F. Puisieux

Nanocapsule formation by interfacial polymer deposition following solvent displacement

Abstract Indomethacin-loaded nanocapsules were prepared by deposition of poly-( D,L -lactide) polymer at the o/w interface following acetone displacement from the oily nanodroplets. An attempt was made to elucidate the mechanisms of formation in terms of interfacial turbulence between two unequilibrated liquid phases involving flow, diffusion and surface tension decrease (Marangoni effect).

Release mechanisms in gelforming sustained release preparations

Abstract A system consisting of quinidine sulfate, excipient and gum (in various concentrations) was tested in tablet form. The insensitivity of this system to (a) the nature of the excipient and (b) the pH of the dissolution liquid is noted. The release mechanism is established as being limited by the rate of water penetration and back diffusion of the dissolved substance, whereas gelation rates and actual dissolution rate of the drug are not rate determining.

Development of a new process for the manufacture of polyisobutylcyanoacrylate nanocapsules

Abstract A new process for the manufacture of nanocapsules is described. The dispersion of an alcoholic solution of isobutylcyanoacrylate and oil in water, by interfacial polymerization, allows the formation of nanocapsules with an average diameter of about 200–300 nm. Physical and technical parameters are studied: temperature of preparation, pH of aqueous phase, concentration of surfactant and ethanol. Investigated with different active molecules and particularly with a radiological tracer, nanocapsule manufacture presents some advantages: (i) preparation is easily transposable to an industrial scale; and (ii) the method allows for a high level of entrapment for lipophilic substances.

Adsorption of Oligonucleotides onto Polyisohexylcyanoacrylate Nanoparticles Protects Them Against Nucleases and Increases Their Cellular Uptake

Oligonucleotides can be adsorbed on polyisohexylcyanoacrylate nanoparticles in the presence of hydrophobic quartenary ammonium salts. Oligonucleotides bound to nanoparticles are protected from nuclease attack both in buffer and in cell culture media. Cellular uptake of Oligonucleotides is increased when they are adsorbed onto nanoparticles as a result of the capture of nanoparticles by an endocytic/phagocytic pathway. Intracellular stability towards nucleolytic degradation is increased in the presence of nanoparticles. These results show that nanoparticles can be considered as convenient carriers for the protection and delivery of oligonucleotides to cells.

Alkylcyanoacrylate drug carriers: II. Cytotoxicity of cyanoacrylate nanoparticles with different alkyl chain length

Abstract The cytotoxicity of four types of alkylcyanoacrylate particles was evaluated in L929 fibroblast cell cultures. The results revealed the ethyl- and isobutyl-derivatives to be the most toxic, the methyl-derivative to be of intermediated toxicity and the isohexyl-cyanoacrylate particles to have the lowest toxicity. The toxic effect was found to be correlated with the velocity of polymer degradation and the rate of release of the degradation products. The mechanism proposed to account for the observed cytotoxicity consists of the degradation of particles in the culture medium and/or of particles adhering to or in close proximity with the cell membrane. A contribution due to the internalization of particles by cells appeared to be negligible, if any, in the cytotoxicity of nanoparticles. Acute toxicity can be avoided by employing low doses of particles consisting of a slowly degrading cyanoacrylate polymer. This aspect is of interest in the development of a colloidal carrier for the chronic delivery of drugs. The use of such systems does not involve problems as a result of long-term toxicity during chronic treatments and the burden placed upon the body by overloading with polymeric drug carriers that undergo degradation more slowly, such as poly(hydroxybutyric acid) and poly(lactic acid).

Surface activity and association of ABA polyoxyethylene—polyoxypropylene block copolymers in aqueous solution

Abstract The surface tension of aqueous solutions of a range of ABA polyoxyethylene-polyoxypropylene nonionic copolymers has been measured over a wide range of concentrations. The surface tension versus concentration plots show an inflection typical of that shown by conventional surfactants, but this occurs at very low concentrations (0.5–5 × 10 −6 M liter −1 ) and it is thought to be the result of monomolecular micelle formation. At higher concentrations (0.5 × 10 −4 to 1.5 × 10 −2 M liter −1 ) polymolecular aggregation probably takes place. The extent of uptake of benzopurpurine and iodine in aqueous solutions increases at high concentrations but the inflection points do not agree with any observable in the surface tension plots. Areas per molecule calculated using the simple form of the Gibbs equation indicate that there is considerable folding of the polymers at the air-water interface. For a given hydrophobic polyoxypropylene block, increasing the size of the hydrophilic polyoxyethylene chains causes an increase in interfacial molecular area. Increasing the length of the central hydrophobic moiety allows the molecule to fold more extensively and results in a decrease in the occupied area per molecule. Raising the temperature causes an increase in solution viscosity, especially near the lower consolute temperature (cloud point) of the system, a further indication of polymolecular association in these systems.

