J.P. Devissaguet

Nanocapsules as carriers for oral peptide delivery

Abstract Nanocapsules composed of biodegradable spherical polymeric vesicles, less than 300 nm in diameter, were applied for the oral administration of peptides, especially insulin. Nanocapsules were formed by interfacial polymerisation of isobutyl 2-cyanoacrylate around a lipidic phase, the peptide being added to this latter. When administered intragastrically in diabetic rats, insulinloaded nanocapsules reduced markedly glycemia measured after an overnight fast. This effect occurred from the second day up to 20 days depending on the dose of insulin administered. In normal rats or dogs, insulin-loaded nanocapsules reduced the glucose-induced peak of hyperglycemia. Thus, nanocapsules are able to preserve the biological effect of insulin after oral administration. They protect insulin against degradation by proteolytic enzymes; they transport insulin rapidly through the intestinal epithelium; and they change the tissular distribution of iodine-125 after oral administration of labeled insulin-loaded nanocapsules.

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 (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.

A novel approach to the preparation of injectable emulsions by a spontaneous emulsification process

Abstract Submicronic emulsions of muramyltripeptide-cholesterol (MTP-Chol), diazepam and amphotericin B were prepared using an original and simple method. This procedure is based on a spontaneous emulsification process, comprising the following steps: (1) dissolving the oil phase containing phospholipid in the alcoholic solution: (2) optionally dissolving the drug into the oily alcoholic phase and (3) mixing the product of step (2) with an aqueous preparation of surfactant, forming an oil-in-water emulsion, and finally, (4) removing at least most of any co-solvent which is present. The emulsions exhibited a mean droplet size in the range 200–300 nm. The results indicated that emulsions prepared by this method are very stable. They can also be sterilized by heat sterilisation or by filtration. In the case of MTP-Chol, the emulsion retained biological activity. Taken together, these results suggest that an emulsion obtained by spontaneous emulsification process would be very suitable for use as a drug carrier.

Influence of sterilization processes on poly(ε-caprolactone) nanospheres

Polymeric vectors and especially poly(epsilon-caprolactone) nanoparticles have already shown promising results in the optimization of the ophthalmic bioavailability of drugs. Any formulation instilled in the eye must be sterile, and preferentially isotonic. Poly(epsilon-caprolactone) nanospheres were thus formulated with Synperonic PE/F68, Synperonic PE/F127, or Cremophor RH40. A tonicity agent, a preservative and, in some cases, a viscosifiant were then added. The pH was finally adjusted to pH 4 or buffered to pH 7. Different sterilization processes were studied to investigate their influence on the physicochemical characteristics of vectors. Autoclaving did not induce any modification on polymer molecular weight or Synperonic nanospheres diameter, but catalysed some reactions with surfactants and tonicity agents. This method could thus be used if the nanosphere excipients are chosen with care. gamma radiation induced preservative degradation and viscosifiant depolymerization. A cross-linking of poly(epsilon-caprolactone) chains was observed, as reflected by a sharp increase of its molecular weight. However, no variation of the mean particle size was detected. Finally, sterile filtration was the only process which ensured the conservation of physicochemical integrity of nanospheres. This process was successfully applied on non-viscosified vectors with a sufficiently small diameter.

Polyalkylcyanoacrylate nanocapsules increase the intestinal absorption of a lipophilic drug

Abstract The advantage of a polymeric drug carrier, poly-isobutylcyanoacrylate nanocapsules, in the intestinal absorption of a lipophilic drug (Lipiodol) has been investigated in the dog. Lipiodol, an iodized oil, was characterized by X-ray emission of iodine in a scanning electron microscope fitted with an X-ray microprobe analyser. Nanocapsules, administered in the jejunal lumen, increased the absorption of Lipiodol: the plasma level of iodine was maximal 45 min after the administration of Lipiodol emulsion (3 times basal value) and nanocapsules (3.5 times). Then iodemia decreased again but remained 2.5-fold higher than control values 105 min after the administration of nanocapsules. At the cellular level, nanocapsules accelerate, intensify and prolong the passage of iodine through the intestinal mucosa. These results could be explained by a direct transport of the drug by nanocapsules through the mucosa, or by increasing the intraluminal concentration of the drug close to absorptive cells.

