivity of nanomaterials and their possible easy penetration into the body arising from their small size. Because inorganic particles are present in sunscreen cosmetic products, attention has been focused on cutaneous penetration. But organic particles of various sizes are also used in pharmaceutical applications such as skin care and transdermal drug delivery. It appears that organic and inorganic particles penetrate the skin quite differently. The apparent discrepancy is addressed in this review focusing on skin penetration of inorganic sunscreen particles and organic particles for drug delivery. After a short description of the physicochemical properties of these particles, the skin penetration of both types is reviewed with emphasis on the mechanistic issues and the differences that could account for such conflicting results. It appears that investigations by cosmetic and pharmaceutical communities focused on the main issue, i.e., no toxicity in cosmetics and maximum activity of the drug in pharmaceutics. This leaves several fundamental issues as open questions and this does not allow a rigorous comparison between both types of material. While it is claimed that inorganic nanoparticles can only penetrate the outer layer of the skin, it appears that organic submicron particles and even microparticles reach the dermis in an in vitro cell. Besides particle size, the surface chemistry of the particles and the presence of other excipients in the formulations contribute to skin absorption.

Process induced transformations during tablet manufacturing: Phase transition analysis of caffeine using DSC and low frequency micro-Raman spectroscopy

The phase transition of a model API, caffeine Form I, was studied during tableting process monitored with an instrumented press. The formulation used had a plastic flow behavior according to the Heckel model in the compression pressure range of 70-170 MPa. The quantitative methods of analysis used were Differential Scanning Calorimetry (DSC) and low frequency Micro Raman Spectroscopy (MRS) which was used for the first time for the mapping of polymorphs in tablets. They brought complementary contributions since MRS is a microscopic spectral analysis with a spatial resolution of 5 μm(3) and DSC takes into account a macroscopic fraction (10mg) of the tablet. Phase transitions were present at the surfaces, borders and center of the tablets. Whatever the pressure applied during the compression process, the transition degree of caffeine Form I toward Form II was almost constant. MRS provided higher transition degrees (50-60%) than DSC (20-35%). MRS revealed that caffeine Form I particles were partially transformed in all parts of the tablets at a microscopic scale. Moreover, tablet surfaces showed local higher transition degree compared to the other parts.

Spray-drying Nanocapsules in Presence of Colloidal Silica as Drying Auxiliary Agent: Formulation and Process Variables Optimization Using Experimental Designs

PurposeSpray-drying process was used for the development of dried polymeric nanocapsules. The purpose of this research was to investigate the effects of formulation and process variables on the resulting powder characteristics in order to optimize them.Materials and MethodsExperimental designs were used in order to estimate the influence of formulation parameters (nanocapsules and silica concentrations) and process variables (inlet temperature, spray-flow air, feed flow rate and drying air flow rate) on spray-dried nanocapsules when using silica as drying auxiliary agent. The interactions among the formulation parameters and process variables were also studied. Responses analyzed for computing these effects and interactions were outlet temperature, moisture content, operation yield, particles size, and particulate density. Additional qualitative responses (particles morphology, powder behavior) were also considered.ResultsNanocapsules and silica concentrations were the main factors influencing the yield, particulate density and particle size. In addition, they were concerned for the only significant interactions occurring among two different variables. None of the studied variables had major effect on the moisture content while the interaction between nanocapsules and silica in the feed was of first interest and determinant for both the qualitative and quantitative responses. The particles morphology depended on the feed formulation but was unaffected by the process conditions.ConclusionThis study demonstrated that drying nanocapsules using silica as auxiliary agent by spray drying process enables the obtaining of dried micronic particle size. The optimization of the process and the formulation variables resulted in a considerable improvement of product yield while minimizing the moisture content.

The effect of monomers on the formulation of polymeric nanocapsules based on polyureas and polyamides

Formulation of nanocapsules based on polyureas and polyamides have been tested using a patented process. This method based on polycondensation reaction of two complementary monomers and spontaneous formation of oil in water emulsion, is an alternative concept to the known technique based on the same type of reaction used for the formulation of microcapsules, and in which the lipophilic monomer was emulsified in the organic phase before the formation of the polymeric membrane. Nanocapsules can be prepared from different monomers. Wall based on cross-linked polymer contributes to the stability of nanocapsules during and after formulation. The permeability of the polymeric wall is related to its crystallinity and contributes to the growth of nanocapsule membrane by the diffusion of the hydrophilic monomers to get stable colloidal suspensions.

Iodinated nano-emulsions as contrast agents for preclinical X-ray imaging: Impact of the free surfactants on the pharmacokinetics.

This study presents new important aspects in the design of contrast agents for X-ray preclinical imaging. The first one is a new simple formulation of long circulating contrast agents, formulated from a commercial iodinated oil, and resulting in CT contrast agents containing more than twice the iodine concentration commercial contrast agents. The second point is a methodological aspect, utilizing tangential filtration for reducing the residual surfactants in the bulk phase and serving as well for concentrating droplets (and iodine) in the suspension. The last point is a more general aspect regarding the influence of the free surfactant on the pharmacokinetics and biodistribution of the nano-emulsion droplets on mice. We showed that cross-flow filtration is efficient for concentrating the droplets and reducing the concentration of free surfactant from 10wt.% to 1wt.%, without any changes in the nano-emulsion droplet morphologies or surface properties. We also showed that the presence of free surfactant has a significant impact on the elimination way of the nano-emulsion droplets, shared between liver and kidneys. The purified nano-emulsions are preferentially eliminated by the kidneys in contrast to raw nano-emulsions, predominantly eliminated by the liver. In practice, for two similar suspensions, half-life decreases from 4.1±1.10h to 2.5±0.77h before and after purification. Since the design and development of long circulating systems are critical in numerous domains, and not for preclinical CT imaging, this study presents important results in that field, taken under a formulation and technical point of view.