Paolo Giunchedi

FORMULATION AND IN VIVO EVALUATION OF CHLORHEXIDINE BUCCAL TABLETS PREPARED USING DRUG-LOADED CHITOSAN MICROSPHERES

This investigation deals with the development of buccal formulations (tablets) based on chitosan microspheres containing chlorhexidine diacetate. The microparticles were prepared by a spray-drying technique, their morphological characteristics were studied by scanning electron microscopy and the in vitro release behaviour was investigated in pH 7.0 USP buffer. Chlorhexidine in the chitosan microspheres dissolves more quickly in vitro than does chlorhexidine powder. The anti-microbial activity of the microparticles was investigated as minimum inhibitory concentration, minimum bacterial concentration and killing time. The loading of chlorhexidine into chitosan is able to maintain or improve the anti-microbial activity of the drug. The improvement is particularly high against Candida albicans. This is important for a formulation whose potential use is against buccal infections. Drug-empty microparticles have an anti-microbial activity due to the polymer itself. Buccal tablets were prepared by direct compression of the microparticles with mannitol alone or with sodium alginate. After their in vivo administration the determination of chlorhexidine in saliva showed the capacity of these formulations to give a prolonged release of the drug in the buccal cavity.

Preparation and characterization of ampicillin loaded methylpyrrolidinone chitosan and chitosan microspheres

Ampicillin was embedded in microparticles made of a new derivative of chitosan: methylpyrrolidinone chitosan. They were prepared using different drug-to-polymer weight ratios and by a spray-drying technique. Spray-dried drug-loaded chitosan microspheres were prepared for comparison. The microparticles were characterized by scanning electron microscopy (SEM), particle size analysis, differential scanning calorimetry (DSC) and in vitro drug release. Microbiological assay was performed using different bacterial strains. Spray-dried microspheres of almost spherical shape, smooth surface and narrow size distribution were always obtained. Ampicillin loaded into both polymer matrices showed amorphous behaviour as determined by DSC. Drug-loaded microspheres resulted to control the drug release in a 30-120 min range, depending on chitosan type. Thermal denaturation of the microspheres does not modify drug release rate. The results of the microbiological assay show that the loading of ampicillin into chitosans is able to maintain or improve the anti-bacterial activity of the drug.

Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopramide: in-vitro/ex-vivo studies

Microparticulate delivery systems designed for the nasal administration of an antiemetic drug, metoclopramide hydrochloride, were prepared. Microspheres composed of sodium alginate, chitosan hydrochloride, or both, were obtained using a spray‐drying method; some batches of drug‐free microparticles were prepared as a comparison. The morphology, in‐vitro swelling behaviour, mucoadhesive properties and drug release from microparticles were evaluated. Ex‐vivo drug permeation tests were carried out using sheep nasal mucosa; permeation test of the drug solution was peformed as comparison. During ex‐vivo permeation tests, transmission electron microscopy (TEM) analyses were carried out on the nasal mucosa to study the morphological changes of epithelial cells and tight junctions, while the change in microsphere morphology was examined using photostereo microscopy (PM). Spray‐dried microparticles had a mean diameter (dvs) in the range of about 3–10 μm. They showed good in‐vitro mucoadhesive properties. In‐vitro release profiles and swelling behaviour depended on their composition: the drug release occurred in 1–3 h. Ex‐vivo studies showed that drug permeation through the mucosa from microparticles based on chitosan was higher than from those consisting of alginate alone. This can be related to the penetration enhancing properties of chitosan. Complexation of chitosan with alginate led to a control of the drug release. Microscopy observation of microspheres during the permeation tests revealed that microparticles swelled and gelled, maintaining their shape. TEM analyses of the mucosa after exposure to the microparticles consisting of alginate/chitosan showed opened tight junctions. This preliminary study shows that alginate/chitosan spray‐dried microspheres have promising properties for use as mucoadhesive nasal carriers of an antiemetic drug.

Solid lipid nanoparticles (SLN) as carriers for the topical delivery of econazole nitrate: in‐vitro characterization, ex‐vivo and in‐vivo studies

Solid lipid nanoparticles (SLN) designed for topical administration of econazole nitrate (ECN), were prepared by o/w high‐shear homogenization method using different ratios of lipid and drug (5:1 and 10:1). SLN were characterized in terms of particle size, morphology, encapsulation efficiency and crystalline structure. After incorporation of SLN into hydrogels, rheological measurements were performed, and ex‐vivo drug permeation tests were carried out using porcine stratum corneum (SC). In‐vivo study of percutaneous absorption of ECN as a function of application time and composition of gels was carried out by tape‐stripping technique. Penetration tests of the drug from a conventional gel were performed as comparison. High‐shear homogenization method resulted in a good technique for preparation of ECN‐loaded SLN. Particles had a mean diameter of about 150 nm and a regular shape and smooth surface. The encapsulation efficiency values were about 100%. Ex‐vivo tests showed that SLN were able to control the drug release through the SC; the release rate depended upon the lipid content on the nanoparticles. In‐vivo studies demonstrated that SLN promoted a rapid penetration of ECN through the SC after 1 h and improved the diffusion of the drug in the deeper skin layers after 3 h of application compared with the reference gel.

