Evangelos Karavas

Miscibility Behavior and Formation Mechanism of Stabilized Felodipine-Polyvinylpyrrolidone Amorphous Solid Dispersions

In the present study, solid dispersion systems of felodipine (FEL) with polyvinylpyrrolidone (PVP) were developed, in order to enhance solid state stability and release kinetics. The prepared systems were characterized by using Differential Scanning Calorimetry, X-Ray Diffraction, and Scanning Electron Microscopy techniques, while the interactions which take place were identified by using Fourier Transformation-Infrared Spectroscopy. Due to the formation of hydrogen bonds between the carbonyl group of PVP and the amino groups of FEL, transition of FEL from crystalline to amorphous state was achieved. The dispersion of FEL was found to be in nano-scale particle sizes and dependent on the FEL/PVP ratio. This modification leads to partial miscibility of the two components, as it was verified by DSC and optimal glass dispersion of FEL into the polymer matrix since no crystalline structure was detected with XRD. The above deformation has a significant effect on the dissolution enhancement and the release kinetics of FEL, as it causes the pattern to change from linear to logarithmic. An impressive optimization of the dissolution profile is observed corresponding to a rapid release of FEL in the system containing 10% w/w of FEL, releasing 100% in approximately 20 min. The particle size of dispersed FEL into PVP matrix could be classified as the main parameter affecting dissolution optimization. The mechanism of such enhancement consists of the lower energy required for the dissolution due to the amorphous transition and the fine dispersion, which leads to an optimal contact surface of the drug substance with the dissolution media. The prepared systems are stable during storage at 40 ± 1°C and relative humidity of 75 ± 5%. Addition of sodium docusate as surfactant does not affect the release kinetics, but only the initial burst due to its effect on the surface tension and wettability of the systems.

Optimizing the ability of PVP/PEG mixtures to be used as appropriate carriers for the preparation of drug solid dispersions by melt mixing technique using artificial neural networks: I

In the present study, the efficiency of PVP/PEG200 mixtures as appropriate carries for the preparation of solid dispersions by melt mixing was evaluated. Felodipine (FELO) was used as a poorly water soluble model drug. The effect of several melt mixing parameters, (PVP/PEG ratio, time and temperature of melt mixing, and drug content), on the physical state of FELO and the dissolution characteristics of the dispersions were investigated. DSC, XRD, and SEM analysis revealed that in all cases, amorphous drug nanodispersions were prepared. This was attributed to the increased miscibility of the PVP-FELO system, induced by the presence of PEG200, which acted as plasticizer. FT-IR analysis showed hydrogen bonding between FELO (NH) and the PVP carrier (CO). The release rate of the drug depends mainly on the drug content and is higher in solid dispersions with low drug content and ratio of carrier to plasticizer (PVP/PEG200). The melt mixing variations (time and temperature of mixing) had lower impact on FELO release rate. Finally, artificial neural networks, used to correlate the examined formulation and process variables of hot melt mixing with dissolution parameters, showed good prediction ability.

Nanoencapsulation of a water soluble drug in biocompatible polyesters. Effect of polyesters melting point and glass transition temperature on drug release behavior

Five polyesters based on 1,3-propanediol or ethylene glycol and an aliphatic dicarboxylic acid were used for the preparation of Ropinirole HCl-loaded nanoparticles. The advantage of the present study is that the used polyesters - as well as poly(lactic acid) (PLA) - have similar degree of crystallinity but different melting points, varying from 46.7 to 166.4°C. Based on polymer toxicity on HUVEC, the biocompatibility of these aliphatic polyesters was found comparable to that of PLA and thus the studied polyesters could be used as drug carriers. Drug encapsulation in polyesters was performed via emulsification/solvent evaporation method. Particle size of drug-loaded nanoparticles was between 140 and 190 nm, as measured by light scattering. Drug loading content for all the polyesters varies between 10 and 16% and their entrapment efficiency is relatively high (32-48%). WAXD patterns of nanoparticles show that Ropinirole HCl lies in amorphous state within polymer matrices. Drug release diagrams reveal that the higher percentage of Ropinirole HCl is released during the first 6h after its insertion in the dissolution medium. Fast release rates of the drug are attributed to high hydrophilicity of Ropinirole HCl. Melting point (T(m)) and glass transition temperature (T(g)) of the host polymer matrices seem to be important parameters, since higher drug release rates are observed in polyesters with low T(m) and T(g).

Surface Modified Multifunctional and Stimuli Responsive Nanoparticles for Drug Targeting: Current Status and Uses.

