Jose L. Vila-Jato

Chitosan and chitosan/ethylene oxide-propylene oxide block copolymer nanoparticles as novel carriers for proteins and vaccines.

AbstractPurpose. The aim of this study was to investigate the interaction between the components of novel chitosan (CS) and CS/ethylene oxide-propylene oxide block copolymer (PEO-PPO) nanoparticles and to evaluate their potential for the association and controlled release of proteins and vaccines. Methods. The presence of PEO-PPO on the surface of the nanoparticles and its interaction with the CS was identified by X-ray photoelectron spectroscopy (XPS). The mechanism of protein association was elucidated using several proteins, bovine serum albumin (BSA), and tetanus and diphtheria toxoids, and varying the formulation conditions (different pH values and concentrations of PEO-PPO), and the stage of protein incorporation into the nanoparticles formation medium. Results. BSA and tetanus and diphtheria toxoids were highly associated with CS nanoparticles partly due to electrostatic interactions between the carboxyl groups of the protein and the amine groups of CS. PEO-PPO also interacted electrostatically with CS, thus competing with the proteins for association with CS nanoparticles. A visible amount of PEO-PPO was projected towards the outer phase of the nanoparticles. Proteins were released from the nanoparticles at an almost constant rate, the intensity of which was closely related to the protein loading. Furthermore, the tetanus vaccine was released in the active form for at least 15 days. Conclusions. CS and CS/PEO-PPO nanoparticles prepared by a very mild ionic crosslinking technique are novel and suitable systems for the entrapment and controlled release of proteins and vaccines.

Enhancement of Nasal Absorption of Insulin Using Chitosan Nanoparticles

AbstractPurpose. To investigate the potential of chitosan nanoparticles as a system for improving the systemic absorption of insulin following nasal instillation. Methods. Insulin-loaded chitosan nanoparticles were prepared by ionotropic gelation of chitosan with tripolyphosphate anions. They were characterized for their size and zeta potential by photon correlation spectroscopy and laser Doppler anemometry, respectively. Insulin loading and release was determined by the microBCA protein assay. The ability of chitosan nanoparticles to enhance the nasal absorption of insulin was investigated in a conscious rabbit model by monitoring the plasma glucose levels. Results. Chitosan nanoparticles had a size in the range of 300−400 nm, a positive surface charge and their insulin loading can be modulated reaching values up to 55% [insulin/nanoparticles (w/w): 55/100]. Insulin association was found to be highly mediated by an ionic interaction mechanism and its release in vitro occurred rapidly in sink conditions. Chitosan nanoparticles enhanced the nasal absorption of insulin to a greater extent than an aqueous solution of chitosan. The amount and molecular weight of chitosan did not have a significant effect on insulin response. Conclusions. Chitosan nanoparticles are efficient vehicles for the transport of insulin through the nasal mucosa.

Evaluation of cationic polymer-coated nanocapsules as ocular drug carriers

New colloidal systems for ocular application were developed and their capacity for increasing the corneal penetration of drugs investigated. Chitosan (CS)-coated and poly-l-lysine (PLL)-coated poly-ϵ-caprolactone (PECL) nanocapsules, were designed based on a strategy that combines the features of PECL nanocapsules as ocular carriers with the advantages of a cationic mucoadhesive coating. Using this approach, an improved interaction of the carrier with the negatively charged corneal epithelium was attempted. The cationic polyaminoacid PLL was directly adsorbed onto preformed PECL nanocapsules whereas the cationic polysaccharide CS was included in the nanocapsules formation medium. The CS and PLL coatings conferred to nanocapsules a high positive surface charge, nevertheless, they did not modify the release profile of the model drug indomethacin from the colloidal system. In vivo studies showed that the systems investigated (uncoated, PLL-coated and CS-coated nanocapsules) increased significantly the concentration of indomethacin in the cornea and aqueous humor with respect of a commercial eye drops. Nevertheless, the ability of PLL-coated and CS-coated nanocapsules of enhancing the ocular penetration of indomethacin was substantially different: the CS coating increased twice, whereas the PLL coating failed to increase the ocular bioavailability of indomethacin when compared to the uncoated particles. Therefore, it is not the positive surface charge but the specific nature of CS that is responsible for the particularly enhanced uptake of the CS-coated nanocapsules. In addition, the PLL-coated and CS-coated nanocapsules displayed a good ocular tolerance. To summarize, the CS-coated nanocapsules represent a useful approach for increasing the ocular bioavailability of drugs.

