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Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V


A number of intravenous immunoglobulin preparations are stabilized with sugar additives that may lead over time to undesirable glycation reactions especially in liquid formulation. This study aims to evaluate the reactivity of sugar excipients on such preparations in condition of temperature, formulation and concentration commonly used for pharmaceutical products. Through an innovative LC-MS method reported to characterize post-translational modifications of IgGs Fc/2 fragments, a stability study of IVIg formulated with reducing and non-reducing sugars has been undertaken. The rate of polyclonal IgGs glycation was investigated during 6 months at 5, 25, 30 and 40°C. High levels of glycation were observed with reducing sugars like glucose and maltose in the first months of the stability study from 25°C. Non-reducing sugars presented a low reactivity even at the highest tested temperature (40°C). Furthermore, a site by site analysis was performed by MS/MS to determine the glycation sites which were mainly identified at Lys246, Lys248 and Lys324. This work points out the high probability of glycation reactions in some commercialized products and describes a useful method to characterize IVIg glycated products issued from reducing sugar excipients.

Concepts: Immune system, Glucose, Posttranslational modification, Carbohydrate, Disaccharide, Fructose, Glycation, Sucrose


Laminar extrusion of wet masses was studied as a novel technology for the production of dosage forms for oral drug delivery. Extrusion was carried out with a ram extruder. Formulations contained either microcrystalline cellulose (MCC) or dicalcium phosphate (DCP) as diluent, hydroxypropyl methylcellulose (HPMC), lactose and water. Extrudates were characterized for their tensile strength, Young’s modulus of elasticity, water absorption, gel forming capacity and release of two model drugs, coumarin (COU) and propranolol hydrochloride (PRO). Cohesive extrudates could be produced with both filling materials (MCC and DCP) when HPMC was included as a binder at low amounts (3.3-4.5% w/w dry weight). Employing more HPMC, the elasticity of the wet masses increased which resulted in distinct surface defects. For MCC, the maximum HPMC amount that could be included in the formulations (15% w/w dry weight) did not affect the mechanical properties or decrease the drug release significantly. For DCP extrudates, the maximally effective HPMC amount was 30% (w/w dry weight) with influence on both the mechanical properties and drug release. This study suggests that laminar extrusion of wet masses is a feasible technique for the production of dosage forms for oral drug delivery.

Concepts: Pharmacology, Tensile strength, Cellulose, Methyl cellulose, Young's modulus, Elasticity, Elastic modulus, Stiffness


An electrostatic dry coating process based on a liquid pan coater was developed for enteric coating of tablets with Eudragit(®) L100-55. Two different liquid plasticizers of triethyl citrate (TEC) and PEG400 were used in the coating process. In contrast to TEC, PEG400 produced good powder adhesion and successful coating. DSC results showed that PEG 400 lowered the glass transition temperature (T(g)) of Eudragit(®) L100-55 to a greater extent than TEC at the same blend ratio, indicating that PEG400 was more effective in plasticizing the polymer. PEG 400 showed higher contact angle on both surfaces of tablet cores and coating powders as well as lower absorption into the tablet cores than TEC, suggesting that more PEG400 existed at the interface between tablet core and coating powders. The combination effects of higher plasticizing efficiency and more PEG400 available at the tablet surface produced higher plasticization of Eudragit(®) L100-55, leading to the successfully initial powder adhesion. The powder adhesion was further enhanced by the electrostatically assisted coating process, as confirmed by the higher coating level and coating efficiency with electrical charging (60 kV) than the ones without it (0 kV). The micrographs of scanning electron microscopy and in vitro drug release tests of the coated tablets showed that higher curing temperature and longer curing time led to enhanced film formation and acid resistance. The electrostatic dry coating process has been demonstrated to be a promising process for enteric coating of tablets.