Evaluation of spray drying as a method for polylactide and polylactide-co-glycolide microsphere preparation

Polylactide and polylactide-co-glycolide microspheres containing a lipophilic model drug (vitamin D3) were prepared by spray drying. The purpose of this work is to evaluate the efficacy of spray drying as a method for microsphere preparation. The study was carried out on five different polymers of lactide class: poly-L-lactide 57000 MW, poly-D,L-lactide 209,000 MW, 109,000 MW, 16,000 MW, and polylactide-co-glycolide 22,000 MW. The process conditions were experimentally assessed for each polymer used. The microspheres obtained were characterized for their shape, size and drug content, and the influence of the polymer on microsphere characteristics was evaluated. Results show that polymer type, polymer molecular weight and its concentration in the spraying solution greatly affect microsphere characteristics. In vitro dissolution tests performed with the rotating bottle method resulted in different release profiles depending on type of polymer and on microsphere morphology.

Solvent evaporation, solvent extraction and spray drying for polylactide microsphere preparation

Abstract Polylactide microspheres containing vitamin D 3 (D 3 ) as a model drug were prepared by solvent evaporation, solvent extraction and spray drying. In this work, these three different preparation methods were compared and the extent to which each can affect the properties and characteristics of microspheres was identified. The experimental conditions yielding the best results were chosen within each method. Solvent extraction proved to be the better of the two traditional methods. It resulted in particles that were more regular in shape, smaller, with a narrower size distribution and higher porosity. Spray drying yields results equivalent to those of solvent extraction with the advantage of a higher encapsulation efficiency and shorter duration for the process of preparation. Moreover, the dissolution profile of microspheres prepared by spray drying demonstrated that more gradual release of drug was promoted.

Pectin microspheres as ophthalmic carriers for piroxicam: evaluation in vitro and in vivo in albino rabbits

Microparticulate polymeric delivery systems have been suggested as a possible approach to improve the low bioavailability characteristics shown by standard ophthalmic vehicles (collyria). Purpose of this study was the evaluation of pectin microspheres as delivery system for piroxicam (Px). The microspheres were prepared by a spray-drying technique; their morphological characteristics were investigated by scanning electron microscopy (SEM), and their in vitro release behavior was evaluated in pH 7.0 USP buffer using a flow-through apparatus. Px loaded in the pectin microspheres showed a faster in vitro dissolution rate with respect to solid micronized drug. The precorneal retention of fluorescein-loaded microspheres was evaluated in vivo in albino rabbits: an aqueous dispersion of fluorescent microspheres showed a significantly increased residence time in the eye (2.5 vs. 0.5 h) when compared with a fluorescein solution. In vivo tests in rabbits of dispersions of Px-loaded microspheres also indicated a significant improvement of Px bioavailability in the aqueous humour (2.5-fold) when compared with commercial Px eyedrops. The potential advantages and limitations of this delivery system are discussed.

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.

In vitro degradation study of polyester microspheres by a new HPLC method for monomer release determination.

Biodegradable polyesters have increasing importance as materials used for the preparation of microspheres. The knowledge of their degradation process is important to prepare microparticulate delivery systems with suitable drug release rates. In this work an in vitro degradation study of empty and drug loaded microspheres is described. Three different polyesters were used: two poly-d, l-lactides of different molecular weight and a poly-d, l-lactide-co-glycolide (50:50). Diazepam has been chosen as the model drug. Solvent evaporation and spray-drying were used as preparation methods. To study the polymer degradation process, a new HPLC method is proposed for the direct and (in the case of the copolymer) simultaneous determination of the monomer(s): lactic acid (LA) and glycolic acid (GA). SEM and particle size analysis highlight the different characteristics of the particles, depending on their preparation method: spray-dried spheres result to be always smaller with respect to particles obtained by solvent evaporation. The results obtained indicate in particular that: the preparation methods play an important role in determining the degradation behaviour of microspheres, as unloaded spray-dried particles are characterized by a higher monomer release rate with respect to microspheres obtained by solvent evaporation; PLGA spheres degrade faster than PDLLA microparticles, according to the higher hydrophilicity of the copolymer; the two monomers are released at a different rate in the case of PLGA (faster for GA, slower for LA); the presence of diazepam increases the polymer degradation rate, with respect to empty particles.

Press-coated tablets for time-programmed release of drugs

A new dry-coated device for the release of drug after a programmable period of time is proposed. It is intended to be used mainly in the therapy of those diseases which depend on circadian rhythms. Some core formulations, characterized by different release rates and mechanisms (containing diltiazem hydrochloride or sodium diclofenac as model drugs), were coated by compression with different polymeric barrier layers (press-coated systems). The shell formulations tested contained either gellable or erodible polymers. The dissolution profiles of uncoated cores and press-coated devices were compared. The gellable and/or erodible characteristics (properties) of the barrier formulations were also examined by means of a penetrometer. The coatings prevent drug release from the core until the polymeric shell is completely eroded or swollen. This delay in release start is not influenced by the core composition and depends only on the shell formulation. Except for the time-lag, the release kinetics of the drug contained in the core are not significantly influenced by the presence of the erodible barrier, but can be widely modulated using a swellable polymeric shell.