Erica Franceschinis

Theoretical and experimental study on theophylline release from stearic acid cylindrical delivery systems

The purpose of this study is to evaluate the possibility of developing a cylindrical sustained-release dosage form for theophylline directly by means of a ram extrusion process. In particular, the formulations contained: stearic acid as a low melting binder, monohydrate lactose and polyethylene glycol 6000 as hydrophilic fillers. The influence of type and percentage of the components was studied considering different parameters such as the time required for 50% of the drug release (t50%)and the drug diffusion coefficient in the delivery system. The choice of the different formulations to be tested is carried out employing an axial design with constraint domains. The limits of each component were fixed on the basis of preliminary trials. The analysis of the t50% values revealed that the release kinetics is mainly affected by stearic acid and theophylline content, whilst lactose effect is almost negligible. A substantial correspondence between the experimental results and the analysis of the drug release kinetics performed by means of an ad hoc developed mathematical model was found. The proposed mathematical model allows to conclude that wherever the release mechanism is initially ruled by dissolution, then diffusion plays the most important role.

Melt pelletization in high shear mixer using a hydrophobic melt binder: influence of some apparatus and process variables

The effects of process conditions and the apparatus variables on the granulometric characteristics of a formulation containing a hydrophobic binder (stearic acid), lactose and paracetamol prepared by melt pelletization process were investigated in a 10-litre high shear mixer. The factors under investigation were: impeller speed, massing time, type of impeller blades and presence of the deflector and their reciprocal interactions. Two granule characteristics were analysed: the percentage of aggregates larger than 3000 microm (Y(1)) and the yield of the 2000-microm pellet size fraction (Y(2)). In order to estimate simultaneously the above-mentioned factors, a particular experimental design was adopted, that allowed the reduction of the number of trials from 378 to 35 and took into consideration other uncontrolled factors with the aid of a block variable. Using the postulated model, we found the optimal operating conditions to minimize Y(1) and increase Y(2) by selecting the type of impeller, and by using an impeller speed lower than 300 rpm, a massing time of 8-9 min and by not using the deflector. Finally, the validity of the adopted strategy has been proved with an additional check point.

Comparative Evaluation of the Effect of Permeation Enhancers, Lipid Nanoparticles and Colloidal Silica on in vivo Human Skin Penetration of Quercetin

Background/Aim: The aim of this study was to evaluate emulsions containing a penetration enhancer, lipid nanoparticles (LNs) or colloidal silica as systems to improve the topical delivery of the flavonoid quercetin. Methods: The skin penetration of quercetin was investigated in vivo on human volunteers by tape stripping. Quercetin-loaded LNs were prepared using hot high-pressure homogenization and characterized by means of dynamic light scattering and release studies. The location of the silica nanoparticles in the skin was determined by inductively coupled plasma mass spectrometry assay of silicon in the stratum corneum strips. Results and Conclusions: The penetration enhancer diethylene glycol monoethyl ether did not produce any significant increase in the fraction of the applied quercetin dose permeated in vivo into human stratum corneum (17.1 ± 3.2%) compared to the control emulsion (18.1 ± 2.3%). A greater but statistically nonsignificant accumulation of the flavonoid in the human horny layer (21.2 ± 2.9% of the applied dose) was measured following topical application of quercetin-loaded LNs (mean particle size: 527 nm). On the other hand, the addition of colloidal silica (average particle diameter: 486 nm) to the emulsion (2%, w/w) significantly increased the in vivo uptake of quercetin by the human stratum corneum to 26.7 ± 4.1% of the applied dose, the enhancing effect on permeation being more marked in the deepest horny layer strips. The measured in vivo skin penetration profile of colloidal silica showed that silica particles diffused down to the intermediate region of the human horny layer and hence could act as carrier for quercetin.

