Dionysios Douroumis

Development and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen granules prepared by hot melt extrusion

In the current study Ibuprofen was embedded in a methacrylate copolymer (Eudragit® EPO) matrix to produce solid dispersions by hot-melt extrusion (HME) processing. The obtained granules were incorporated in orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and crosslinked polyvinylpyrrolidone grades while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets which included porosity, hardness, friability and dissolution profiles were further evaluated and compared with Nurofen® Meltlet ODTs. The taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and improved tablet palatability.

In vitro–in vivo correlations of self-emulsifying drug delivery systems combining the dynamic lipolysis model and neuro-fuzzy networks

The aim of the current study was to evaluate the potential of the dynamic lipolysis model to simulate the absorption of a poorly soluble model drug compound, probucol, from three lipid-based formulations and to predict the in vitro-in vivo correlation (IVIVC) using neuro-fuzzy networks. An oil solution and two self-micro and nano-emulsifying drug delivery systems were tested in the lipolysis model. The release of probucol to the aqueous (micellar) phase was monitored during the progress of lipolysis. These release profiles compared with plasma profiles obtained in a previous bioavailability study conducted in mini-pigs at the same conditions. The release rate and extent of release from the oil formulation were found to be significantly lower than from SMEDDS and SNEDDS. The rank order of probucol released (SMEDDS approximately SNEDDS > oil formulation) was similar to the rank order of bioavailability from the in vivo study. The employed neuro-fuzzy model (AFM-IVIVC) achieved significantly high prediction ability for different data formations (correlation greater than 0.91 and prediction error close to zero), without employing complex configurations. These preliminary results suggest that the dynamic lipolysis model combined with the AFM-IVIVC can be a useful tool in the prediction of the in vivo behavior of lipid-based formulations.

Preparation and optimization of PMAA–chitosan–PEG nanoparticles for oral drug delivery

The objective of this study was to develop pH sensitive polymethacrylic acid-chitosan-polyethylene glycol (PCP) nanoparticles. This was achieved by dispersion polymerization of methacrylic acid (MAA), polyethylene glycol (PEG) and different chitosan (CS) grades in the presence of cross linking agent ethylene dimethacrylate (EDMA) and polymer initiator potassium persulphate. Method development was carried out by varying formulation parameters such as type of CS, ratio of PEG to CS, quantity of solvent and polymer initiator. Metoprolol (MTP) tartrate was incorporated into the nanoparticles (NPs) as a model drug. Laser diffraction, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) studies revealed that the NPs were spherical with smooth surfaces ranging in size from 190 to 450 nm. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) findings showed the presence of amorphous MTP in PCP NPs. The MTP loading of PCP and glycol chitosan (GC) NPs varied from 10 to 45% depending on the CS grade while both types of NPs showed excellent binding efficiency on mucin from porcine stomach. The in vitro dissolution study showed pH dependent release profiles suggesting that the PCP NPs system have great potential for oral controlled drug delivery as an alternative to conventional dosage forms.

Physicochemical characterization of solid dispersions of three antiepileptic drugs prepared by solvent evaporation method

We have investigated the solid dispersion and dissolution profiles of three antiepileptic drugs (carbamazepine (CBZ), oxcarbazepine (OXC) and rufinamide (RFN)) with different aqueous solubilities, prepared by the solvent evaporation method. Solid dispersions of the three drugs in hydroxy‐propylmethylcellulose (HPMC), with drug:polymer ratios of 1:4, were prepared and characterized by differential scanning calorimetry (DSC), Fourier transformation infrared (FTIR) spectroscopy, X‐ray diffraction (XRD) and scanning electron microscopy. The release mechanism was also investigated and the kinetic order of the solid dispersions was evaluated. It appeared that the dissolution behaviour depended on the physicochemical properties of the drug and drug‐polymer interactions. DSC thermographs showed amorphous forms for all drugs confirmed by XRD patterns. The FTIR spectra of CBZ and OXC demonstrated drug interactions with HPMC through hydrogen polymer bonds. Thus, solid dispersions of these drugs had an improved dissolution profile. In contrast, solid dispersions of RUF showed modest enhancement of dissolution, suggesting negligible drug‐polymer interactions. The different dissolution behaviour is attributed to the extent of interactions between the polymer hydroxyl group and the drug amide groups.

Mechanism of synergistic interactions and its influence on drug release from extended release matrices manufactured using binary mixtures of polyethylene oxide and sodium carboxymethylcellulose.