DESIGN AND EVALUATION OF CHITOSAN/ETHYLCELLULOSE MUCOADHESIVE BILAYERED DEVICES FOR BUCCAL DRUG DELIVERY

This paper describes the preparation of new buccal bilayered devices comprising a drug-containing mucoadhesive layer and a drug-free backing layer, by two different methods. Bilaminated films were produced by a casting/solvent evaporation technique and bilayered tablets were obtained by direct compression. The mucoadhesive layer was composed of a mixture of drug and chitosan, with or without an anionic crosslinking polymer (polycarbophil, sodium alginate, gellan gum), and the backing layer was made of ethylcellulose. The double-layered structure design was expected to provide drug delivery in a unidirectional fashion to the mucosa and avoid loss of drug due to wash-out with saliva. Using nifedipine and propranolol hydrochloride as slightly and highly water-soluble model drugs, respectively, it was demonstrated that these new devices show promising potential for use in controlled delivery of drugs to the oral cavity. The uncrosslinked chitosan-containing devices absorbed a large quantity of water, gelled and then eroded, allowing drug release. The bilaminated films showed a sustained drug release in a phosphate buffer (pH 6.4). Furthermore, tablets that displayed controlled swelling and drug release and adequate adhesivity were produced by in situ crosslinking the chitosan with polycarbophil.

Design of a new multiparticulate system for potential site-specific and controlled drug delivery to the colonic region

A multiparticulate dosage form consisting of a hydrophobic core coated with a pH-dependent polymer is proposed for colonic specific delivery of drugs. Different approaches for colon-specific drug delivery have been studied over the last decade, including prodrugs, polymeric coating using pH-sensitive or bacterial degradable polymers and matrices. In this work, we present a new multiparticulate system to deliver active molecules to the colonic region, which combines pH-dependent and controlled drug release properties. This system was constituted by drug loaded cellulose acetate butyrate (CAB) microspheres coated by an enteric polymer (Eudragit(R) S). Both, CAB cores and pH-sensitive microcapsules, were prepared by the emulsion-solvent evaporation technique in an oily phase. Ondansetron (OS) and budesonide (BDS), two interesting drugs with a potentially new application for the local treatment of intestinal disorders, were efficiently microencapsulated in CAB microspheres at different polymer concentrations (6 and 8%). These hydrophobic cores (about 60 and 110 micrometer in size, respectively) were then microencapsulated with Eudragit(R) S, resulting in multinucleated structures, except in the case of BDS-CAB microspheres prepared at 8% CAB concentration, in which more mononucleated microcapsules were obtained. The in vitro drug release studies of pH-sensitive microcapsules containing the hydrophobic cores showed that no drug was released below pH 7. After that, CAB microspheres efficiently controlled the release of BDS, the release behavior being affected by the different polymer concentration used in their preparation. However, OS-CAB microspheres did not maintain their controlled-release properties once the enteric polymer dissolved. The extraction of the drug by the Eudragit(R) solvent during the second microencapsulation process was in this case the cause for the failure of the controlling release mechanism.

Improved Ocular Bioavailability of Indomethacin by Novel Ocular Drug Carriers

The ability of different drug carriers to improve the ocular bioavailability of drugs was investigated in the rabbit eye. The assayed drug carriers were suspensions of nanoparticles, nanocapsules and microparticles made of poly‐ε‐caprolactone (PECL) and a submicron emulsion.