Preparation and evaluation of a melt pelletised paracetamol/stearic acid sustained release delivery system

The potential of a sustained release formulation for paracetamol produced by melt pelletisation was investigated. The chosen formulation was based on the combination of stearic acid as a melting binder and anhydrous lactose as a filler. After determination of the size distribution, the pellet characterisation included scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), specific surface area and true density determination. Hence, the in vitro release from every single size fraction (2000, 1250, 800, 630, <630 microm) was evaluated and the release mechanism was analysed with the help of an appropriate mathematical model. The results of drug content and superficial atomic composition were found to be constant in all pellets size fractions, attesting the ability of melt pelletisation in a high shear mixer to form a product with homogeneous composition. The mathematical model is built on the hypotheses that drug diffusion and solid drug dissolution in the release environment are the key phenomena affecting drug release kinetics. Smaller classes apart (particles are not perfectly spherical), the comparison between model best fitting and experimental data indicated the reasonability of these hypotheses. Moreover, model reliability is proved by its ability of predicting drug release from a known mixture of the above mentioned particles classes.

Multidisciplinary Approach on Characterizing a Mechanochemically Activated Composite of Vinpocetine and Crospovidone

Significant improvement of solubilization kinetics of poorly soluble vinpocetine was obtained through a mechanochemical activation process in presence of micronized crospovidone. Drug-to-polymer weight ratio and milling time variables resulted to have statistically significant impacts on the activation of the product. The complete amorphization was obtained in the coground with the highest crospovidone contents (>80% wt), milled for the longest time (180 min). An ad hoc software was then used to calculate the dimensions of the drug crystallites in the samples on the basis of the calorimetric data. The thermal analyses were then accompanied and confirmed by an extensive solid-state characterization, performing X-ray diffraction, Raman imaging/spectroscopy, DRIFT, and SS-NMR spectroscopy, followed by laser diffraction and solubilization kinetics tests. All the analyses agreed on attesting the progressive loosing of crystalline structure of the drug when increasing milling time and amount of polymer in the formulations. This activated status of the drug, which resulted to be homogeneously distributed on the coground sample and stable for at least 1 year, was reflected on favorable solubilization kinetics. The in vivo studies on rats revealed that coground systems promoted a fivefold higher oral bioavailability enhancement in comparison to a commercial formulation (Vimpocetin 5mg Capsules, Pharma).

A new approach to enhance oral bioavailability of Silybum Marianum dry extract: association of mechanochemical activation and spray congealing.

The aim of the work was to produce a delivery system for Silybum Marianum dry extract with enhanced oral bioavailability by combining two technologies (mechanochemical activation and spray congealing). Initially, the active was coground with sodium croscarmellose in a planetary mill in order to reach an activated state more prone to dissolution. DSC, XRD, FT-IR and LD analyses showed the formation of nanosized particles of dry extract, with reduced degree of crystallinity of the main crystalline flavolignans (silybine A and B). Then, microparticles containing the activated coground and, as comparison, the corresponding physical mixture of extract and polymer and the dry extract alone were produced by spray congealing technology using Gelucire(®) 50/13 as a hydrophilic low m.p. carrier. Microparticles containing the activated coground were produced spherical in shape, achieved satisfactory yield and high encapsulation efficiency. These microparticles, in addition to a favourable in vitro solubilisation kinetic, in a preliminary in vivo study in five rats demonstrated their ability to improve very significantly the oral bioavailability of the main flavolignans of Silybum Marianum dry extract (silybin A and B). These results suggested that the association of mechanochemical activation and spray congealing could be considered an innovative and very useful approach to the oral delivery of Silybum Marianum. Furthermore, for the first time the possibility of successfully applying the spray congealing technology for the preparation of a herbal drug delivery system was shown.

Combining formulation and process aspects for optimizing the high-shear wet granulation of common drugs