Preparation of pseudolatex by nanoprecipitation: Influence of the solvent nature on intrinsic viscosity and interaction constant

Abstract The importance of the nature of two solvents used in a patented method for obtaining aqueous dispersions of polymers is discussed. The principle of the method resides in the fact that a preformed polymer can precipitate as nanospheres when a solution in a water-miscible organic solvent (organic phase) is mixed with water containing surfactants (aqueous phase). To obtain HP55 (hydroxypropyl methyl cellulose phthalate) pseudolatex suitable for coating by this method, i.e. with a high polymer concentration, the amount of polymer in the organic phase was increased, but this caused considerable precipitation of the polymer in large aggregates when the two phases were mixed. Changing the nature of the organic solvent by replacing acetone with a mixture of acetone and water resulted in reducing aggregation. To explain this phenomenon, hypothesis based on viscosity parameters of dilute polymer solutions i.e. the intrinsic viscosity [r7], and the interaction constant k ′, were advanced. The influence of the dielectric constant (ϵ) of the final dispersant medium (a mixture of acetone and water after dispersion of organic phase with aqueous phase) is also discussed.

Poly(D,L‐Lactide) Nanocapsules Prepared by a Solvent Displacement Process: Influence of the Composition on Physicochemical and Structural Properties

Nanocapsules (NC) were prepared by interfacial deposition of preformed biodegradable polymer (PLA(50)) after a solvent displacement process. The influence of the composition used for the preparation of NC was evaluated in terms of particle size, polydispersity, zeta potential, homogeneity, and structural characteristics of the systems. The nature of the oil phase, polymer molecular weight, type and concentration of different surfactants were investigated to optimize the formulation to obtain NC suitable for intravenous administration. The influence of the physicochemical properties of the different oils used in NC preparation on the NC size was evaluated. The interfacial tension between the oil and water phases seems to have a greater effect on NC size than the oil viscosity. Miglyol 810 and ethyl oleate lead to the formation of smaller NC, probably because of the reduced interfacial tension. The polymer molecular weight plays only a small role in NC surface charge in the presence of lecithin, whereas NC surface charge, size, polydispersity, and short-term stability were highly influenced by lecithin purity. It appears that the absence of poloxamer 188 leads to smaller polydispersity, less contamination with nanospheres, and reduced formation of structures other than NC. Furthermore, electron microscopy and density gradient density techniques were used to examine the structure of the particles formed and their homogeneity. NC formation was evidenced by the bands with intermediate density between nanoemulsion and nanospheres; however, other bands of low intensity were observed. The presence of liposomes and multilayers in NC preparation was confirmed by electron microscopy. The percentage of carboxyfluorescein entrapped in different NC formulations allowed us to estimate the contamination by liposomes. It has been show that, under our experimental conditions, an excess of lecithin is an essential prerequisite for a stable preparation of PLA NC.

Uptake of doxorubicin from loaded nanoparticles in multidrug-resistant leukemic murine cells

Previous studies have clearly demonstrated that polyisobutylcyanoacrylate (PIBCA) doxorubicin-loaded nanoparticles (NS-Dox PIBCA) can overcome the resistance of P388/ADR cells. In the present paper, we found that overcoming multidrug resistance with the aid of doxorubicin (Dox) loaded onto these nanoparticles was associated with an increased intracellular drug content. Indeed, after a 6-h incubation period, the amount of cell-associated drug was 5 times higher when the cells were incubated with NS-Dox PIBCA as compared with free Dox. Further experiments, such as uptake studies in the presence of cytochalasin chalasin B or efflux studies, indicated a possible mechanism of nanoparticle/cell interaction. These results suggested that nanoparticles did not enter the cells by an endocytic process, in contrast to a previous hypothesis.

Poly (DL-lactide) nanocapsules containing diclofenac: I. Formulation and stability study

Abstract The aim of this work was to formulate nanocapsules prepared from poly(DL-lactide) containing a non-steroidal anti-infammatory drug, diclofenac, and to study their stability during storage at room temperature. The influence of some factors wich could affect stability, namely, the type of oily phase used or/and its concentration, the concentrations of drug and of surfactants, was investigated. The pH of the preparation, the particle size, the quantity of drug remaining (encapsulated and total) and polymer molecular weight were determined at intervals for up to 8 months after nanocapsule preparation. Although colloidal systems which were physically stable over this period could be obtained with either of the two oils tested, polymer degradation was more rapid in the presence of benzyl benzoate than with Miglyol 810®. The optimal concentration of the latter was found to be 3.33%. The highest loading of diclofenac consistent with a stable preparation was 1.00 mg/ml. Stable nanocapsules could be obtained with as little as 0.75% lipophilic surfactant together with a similar concentration of hydrophilic surfactant. These concentrations are considerably lower than those described in the literature for the formulation of this type of colloid.