Concepts: Electron, Pharmacology, Liquid, Differential scanning calorimetry, Scanning electron microscope, Glass transition, Coatings, Plasticizer


The objective of this study was to investigate the effect of polymeric microcarriers on the in-vivo intranasal uptake of an anti-migraine drug for brain targeting. Mucoadhesive powder formulations consisted of antimigraine drug, zolmitriptan, and chitosans (various molecular weights and types) or hydroxypropyl methylcellulose (HPMC). Their suitability for nasal administration was evaluated by in-vitro and ex-vivo mucoadhesion and permeation tests. The formulations based on chitosan glutamate (CG) or HPMC were tested in-vivo because they showed good mucoadhesive properties and altered the permeation rate of the drug. The in-vivo results from intravenous infusion and nasal aqueous suspension of the drug or nasal particulate powders were compared. The plasmatic AUC values obtained within 8 h following intravenous administration appeared about three times higher than those obtained by nasal administration, independent of the formulations. Zolmitriptan concentrations in the cerebrospinal fluid obtained from nasal and intravenous administrations were respectively 30 and 90 times lower than the concentrations of the drug in the blood. Thus, nasal administration potentiated the central zolmitriptan activity allowing a reduction of the drug peripheral levels, with respect to the intravenous administration. Among nasally administered formulations, CG microparticles showed the highest efficacy in promoting the central uptake of zolmitriptan within 1 h.

Concepts: Chemistry, Intravenous therapy, Cerebrospinal fluid, Route of administration, Methyl cellulose, Psychoactive drug, Hypromellose, Bolus


A novel antioxidant regenerating system consisting of cellobiose dehydrogenase (CDH), cellobiose and phenolic antioxidants with potential application for continuous quenching of free radical species in chronic wounds was developed. This antioxidant regenerating system, continuously quenched in situ produced .NO, O(2)(•-) and OH(•) radicals and the produced oxidized phenolic antioxidants were regenerated back to their original parent compounds by CDH using cellobiose as electron donor. This system therefore prevented the accumulation of oxidized phenolic antioxidants. Interestingly, this study also challenges the relevance of using total antioxidant capacities values of plant crude extracts obtained using biologically none relevant radical species like (2,2-diphenyl-1-picrylhydrazyl (DPPH), Trolox Equivalent Antioxidant Capacity (TEAC) etc. when applied as medicinal remedies. This is because methoxylated phenolic antioxidants like sinapic acid, ferulic acid; 2,6-dimethoxyphenol readily donate their electrons to these radicals (DPPH, TEAC etc.) thereby greatly influencing the total antioxidant values although this study showed that they are not at all effective in quenching O(2)(•-) radicals and again are not the most effective quenchers of .NO and OH(•) radicals as demonstrated during this study.

Concepts: Atherosclerosis, Oxidative stress, Radical, Vitamin C, Nitric oxide, Free-radical theory, Matrix-assisted laser desorption/ionization, Oxygen radical absorbance capacity


A method based on a double emulsion system (solid-in-water-in-oil-in-water) has been developed for the production of nanoparticles-in-microparticles (NIMs). The distribution of nanoparticles within the NIMs was explored using light and electron microscopy and through assessment of drug loading and release profiles. The extent of nanoparticle entrapment within the NIMs was found to be dependent on the state (wet vs. dry) in which the nanoparticles were introduced to the formulation. The technique was readily adaptable to produce NIMs of different morphologies. It is proposed that NIMs and this method to produce them have broad application in drug delivery research.

Concepts: Electron, Nanoparticle, Colloid, Gold, Scanning tunneling microscope, State, Distribution of wealth, The Technique


The purpose of this study was to develop novel dissolving microneedle arrays fabricated from hyaluronic acid (HA) as a material and to improve the transdermal permeability of relatively high molecular weight drugs. In this study, fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4 kDa (FD4) was used as a model drug with a relatively high molecular weight. The microneedle arrays significantly increased transepidermal water loss (TEWL) and reduced transcutaneous electrical resistance (TER), indicating that they could puncture the skin and create drug permeation pathways successfully. Both TEWL and TER almost recovered to baseline levels in the microneedle array group, and relatively small pathways created by the microneedles rapidly recovered as compared with those created by a tape stripping treatment. These findings confirmed that the microneedle arrays were quite safe. Furthermore, we found that the transdermal permeability of FD4 using the microneedle arrays was much higher than that of the FD4 solution. Furthermore, we found that the microneedle arrays were much more effective for increasing the amount of FD4 accumulated in the skin. These findings indicated that using novel microneedle arrays fabricated from HA is a very useful and effective strategy to improve the transdermal delivery of drugs, especially relatively high molecular weight drugs without seriously damaging the skin.