The ability of anionic polymer sodium carboxymethylcellulose to influence the release of four model cationic drugs (chlorpheniramine maleate, venlafaxine hydrochloride, propranolol hydrochloride and verapamil hydrochloride) from extended release (ER) hydrophilic matrices based on non-ionic polymer polyethylene oxide was investigated by X-ray photoelectron spectroscopy (XPS), isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC). For all studied APIs, a combination of polyethylene oxide with sodium carboxymethylcellulose produced slower drug release compared to the matrices of single polymers. This behaviour was mainly attributed to the interaction of ester/carboxylic acid functionalities to yield H-bonding between the anionic polymer groups and the additionally protonated N-atoms of the active substances. X-ray photoelectron and isothermal titration calorimetry studies confirmed drug-polymer interaction and polymer-polymer interaction (i.e. the PEO binding with negatively charged NaCMC), whilst differential scanning calorimetry indicated the existence of both crystalline and molecularly dispersed active forms in the created complexes. The drug release mechanisms were fitted to various models suggesting diffusion control for the majority of the formulations. The Korsmeyer-Peppas model was found to be the most suitable for description of release profiles of all formulations. The present study showed that XPS and ITC in combination with DSC can be valuable tool to investigate the presence and nature (mechanism) of synergistic interactions between polymers and drugs in extended release matrix tablets.

Chitosan derivatives alter release profiles of model compounds from calcium phosphate implants.

The aim of the current study was to evaluate the impact of chitosan derivatives, namely N-octyl-chitosan and N-octyl-O-sulfate chitosan, incorporated in calcium phosphate implants to the release profiles of model drugs. The rate and extent of calcein (on M.W. 650 Da) ED, and FITC-dextran (M.W. 40 kDa) on in vitro release were monitored by fluorescence spectroscopy. Results show that calcein release is affected by the type of chitosan derivative used. A higher percentage of model drug was released when the hydrophilic polymer N-octyl-sulfated chitosan was present in the tablets compared with the tablets containing the hydrophobic polymer N-octyl-chitosan. The release profiles of calcein or FD from tablets containing N-octyl-O-sulfate revealed a complete release for FD after 120 h compared with calcein where 20% of the drug was released over the same time period. These results suggest that the difference in the release profiles observed from the implants is dependent on the molecular weight of the model drugs. These data indicate the potential of chitosan derivatives in controlling the release profile of active compounds from calcium phosphate implants.

Development and release mechanism of diltiazem HCl prolonged release matrix tablets

A coated matrix tablet formulation has been used to develop controlled release diltiazem HCl (DIL) tablets. The developed drug delivery system provided prolonged drug release rates over a defined period of time. DIL tablets prepared using dry mixing and direct compression and the core consisted of hydrophilic and hydrophobic polymers such as hydroxypropylmethylcellulose (HPMC), Eudragits RLPO/RSPO, microcrystalline cellulose, and lactose. Tablets were coated with Eudragit NE 30D, and the influence of varying the inert hydrophobic polymers and the amount of the coating polymer were investigated. The release profile of the developed formulation was described by the Higuchi model. Stability trials up to 6 months displayed excellent reproducibility.

Adaptive Neuro-Fuzzy Modeling of Poorly Soluble Drug Formulations

PurposeThe purpose of this study was to evaluate the efficiency of a neuro-fuzzy logic-based methodology to model poorly soluble drug formulations and predict the development of the particle size that has been proven to be an important factor for long-term stability.MethodsAn adaptive neuro-fuzzy inference system was used to model the natural structures within the data and construct a set of fuzzy rules that can subsequently used as a predictive tool. The model was implemented in Matlab 6.5 and trained using 75% of an experimental data set. Subsequently, the model was evaluated and tested using the remaining 25%, and the predicted values of the particle size were compared to the ones from the experimental data. The produced adaptive neuro-fuzzy inference system-based model consisted of four inputs, i.e., acetone, propylene glycol, POE-5 phytosterol (BPS-5), and hydroxypropylmethylcellulose 90SH-50, with four membership functions each. Moreover, 256 fuzzy rules were employed in the model structure.ResultsModel training resulted in a root mean square error of 4.5 × 10−3, whereas model testing proved its highly predictive efficiency, achieving a correlation coefficient of 0.99 between the actual and the predicted values of the particle size (mean diameter).ConclusionsNeuro-fuzzy modeling has been proven to be a realistic and promising tool for predicting the particle size of drug formulations with an easy and fast way, after proper training and testing.

Novel Coating Technologies of Drug Eluting Stents

In the last decade, drug eluting (DES) stent have been introduced as a useful tool in modern interventional cardiology. A wide variety of stent platforms are already in the market or under development undergoing clinical evaluation. The stent characteristics including stent design, coating strategies and pharmacological agents are related to different rates of restenosis. In this chapter we emphasise the current coating technologies employed for drug and delivery-vehicle material deposition onto the stent surface. A discussion about the existing platforms, recent developments and clinical outcomes is also included.

Polymeric coatings and their fabrication for medical devices

Biomaterials are classified as any foreign materials used in a biological setting whether they are metallic, ceramic, polymers, colloidal particles, or a combination. After introduction to the body or contact with biological materials outside the body, interactions can occur between proteins and the biomaterial. Coatings can either be passive providing an improved tissue interface or active to elute drugs which can control neointimal growth, restenosis, and inflammation which would narrow the lumen and may give rise to dangerous thrombi. This article covers the most important techniques and applications of a thin coating on medical devices.