Indomethacin-loaded poly (D,L-lactide) nanocapsules: protection from gastrointestinal ulcerations and anti-inflammatory activity evaluation in rats

Abstract Indomethacin-loaded nanocapsules were prepared by deposition of poly ( d,l -lactide) polymer (PLA) at the oil/water interface following acetone displacement from the oily nanodroplets. Rapid in-vitro release profiles of indomethacin from PLA nanocapsules were observed at pH above 7·0 Nanoencapsulation of indomethacin induced a marked protective effect on the gastro-intestinal tissues as compared to the ulcerative effect observed with the aqueous solution of the drug following three consecutive oral daily doses of 10 mg/kg. It was shown that the induced protective effect displayed by the PLA nanocapsules was rather associated with low tissue concentration than with high plasma concentration. The incorporation of indomethacin in the PLA nanocapsules did not alter the pharmacological activity of the drug, since similar edema inhibition profiles were observed for the aqueous solution and for the PLA nanocapsules using the carrageenininduced edema test in the hind paw of rats. Furthermore, the anti-inflammatory activity of indomethacin was enhanced following incorporation in the PLA nanocapsules. Two possible explanations were proposed for the overall result interpretations.

Evaluation of indomethacin nanocapsules for their physical stability and inhibitory activity on inflammation and platelet aggregation

Indomethacin nanocapsules were investigated for their physical stability and anti-inflammatory activity in the carrageenan paw oedema tests in rats and also for their inhibitory activity on platelet aggregation induced by ADP. From the physical stability view point, there was a marked difference for the extent of drug loss between the indomethacin nanocapsules which were stored for 12 months at ambient temperature when freeze-dried and in the form of suspension. The indomethacin content of the freeze-dried nanocapsules and in the suspension from decreased by 52.8% and by 17.5% respectively. Compared to free indomethacin the anti-inflammatory activity of indomethacin increased 10 times when it was prepared as nanocapsules and the inhibition of platelet aggregation also increased with nanocapsulated indomethacin. But empty nanocapsules also showed an inhibition in the platelet aggregation because of their isobutylcyanoacrylate content.

A morphological study of an amphotericin B emulsion-based delivery system

Abstract The structure of an amphotericin B emulsion-based delivery system (AmB-E) was investigated using spectroscopic methods (electronic absorption and circular dichroism (CD)), photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM) at various amphotericin B (AmB) concentrations, in comparison with AmB-deoxycholate micelles, Fungizone® (Fungi-SS) and free AmB suspension (AmB-SS). Our results show that AmB-E absorption and CD spectra, mean particle size determination by PCS and morphological examination are only weakly concentration-dependent, between 5.10 −5 and 5.10 −7 M, as compared with Fungizone® and free AmB suspension. The only difference observed was at high dilution (5.10 −8 M), where AmB dissociation appeared in spectroscopic studies, together with emulsion droplet fusion observed in PCS. These data seem to indicate that AmB could be located in the droplets of the emulsion, preferentially in the phospholipid layer, because AmB is not soluble in the oil inner phase. All these results suggest that AmB-E is a system which has potential applications and merits further evaluation.

Disposition and protective effect against irritation after intravenous and rectal administration of indomethacin loaded nanocapsules to rabbits

Abstract Indomethacin loaded poly(D,L-lactide) nanocapsules (PLA-NCs) were investigated after intravenous and rectal administration to rabbits. A rebound of indomethacin plasma concentrations attributed to enterohepatic circulation of indomethacin was observed with all preparations. Following i.v. infusions, results showed that PLA-NCs altered the pharmacokinetics of indomethacin in ways that accelerate the extravascular distribution by enhancing the capture of the colloidal carrier by the liver and, at the same time, modifying the elimination rate of indomethacin. After rectal administration of indomethacin formulations, drug plasma concentration profiles revealed that absorption was more complete and more progressive with nanocapsules than with solution. T max had nearly the same value for all formulations, and bioavailability of indomethacin by this route was increased by nanoencapsulation. The terminal half-life of indomethacin was significantly lower when the drug was given by the rectal route either in solution by PLA-NCs, as compared to suppository. PLA-NCs exhibited a protective effect against the rectal irritability of indomethacin which can be attributed to the reduction of direct contact of free indomethacin with rectal mucosa.