The purpose of this research was to determine the effects of some important drug properties (such as particle size distribution, hygroscopicity and solubility) and process variables on the granule growth behaviour and final drug distribution in high shear wet granulation. Results have been analyzed in the light of widely accepted theories and some recently developed approaches. A mixture composed of drug, some excipients and a dry binder was processed using a lab-scale high-shear mixer. Three common active pharmaceutical ingredients (paracetamol, caffeine and acetylsalicylic acid) were used within the initial formulation. Drug load was 50% (on weight basis). Influences of drug particle properties (e.g. particle size and shape, hygroscopicity) on the granule growth behaviour were evaluated. Particle size distribution (PSD) and granule morphology were monitored during the entire process through sieve analysis and scanning electron microscope (SEM) image analysis. Resistance of the wet mass to mixing was furthermore measured using the impeller torque monitoring technique. The observed differences in the granule growth behaviour as well as the discrepancies between the actual and the ideal drug content in the final granules have been interpreted in terms of dimensionless quantity (spray flux number, bed penetration time) and related to torque measurements. Analysis highlighted the role of liquid distribution on the process. It was demonstrated that where the liquid penetration time was higher (e.g. paracetamol-based formulations), the liquid distribution was poorer leading to retarded granule growth and selective agglomeration. On the other hand where penetration time was lower (e.g. acetylsalicylic acid-based formulations), the growth was much faster but uniformity content problem arose because of the onset of crushing and layering phenomena.

Simultaneous Release and ADME Processes of Poorly Water-Soluble Drugs: Mathematical Modeling

The importance of studying oral drug absorption is well recognized by both research facilities/institutions and the pharmaceutical industry. The use of mathematical models can represent a very profitable and indispensable tool to understand oral drug absorption. Indeed, mathematical models can verify the correctness of the mechanisms proposed to describe drug release, absorption, distribution and elimination thus reducing the number of expensive and time-consuming experiments. In this paper we develop a mathematical approach able to model both the polymeric particle mediated delivery and the gastrointestinal absorption-metabolism-excretion (ADME) of a given drug. As a model drug a poorly water-soluble drug (vinpocetine) in both the amorphous and nanocrystalline state is considered. The delivery system is obtained by drug cogrinding with a polymer (cross-linked polyvinilpyrrolidone). As the proposed mathematical model can properly fit the in vivo data on the basis of information obtained in vitro, it represents a powerful theoretical tool connecting in vitro and in vivo behavior.

Texture analysis as a tool to study the kinetics of wet agglomeration processes

In this work wet granulation experiments were carried out in a planetary mixer with the aim to develop a novel analytical tool based on surface texture analysis. The evolution of a simple formulation (300g of microcrystalline cellulose with a solid binders pre-dispersed in water) was monitored from the very beginning up to the end point and information on the kinetics of granulation as well as on the effect of liquid binder amount were collected. Agreement between texture analysis and granules particle size distribution obtained by sieving analysis was always found. The method proved to be robust enough to easily monitor the process and its use for more refined analyses on the different rate processes occurring during granulation is also suggested.

Role of proton pump inhibitor on esophageal carcinogenesis and pancreatic acinar cell metaplasia development: an experimental in vivo study.

Chronic gastro-duodenal reflux in the esophagus is a major risk for intestinal metaplasia and Barrett’s adenocarcinoma. A role for chronic use of proton pump inhibitor (PPI) in the increased incidence of esophageal adenocarcinoma in Western countries has been previously suggested. The aim of this work was to study the effect of chronic administration of omeprazole (a proton pump inhibitor) per os in a model of reflux induced esophageal carcinogenesis. One week after esophago-gastro-jejunostomy, 115 Sprague-Dawley rats were randomized to receive 10 mg/Kg per day of omeprazole or placebo, 5 days per week. The esophago-gastric specimens were collected 28±2 weeks after randomization and analyzed in a blinded fashion. Mortality and esophageal metaplasia rates did not differ between the two groups (p = 0.99 for mortality, p = 0.36 for intestinal metaplasia and p = 0.66 for multi-layered epithelium). Gastric pancreatic acinar cell metaplasia (PACM) was more frequently observed in PPI-treated rats (p = 0.003). Severe ulcer lesions significantly prevailed in the placebo group (p = 0.03). Locally invasive esophageal epithelial neoplasia were observed in 23/39 PPI-treated versus 14/42 placebo-animals (p = 0.03). In conclusion, chronic omeprazole treatment improved the healing of esophageal ulcerative lesions. Locally invasive neoplastic lesions and PACM prevailed among PPI-treated animals. However, neither an effect on the overall mortality nor on the incidence of pre-neoplastic lesions was observed in this work.