Concepts: Pharmacology, Molecule, Drug, Mass, Array, Atomic mass unit, Molecular mass


Nanofibrillar cellulose (NFC) (also referred to as cellulose nanofibers, nanocellulose, microfibrillated, or nanofibrillated cellulose) has recently gotten wide attention in various research areas and it has also been studied as excipient in formulation of the pharmaceutical dosage forms. Here, we have evaluated the interactions between NFC and the model drugs of different structural characteristics (size, charge, etc.). The series of permeation studies were utilized to evaluate the ability of the drugs in solution to diffuse through the thin, porous, dry NFC films. An incubation method was used to determine capacity of binding of chosen model drugs to NFC as well as isothermal titration calorimetry (ITC) to study thermodynamics of the binding process. A genetically engineered fusion protein carrying double cellulose binding domain was used as a positive control since its affinity and capacity of binding for NFC have already been reported. The permeation studies revealed the size dependent diffusion rate of the model drugs through the NFC films. The results of both, binding and ITC studies showed that the studied drugs bind to the NFC material and indicated the pH dependence of the binding and electrostatic forces as the main mechanism.

Concepts: Pharmacology, Electric charge, Fundamental physics concepts, Drug, Thermodynamics, Molecular diffusion, Diffusion, Cultural studies


DSC thermograms of solid state pure proteins often show a distinct endotherm at a temperature far below the glass transition temperature of the system (Tg). We hypothesized this endotherm represents enthalpy recovery associated with an internal mobility transition of the protein molecule. Although the existence of an internal transition has been postulated, whether this endotherm is associated with such a transition has not previously been discussed. The purpose of this study was to investigate the origin of the pre-Tg endotherm in lyophilized bovine serum albumin (BSA). Due to strong glass behavior, the system Tg was determined by extrapolating Tg data of disaccharide/BSA formulations to zero saccharide. A small pre-Tg endotherm around 40-60°C was observed in amorphous BSA equilibrated at 11%RH. The apparent activation energy suggested the endotherm was “α-mobility”-related. A solid state hydrogen/deuterium exchange study using FTIR was conducted over a temperature range spanning the endotherm. We found a fast phase, followed by essentially a plateau level which is highly temperature dependent in the 40-60°C range, suggesting enhanced internal protein motion as the system passes through the temperature range of the endotherm. These results suggest the pre-Tg endotherm is associated with a protein internal mobility transition.

Concepts: Proteins, Temperature, Thermodynamics, Serum albumin, Liquid, Glass, Glass transition, Amorphous solid


Hot-melt extrusion is gaining importance for the production of amorphous solid solutions; in parallel, predictive tools for estimating drug solubility in polymers are increasingly demanded. The Hansen solubility parameter (SP) approach is well acknowledged for its predictive power of the miscibility of liquids as well as the solubility of some amorphous solids in liquid solvents. By solely using the molecular structure, group contribution (GC) methods allow the calculation of Hansen SPs. The GC parameter sets available were derived from liquids and polymers which conflicts with the object of prediction, the solubility of solid drugs. The present study takes a step from the liquid based SPs towards their application to solid solutes. On the basis of published experimental Hansen SPs of solid drugs and excipients only, a new GC parameter set was developed. In comparison to established parameter sets by van Krevelen/Hoftyzer, Beerbower/Hansen, Breitkreutz and Stefanis/Panayiotou, the new GC parameter set provides the highest overall predictive power for solubility experiments (correlation coefficient r=-0.87 to -0.91) as well as for literature data on melt extrudates and casted films (r=-0.78 to -0.96).

Concepts: Solubility, Solid, Viscosity, Liquid, Glass, Glass transition, Phases of matter, Amorphous solid