Influence of Method of Preparation on Inclusion Complexes of Naproxen with Different Cyclodextrins

AbstractThe aim of this study is to increase the solubility of naproxen by inclusion complex formation with α, β, γ, hydroxypropylbeta and dimethylbetacyclodextrin. The apparent stability constants were calculated from the slope and intercept of the AL-solubility diagrams. The solid inclusion complexes of naproxen with cyclodextrins in 1:1 molar ratio were prepared by the kneaded-mix, spray-drying and freeze-drying method. The formation of inclusion complexes in the solid state were confirmed by X-Ray diffractometry I.R. spectroscopy and differential scanning calorimetry. The dissolution rate of naproxen from the inclusion complexes was much more rapid than naproxen alone. The best results were obtained with β-cyclodextrin inclusion complex prepared by the spray-drying method.

Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

Abstract Terbutaline-loaded ion-exchange resins were entrapped within cellulose acetate butyrate (CAB) microcapsules using either an aqueous (O/W) or a non-aqueous (O/O) solvent evaporation method. Scanning electron micrographs of the cross-sections of microcapsules prepared by both techniques revealed that the degree of multinucleation was dependent on the polymer concentration. A low polymer concentration led to a typical mononucleated reservoir structure whereas more multicore microcapsules were formed at high polymer concentrations. These differences on the inner structure affected the in vitro terbutaline release profiles. Terbutaline released very rapidly from the mononucleated microcapsules, however its release was controlled from the multinucleated systems. In addition, terbutaline release was influenced by the microencapsulation method. Using the higher CAB concentrations, the O/O technique produced microcapsules which adequately controlled the release of terbutaline; in contrast, microcapsules obtained by the O/W method showed a biphasic behaviour, with an initial burst effect followed by stabilization of the drug release, which became finally incomplete. With the aim of elucidating the main causes which were responsible for the differences in drug release, CAB films were obtained by casting the polymeric solutions prepared with the solvents used in each encapsulation procedure, acetone and methylene chloride for O/O and O/W methods, respectively. Thermal properties of the polymer in films and microcapsules were compared, and terbutaline diffusion studies through the films were performed. Results revealed that the polymer solvent was a key factor that determined the structure of the polymer wall formed, and thereby the in vitro release properties of the polymer films. After an initial rapid permeation step in both films, the CAB film cast from acetone allowed a faster permeation of terbutaline by diffusion through the pores, whereas the diffusion through the polymer chains was probably the only possible mechanism of drug release in the dense film formed from methylene chloride polymer solutions, this process being extremely slow for terbutaline.

The properties of solid dispersions of clofibrate in polyethylene glycols

Abstract The effect of molecular weight of polyethylene glycols (PEGs) and drug/PEG ratio on the structure and dissolution rates of the solid dispersions with clofibrate have been examined. The differential scanning calorimetry curves showed a possible evidence for the presence of interstitial solid solution. Infra-red spectra suggested that little or no interaction is present between the drug and carrier. The dissolution rates of clofibrate increased as the molecular weight of PEG increased, but the best results were obtained with PEG 20000. Although the dissolution rate increased with the drug ratio, solid dispersions containing more than 20% of the drug were not real solid products and therefore these dispersions could not be prepared.

Microencapsulation of ion-exchange resins by interfacial nylon polymerization

Abstract Microcapsules of nylon containing ion-exchange resins have been prepared, using an interfacial polycondensation procedure. A complex formed by anion-exchange resins (Dowex-1) and sodium fluoresceinate was used as a model resinate. Observation of the microcapsules by optical microscopy permitted us to confirm the continuity of the polymeric film around the particles of resin, as well as their perfect individualization. In vitro release studies revealed that the degree of reticulation of the resins, as well as the presence of the polymeric coat of nylon, delayed the release of the drug.