Nanocarriers, due to their unique features, are of increased interest among researchers working with pharmaceutical formulations. Polymeric nanoparticles and nanocapsules, involving non-toxic biodegradable polymers, liposomes, solid lipid nanoparticles, and inorganic–organic nanomaterials, are among the most used carriers for drugs for a broad spectrum of targeted diseases. In fact, oral, injectable, transdermal-dermal and ocular formulations mainly consist of the aforementioned nanomaterials demonstrating promising characteristics such as long circulation, specific targeting, high drug loading capacity, enhanced intracellular penetration, and so on. Over the last decade, huge advances in the development of novel, safer and less toxic nanocarriers with amended properties have been made. In addition, multifunctional nanocarriers combining chemical substances, vitamins and peptides via coupling chemistry, inorganic particles coated by biocompatible materials seem to play a key role considering that functionalization can enhance characteristics such as biocompatibility, targetability, environmental friendliness, and intracellular penetration while also have limited side effects. This review aims to summarize the “state of the art” of drug delivery carriers in nanosize, paying attention to their surface functionalization with ligands and other small or polymeric compounds so as to upgrade active and passive targeting, different release patterns as well as cell targeting and stimuli responsibility. Lastly, future aspects and potential uses of nanoparticulated drug systems are outlined.

Novel Biodegradable Polyesters. Synthesis and Application as Drug Carriers for the Preparation of Raloxifene HCl Loaded Nanoparticles

Raloxifene HCl is a drug with poor bioavailability and poor water solubility. Furthermore nο pharmaceutically acceptable organic solvent has been reported before to dilute the drug. It was observed that Raloxifene HCl can be diluted in a solvent mixture of acetone/water or ethanol/water. The aim of this study was to use biodegradable polymers in order to prepare Raloxifene HCl nanoparticles. For this purpose a series of novel biodegradable poly(ethylene succinate-co-propylene adipate) P(ESu-co-PAd) polyesters were synthesized following the polycondensation method and further, poly(ethylene succinate) (PESu) and poly(propylene adipate) (PPAd) were used. The prepared polyesters were characterized by intrinsic viscosity measurements, end group analysis, enzymatic hydrolysis, Nuclear Magnetic Resonance Spectroscopy (1Η-NMR and 13C-NMR) and Wide-angle X-ray Diffractometry (WAXD). The drug nanoparticles have been prepared by a variation of the co-precipitation method and were studied by Wide-angle X-ray Diffractometry (WAXD), FTIR spectrometry, light scattering size distribution, Scanning Electron Microscopy (SEM) and release behavior measurements. The interactions between the polymers and the drug seem to be limited, so the drug occurs in crystalline form in all nanoparticles. The size of the nanoparticles seems to be in the range of 150-350 nm, depending on the polymer that was used. The drug release depends on the melting point and degree of crystallinity of the polyesters used. An initial high release rate was recorded followed by very slow rates of controlled release.

Recent advances in oral pulsatile drug delivery.

Pulsatile drug delivery aims to release drugs on a programmed pattern i.e.: at appropriate time and/or at appropriate site of action. Currently, it is gaining increasing attention as it offers a more sophisticated approach to the traditional sustained drug delivery i.e: a constant amount of drug released per unit time or constant blood levels. Technically, pulsatile drug delivery systems administered via the oral route could be divided into two distinct types, the time controlled delivery systems and the site-specific delivery systems. The simplest pulsatile formulation is a two layer press coated tablet consisted of polymers with different dissolution rates. Homogenicity of the coated barrier is mandatory in order to assure the predictability of the lag time. The disadvantage of such formulation is that the rupture time cannot be always adequately manipulated as it is strongly correlated with the physicochemical properties of the polymer. Gastric retentive systems, systems where the drug is released following a programmed lag phase, chronopharmaceutical drug delivery systems matching human circadian rhythms, multiunit or multilayer systems with various combinations of immediate and sustained-release preparation, are all classified under pulsatile drug delivery systems. On the other hand, site-controlled release is usually controlled by factors such as the pH of the target site, the enzymes present in the intestinal tract and the transit time/pressure of various parts of the intestine. In this review, recent patents on pulsatile drug delivery of oral dosage forms are summarized and discussed.

