Carla Caramella

Characterization of chitosan hydrochloride–mucin interaction by means of viscosimetric and turbidimetric measurements

In the present work the interaction between chitosan hydrochloride (HCS) and two different types of mucin - one obtained from bovine submaxillary glands and the other from porcine stomach - was investigated. Two hydration media were tested: distilled water and 0. 1 M HCl. Intrinsic viscosity, which provides information about polymeric chain conformation, was assessed in both media for HCS and bovine submaxillary mucin. Changes in the specific viscosity of HCS-mucin mixtures were observed as a function of the polymer:mucin weight ratio. The formation of interaction products was indicated by a minimum in the specific viscosity. Such a minimum occurred at different polymer:mucin weight ratios depending on the hydration medium and mucin type. This suggested a different stoichiometry of interaction. Turbidimetric measurements were also effected in order to evidentiate the eventual precipitation of the polymer-mucin interaction products. While in distilled water the precipitation of the interaction product did occur, in acidic medium, although a minimum in specific viscosity was observed, no precipitate was formed. The two techniques employed, viscosimetric and turbidimetric, allowed us to investigate for both mucins the influence of hydration medium on the formation of the HCS-mucin interaction products and to conclude that a slightly acid-neutral pH favours the interaction between HCS and mucins.

Buccal drug delivery: A challenge already won?

The main obstacles that drugs meet when administered via the buccal route derive from the limited absorption area and the barrier properties of the mucosa. The effective physiological removal mechanisms of the oral cavity that take the formulation away from the absorption site are the other obstacles that have to be considered. The strategies studied to overcome such obstacles include the employment of new materials that, possibly, combine mucoadhesive, enzyme inhibitory and penetration enhancer properties and the design of innovative drug delivery systems which, besides improving patient compliance, favor a more intimate contact of the drug with the absorption mucosa.:

Cyclosporine A loaded SLNs: evaluation of cellular uptake and corneal cytotoxicity.

Cyclosporine A (CsA) loaded solid lipid nanoparticles (SLNs) for topical ophthalmic applications were prepared by high shear homogenization and ultrasound method using Compritol 888 ATO, Poloxamer 188 and Tween 80, to investigate the cellular uptake of rabbit corneal epithelial cells (RCE) and to evaluate the cytotoxicity. The size of the optimized formulation was 225.9+/-5.5 nm with a polydispersity index of 0.253+/-0.05. The zeta potential and entrapment efficiency was detected as -16.9+/-0.7 mV and 95.6%, respectively. The CsA release was found to be enzyme (lipase/co-lipase complex) dependent. SLNs were sterilized at 110 and 121 degrees C. The cytotoxicity was evaluated in vitro by means of RCE cells and was higher at 121 degrees C sterilization temperature, probably due to a supposed leakage of Tween 80 following lipid re-crystallization. The permeation and penetration of CsA across/into the corneal cells were evaluated using in vitro and ex vivo experiments. The cellular uptake was investigated by replacing CsA with the fluorescent dye Rhodamine B. The penetration enhancement properties were supported by confocal laser scanning microscopy analysis. The internalization of SLNs in cornea and in RCE cell lines was confirmed, pointing out the possibility of CsA targeting to the cornea.

Co-delivery of a hydrophobic small molecule and a hydrophilic peptide by porous silicon nanoparticles

Nanoparticulate drug delivery systems offer remarkable opportunities for clinical treatment. However, there are several challenges when they are employed to deliver multiple cargos/payloads, particularly concerning the synchronous delivery of small molecular weight drugs and relatively larger peptides. Since porous silicon (PSi) nanoparticles (NPs) can easily contain high payloads of drugs with various properties, we evaluated their carrier potential in multi-drug delivery for co-loading of the hydrophobic drug indomethacin and the hydrophilic human peptide YY3-36 (PYY3-36). Sequential loading of these two drugs into the PSi NPs enhanced the drug release rate of each drug and also their amount permeated across Caco-2 and Caco-2/HT29 cell monolayers. Regardless of the loading approach used, dual or single, the drug permeation profiles were in good correlation with their drug release behaviour. Furthermore, the permeation studies indicated the critical role of the mucus intestinal layer and the paracellular resistance in the permeation of the therapeutic compounds across the intestinal wall. Loading with PYY3-36 also greatly improved the cytocompatibility of the PSi NPs. Conformational analysis indicated that the PYY3-36 could still display biological activity after release from the PSi NPs and permeation across the intestinal cell monolayers. These results are the first demonstration of the promising potential of PSi NPs for simultaneous multi-drug delivery of both hydrophobic and hydrophilic compounds.

Buccal Delivery of Acyclovir from Films Based on Chitosan and Polyacrylic Acid

The aim of the present work was to investigate the possibility of achieving buccal delivery of a problematic drug, acyclovir, from films based on chitosan hydrochloride (HCS) and polyacrylic acid sodium salt (PAA). At first, the ionic interaction between HCS and PAA in distilled water was investigated by means of rheological and turbidimetric analysis. Films containing 1 mg/cm2 of acyclovir and based on pure HCS and on HCS and PAA mixed in different ratios were prepared by casting technique. The films were subjected to hydration, rheological, mucoadhesion, drug release, “wash away,” and permeation/penetration measurements. A commercial cream containing acyclovir and an aqueous acyclovir suspension were used as references. The addition of PAA to HCS produced a decrease in film hydration. Films based on HCS/PAA weight ratio close to interaction product stoichiometry were characterized by higher rigidity and better “wash away” properties with respect to the other films and the reference formulation. The worst mucoadhesive properties were shown by films based on mixing ratios close to interaction product stoichiometry. The addition of PAA to HCS produced a lowering in drug release profile. All the films examined promoted the permeation of acyclovir across porcine cheek epithelium when compared with acyclovir suspension and the commercial cream. The penetration enhancement properties were affected by the mixing ratio of the two polymers. The film based on 1/1.3 HCS/PAA weight ratio, besides possessing the best resilience properties on the mucosa, was also characterized by the highest permeation profile and, therefore, represents a promising formulation for buccal delivery of acyclovir.

