Poly(ethylene carbonate) microspheres: manufacturing process and internal structure characterization.

The granulocyte-macrophage colony stimulating factor (GM-CSF), a water-soluble cytokine, was encapsulated in poly(ethylene carbonate) microspheres (MS) by a double emulsion w(1)/o/w(2) solvent evaporation method. Poly(ethylene carbonate) is a new polymer of high molecular weight (MW) and forms polymer matrices that are exclusively surface bioerodible. In the frame of this study, the influence of the polymer molecular weight and the polymer concentration in the organic phase on the physico-chemical characteristics of the microspheres were investigated. Ninety percent of the microspheres had a diameter ranging between 4 and 136 microm, with a mean value of 30 microm. The encapsulation ratios ranged from 2.22 to 2.51% (w/w) depending on the molecular weight of the polymer corresponding to an encapsulation efficiency of 70 to 100%, respectively. Independent of the polymer molecular weight used, the in vitro drug release was very low, ranging from 5.61 to less than 1% of the total encapsulated GM-CSF amount. Scanning electron microscopy (SEM) analysis showed microparticles with spherical shapes and smooth surfaces containing a few small globules. The inner structure of the microspheres appeared to consist of a polymeric matrix surrounding numerous globules. These globules have different sizes, shape and distribution in the polymeric matrix, depending on the concentration of the polymer solution and on the polymer molecular weight. In addition, it was demonstrated that the GM-CSF lowered the interfacial tension between the GM-CSF aqueous solution and the methylene chloride organic phase. The active critical concentration was as low as 0.008 mg/ml. It was therefore suggested that this particular behavior contributed to the stabilization of the primary emulsion during the formation of the microspheres, leading to rather high encapsulation efficiency.

Comparison of the biodistribution in mice of 111indium oxine encapsulated into poly(lactic-co-glycolic)-D,L-85/15 and poly(epsilon caprolactone) nanocapsules.

Poly(lactic-co-glycolic)-D,L-85/15 (PLAGA) nanocapsules and poly(epsilon caprolactone) (PCL) nanocapsules were labeled with a relatively long half-life compound that is usually used in humans; that is, 111In-labelled oxine (111In oxine). This labeling technique led to a high 111In oxine entrapment efficiency and good stability during dialysis against phosphate buffer and phosphate buffered albumin solution. Because of these characteristics, the nanocapsules biodistribution was followed up after intravenous administration for up to 96 h by determining the gamma activity in the tissues after sampling. The administration of the PCL-encapsulated 111In oxine led to a decrease in the blood radioactivity and an increase in the liver radioactivity compared with the solution. This effect was even more pronounced with the PLAGA nanocapsules. Finally, the activity level in other tissues, such as the kidneys, the lungs, and the spleen, appeared to be rather low and only slightly affected by the encapsulation into one or the other polymer.

[Nanocapsules of beta-blocking agents: a new drug carrier in ophthalmology. Application to medical treatment of glaucoma in rabbits]. / Nanocapsules de beta-bloquants: un nouveau vecteur de médicaments en ophtalmologie. Application au traitement médical du glaucome chez le lapin.

In order to reduce the lacrimal elimination and to increase the intraocular penetration of betaxolol after ocular administration, we prepared a new drug carrier, polycaprolactone nanocapsules, containing betaxolol in the base form. The instillation of nanocapsules containing only 0.1% of betaxolol into glaucomatous rabbit eyes induced a greater decrease of IOP in intensity, time and stability compared to the reduction of IOP induced after instillation of the commercial eye drops (Betoptic) containing 5 times more betaxolol (0.56%). This new pharmaceutical dosage form produces very interesting therapeutic effects with much lower drug concentrations than that commonly used in aqueous commercial eye drops; thus, systemic and local side effects could be minimized. All drugs used in medical treatments of eye diseases should be able to be included in this carrier. In addition, effective drugs not used because of their toxicity will become suitable for use at lower and safer doses.

[Ways to improve ocular bioavailability for topical applications]. / Moyens d'amélioration de la biodisponibilité pour la voie topique.

The anatomical, physiological and pharmacological properties of the eye explain the short pre-corneal residence time and the poor bioavailability of most eye-drop solutions. Many approaches have been proposed to increase ocular bioavailability of drugs. Most eye-drops include a viscosity agent in their formulation to significantly prolong residence time although the increased viscosity is limited due to patient discomfort. More recent developments include biodegradable inserts, eye-drop based on cyclodextrins, liposomes or nanoparticles.

Poly(epsilon-caprolactone) nanocapsules in carteolol ophthalmic delivery.

In order to increase the ocular absorption of carteolol, this antiglaucomatous drug was incorporated into either nanoparticles (NP) or nanocapsules (NC). The polymer used was poly(epsilon-caprolactone) (PCL). The dosage forms were tested on intraocular hypertensive-induced rabbits. Results are presented as the chronological variations of the intraocular pressure (IOP) in comparison with the commercial aqueous solution (Carteol eye drops). The therapeutic results (decrease in IOP) were much more pronounced with carteolol incorporated into the colloidal carriers than with the commercial eye drops. Further, NC displayed a better effect than NP because the drug was entrapped in the oily core of the carrier, thus more readily available to the eye. The incorporation of the drug into nanocapsules produced a decline in the cardiovascular side effects in comparison with aqueous eye drops, thus showing that the undesired noncorneal absorption was reduced. In conclusion, colloidal suspension made of poly(epsilon-caprolactone) could offer a good opportunity for ophthalmic delivery of drugs.

Design of new formulations for topical ocular administration: polymeric nanocapsules containing metipranolol.

To investigate the potential of polymeric nanocapsules for ocular delivery of beta-blockers, several formulations of polyisobutylcyanoacrylate and polyepsiloncaprolactone nanocapsules containing metipranolol base were developed. These formulations differed in the polymer forming the coating and in the type and volume of the oil encapsulated. Analysis of particle-size distribution, electrophoretic mobility, and loading efficiency of the nanocapsules revealed that the type of oil is the most important factor influencing these properties. From the in vitro release studies, we concluded that drug diffusion through a dialysis membrane is delayed as a consequence of the encapsulation process. However, the release profiles were not influenced by the polymeric coating, suggesting that drug release from these systems is governed mainly by the partition of the drug between the oily core and the aqueous release medium. Nevertheless, despite the inability of the polymer coat to control the release of the drug, its contribution to the stabilization of the emulsion was noted. Finally, the suitability of these formulations for ophthalmic administration was investigated. Although the pharmacologic response was not affected by the encapsulated metipranolol compared with the commercial eye drops, a drastic reduction of the drug's systemic side effects was observed.