Hydrophilic matrices as carriers in felodipine solid dispersion systems

Hydrophilic matrices or hydrocolloids are polymers which swell on contact with aqueous solutions and dissolve slowly from the surface forming a gel mass. Several studies have been carried out in the past few years on the use of hydro-colloids in controlled release formulations. The present study used three modified celluloses, carboxymethyl cellulose sodium, hydroxyethyl cellulose (HEC), and hydroxypro-pylmethyl cellulose (HPMC) in systems using the dihydropyridine felodipine, which is slightly soluble in water, as the active ingredient. This study was concerned with solid dispersions, which were prepared following the dissolution method using a common solvent. The drug—polymer interactions were studied using differential scanning calorimetry and IR techniques, as well as high-performance liquid Chromatographic purity after storage in strength conditions. Neither significant interactions nor degradation of the active ingredient was observed after storage at 40 °C for 3 months. In addition, felodipine release from the solid dispersion systems was studied and the factors influencing release, such as the drug—polymer ratio, interactions, and polymer properties were investigated. HPMC was observed to promote a more significant retard and a more linear release of the active ingredient than HEC. Finally, the natural mixtures presented a larger variation and high relative standard deviation values.

Evaluating the effects of crystallinity in new biocompatible polyester nanocarriers on drug release behavior.

Four new polyesters based on 1,3-propanediol and different aliphatic dicarboxylic acids were used to prepare ropinirole HCl-loaded nanoparticles. The novelty of this study lies in the use of polyesters with similar melting points but different degrees of crystallinity, varying from 29.8% to 67.5%, as drug nanocarriers. Based on their toxicity to human umbilical vein endothelial cells, these aliphatic polyesters were found to have cytotoxicity similar to that of polylactic acid and so may be considered as prominent drug nanocarriers. Drug encapsulation in polyesters was performed via an emulsification/solvent evaporation method. The mean particle size of drug-loaded nanoparticles was 164–228 nm, and the drug loading content was 16%–23%. Wide angle X-ray diffraction patterns showed that ropinirole HCl existed in an amorphous state within the nanoparticle polymer matrices. Drug release diagrams revealed a burst effect for ropinirole HCl in the first 6 hours, probably due to release of drug located on the nanoparticle surface, followed by slower release. The degree of crystallinity of the host polymer matrix seemed to be an important parameter, because higher drug release rates were observed in polyesters with a low degree of crystallinity.

Improvement in chemical and physical stability of fluvastatin drug through hydrogen bonding interactions with different polymer matrices.

Solid dispersions of Fluvastatin with polyvinylpyrrolidone (PVP), eudragit RS100 (Eud), and chitosan (CS) as drug carrier matrices, were prepared using different techniques in order to evaluate their effect on Fluvastatin stability during storage. The characterization of the three different systems was performed with the use of differential scanning calorimetry (DSC) and wide angle X-ray diffractometry (WAXD). It was revealed that amorphization of the drug occurred in all of the solid dispersions of Fluvastatin as a result of drug dissolution into polymer matrices and due to physical interactions (hydrogen bonding) between the polymer matrix and Fluvastatin. This was established through the use of FTIR spectroscopy. SEM and micro-Raman spectroscopy showed that Fluvastatin was interspersed to the polymer matrices in the form of molecular dispersion and nanodispersion, too. The finding that completely different polymer matrices, used here as drug carriers, produce completely different dissolution profiles for each one of the solid dispersions, suggests that each matrix follows a different drug release mechanism. Hydrogen bonding interactions as in the case of CS/Fluva solid dispersions lead to controlled release profiles. All formulations were subjected to accelerated aging in order to evaluate Fluvastatin stability. From by-products analysis it was found that Fluvastatin is very unstable during storage and anti-isomer as well as lactones are the main formed by-products. On the other hand, solid dispersions due to the evolved interactions of their reactive groups with Fluvastatin provide a sufficient physical and chemical stability. The extent of interactions seems to play the most important role in the drug stabilization.

Chitosan derivatives as effective nanocarriers for ocular release of timolol drug.

The aim of the present study was to evaluate the effectiveness of neat chitosan (CS) and its derivatives with succinic anhydride (CSUC) and 2-carboxybenzaldehyde (CBCS) as appropriate nanocarriers for ocular release of timolol maleate (Tim). Drug nanoencapsulation was performed via ionic crosslinking gelation of the used carriers and sodium tripolyphosphate (TPP). Nanoparticles with size ranged from about 190 to 525 nm were prepared and it was found that the formed size was directly depended on the used carrier and their ratios with TPP. For CS derivatives it was found that as the amount of TPP increased, the particle size increased too, while both derivatives proceeded to nanoparticles with smaller size than that of neat CS. The interactions between carriers and TPP were studied theoretically using all-electron calculations within the framework of density functional theory (DFT). In most of nanoparticles formulations, Tim was entrapped in amorphous form, while the drug entrapment efficiency was higher in CBCS derivative.It was indicated that Tim release rate depended mainly on the used carrier, particle size of prepared nanocarriers and drug loading. From the theoretical release data analysis, it was found that the Tim release was a stagewise procedure with drug diffusion being the dominant release mechanism for each stage.