On the employment of λ-carrageenan in a matrix system. II. λ-Carrageenan and hydroxypropylmethylcellulose mixtures

Abstract The suitability of λ-carrageenan-hydroxypropylmethylcellulose (HPMC) matrices for the controlled release of two basic drugs (salbutamol sulphate and chlorpheniramine maleate) has been assessed. The influence that the amounts of the two polymers and their ratios have on drug release profiles was studied. Percentages of λ-carrageenan as high as 40% in the matrix gave rise to good early control of drug release, resulting in release profiles close to linearity. The overall release rate was usually higher in buffer at pH 1.2 than at pH 6.8, indicating the matrix is somewhat sensitive to the dissolution medium pH. This is possibly due to the effect of medium composition on the rate of matrix erosion. By increasing the content of the more slowly erodible HPMC, differences in release rate related to the dissolution medium could sometimes be reduced.

Influence of mucin type on polymer-mucin rheological interactions

There are numerous in vitro methods with which to investigate the mucoadhesive properties of polymers. One recent method is based on the measurement of rheological interactions between polymer and mucin, which implies the use of mucins isolated from the mucous tissue. The extraction and purification of glycoprotein fraction, which is responsible for rheological interaction, can modify the native structure of mucin or spoil it with exogenous substances. Therefore the particulars of the mucin employed (origin, purification grade, the effect of further treatments such as freezing or freeze-drying) are likely to be critical for the interaction. The aim of this work was to compare some commercial mucins of differing origin and grade of purification for their rheological interaction with well-known mucoadhesive polymers (polyacrylic acid and sodium carboxymethylcellulose). For polyacrylic acid, which is sensitive to ions, we found rheological interaction to be strongly influenced by mucin type. The removal of ions, with dialysis, improved the interaction. For sodium carboxymethylcellulose, which is less sensitive to ions, rheological interaction proved to be less dependent on mucin type and improved upon glycoprotein solubilization.

On the employment of λ-carrageenan in a matrix system. I. Sensitivity to dissolution medium and comparison with Na carboxymethylcellulose and xanthan gum

Abstract Three anionic polysaccharidic materials, characterized by their differing sensitivity to pH, especially at low values, were compared in order to assess their behaviour on the performance in matrix systems. λ-Carrageenan, a sulphated polymer, was compared with two carboxylic polymers, Na carboxymethylcelluse (Na CMC) and xanthan gum. In the case of Na CMC both the gelation rate and the ionic charge are affected by gastric pH. Gelation properties of xanthan gum are described as being more or less insensitive to pH. The more acidic λ-carrageenan, however, was expected to maintain both gelation capability and ionization even at low pH values. Erosion in distilled water and buffers at pH 1.2 and 6.8 was evaluated. Matrices containing as model drug either salbutamol sulphate or diprophylline were prepared and tested for release rate in the same three media. λ-Carrageenan shows characteristic behaviour. Its control of the initial drug release, ascribed to ionic drug-polymer interactions, appears to be remarkably effective and independent of the characteristics of the dissolution medium.

Mucoadhesive and thermogelling systems for vaginal drug delivery.

This review focuses on two formulation approaches, mucoadhesion and thermogelling, intended for prolonging residence time on vaginal mucosa of medical devices or drug delivery systems, thus improving their efficacy. The review, after a brief description of the vaginal environment and, in particular, of the vaginal secretions that strongly affect in vivo performance of vaginal formulations, deals with the above delivery systems. As for mucoadhesive systems, conventional formulations (gels, tablets, suppositories and emulsions) and novel drug delivery systems (micro-, nano-particles) intended for vaginal administration to achieve either local or systemic effect are reviewed. As for thermogelling systems, poly(ethylene oxide-propylene oxide-ethylene oxide) copolymer-based and chitosan-based formulations are discussed as thermogelling systems. The methods employed for functional characterization of both mucoadhesive and thermogelling drug delivery systems are also briefly described.

Chitosan gels for the vaginal delivery of lactic acid: relevance of formulation parameters to mucoadhesion and release mechanisms.

The aim of this work was to assess the effect of formulation parameters of a mucoadhesive vaginal gel based on chitosan and lactic acid, and to highlight its release mechanisms. Two molecular weight chitosans were used to prepare gels with 2 lactic acid concentrations. Both chitosan molecular weight and lactic acid concentration had a significant and mutually dependent influence on mucoadhesion, measured on pig vaginal mucosa. Similarly, the lactate release profiles were found to be dependent on lactic acid content and polymer molecular weight.One gel formulation based on the stoichiometric lactate to chitosan ratio was subjected to release test in media with 2 different counterions and increasing ionic strength. This test demonstrated that the lactate release is mainly due to ionic displacement.