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


Lipid-based formulations have established a significant role in the formulation of poorly soluble drugs for oral administration. In order to better understand their potential advantages over solid oral dosage forms, we studied the solubility and dissolution/precipitation characteristics of three self-microemulsifying drug delivery system (SMEDDS) formulations and one suspension of micronized fenofibrate in lipid excipients, for which pharmacokinetic studies had already been reported in the open literature. The in vitro dispersion/dissolution studies were carried out in biorelevant media using USP II apparatus. These were followed up by in silico simulations using STELLA(®) software, in which not only dispersion/dissolution, but also the precipitation and re-dissolution of fenofibrate was taken into account. While unformulated drug exhibited poor solubility (0.22 μg/mL in FaSSGF and 4.31 μg/mL in FaSSIF-V2(PO4)) and dissolved less than 2% in dissolution tests, the solubility of fenofibrate in the presence of the lipid excipients increased dramatically (e.g. to 65.44 μg/mL in the presence of the Myritol 318 / TPGS / Tween 80 SMEDDS) and there was an attendant increase in the dissolution (over 80% from capsules containing the Myritol 318 / TPGS / Tween 80 SMEDDS and about 20% from the dispersion of fenofibrate in lipid excipients). For the four lipid-based fenofibrate formulations studied, combining in vitro data in biorelevant media with in silico simulation resulted in accurate prediction of the in vivo human plasma profiles. The point estimates of Cmax and AUC ratio calculated from the in silico and in vivo plasma profiles fell within the 0.8-1.25 range for the SMEDDS solution and capsule formulations, suggesting an accurate simulation of the in vivo profiles. This similarity was confirmed by calculation of the respective f2 factors. Sensitivity analysis of the simulation profiles revealed that the SMEDDS formulations had virtually removed any dependency of absorption on the dissolution rate in the small intestine, whereas for the dispersion in lipid excipients this barrier remained. Such results pave the way to optimizing the performance of oral lipid-based formulations via an in vitro - in silico - in vivo approach.

Concepts: Pharmacokinetics, Solvation, Biopharmaceutics Classification System, In vivo, In vitro, Pharmacology


Polymeric nanoparticles have tremendous potential either as carriers or markers in treatment of diseases or diagnostics in biomedical applications. Finding the optimal conditions for effective intracellular delivery of the payload to the place of interest is still a big challenge. The particles have to overcome the cell membrane representing a barrier. Here, we investigated the uptake in HeLa cells of fluorescent polystyrene particles with different size and surface charge. Particles stabilized with the non-ionic surfactant Lutensol AT50® (132 nm, 180 nm, 242 nm, 816 nm, 846 nm) were synthesized via dispersion polymerization. Cationic particles (120 nm, 208 nm, 267 nm, 603 nm) were obtained by a combination of miniemulsion and seed dispersion polymerization using cationic surfactant (cetyltrimethylammonium chloride (CTMA-Cl). The particle uptake into HeLa cells was studied by confocal laser scanning microscopy and flow cytometry. Non-ionic particles were - independent of their size - taken up by cells only at a barely detectable level thus aggravating a quantitative comparison. The uptake of positively charged particles was substantially higher and therefore further investigation keeping constant one of these parameters: either material amount or particles number or total interaction surface area. It was found that the uptake rather depends on the total amount of polymeric material present in the media than on the number of particles. The total particle’s surface area does not correlate linearly with the uptake, thus indicating that there is no direct dependency between the total surface area and the cellular endocytotic process to overcome the biobarrier “cell membrane”. A new uptake mechanism is found which can be described as an excavator shovel like mechanism. It is a kind of macropinocytosis dependent on actin filaments as well as dynamin, but is clathrin-independent.

Concepts: Emulsion, Cell, Electric charge, Endocytosis, Protein, Cell biology, Surfactant, Cell membrane


A novel model of infected nail plate for testing the efficacy of topical antifungal formulations has been developed. This model utilized keratin film made of human hair keratin as a nail plate model. Subsequent to infection by T. rubrum, the common causative agent of onychomycosis, keratin films as infected nail plate models were treated with selected topical formulations, i.e., cream, gel and nail lacquer. Bovine hoof was compared to keratin film. In contrast to the common antifungal susceptibility test, the antifungal drugs tested were applied as ready-to-use formulations because the vehicle may modify and control the drug action both in vitro and in vivo. Extrapolating the potency of an antifungal drug from an in vitro susceptibility test only would not be representative of the in vivo situation since these drugs are applied as ready-to-use formulations, e.g., as a nail lacquer. Although terbinafine has been acknowledged to be the most effective antifungal agent against T. rubrum, its antifungal efficacy was improved by its incorporation into an optimal formulation. Different gels proved superior to cream. Therefore, this study is able to discriminate between efficacies of different topical antifungal formulations based on their activities against T. rubrum.

Concepts: Keratin, Ketoconazole, Antifungals, Griseofulvin, Antifungal drug, Onychomycosis, Ringworm, Athlete's foot


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


PURPOSE: In the present study we evaluated a novel processing technique for the continuous production of hotmelt extruded controlled release matrix systems. A cutting technique derived from plastics industry, where it is widely used for cutting of cables and wires was adapted into the production line. Extruded strands were shaped by a rotary-fly cutter. Special focus is laid on the development of a process analytical technology by evaluating signals obtained from the servo control of the rotary fly cutter. The intention is to provide a better insight into the production process and to offer the ability to detect small variations in process-variables. MATERIALS AND METHODS: A co-rotating twin-screw extruder ZSE 27 HP-PH from Leistritz (Nürnberg, Germany) was used to plasticize the starch; critical extrusion parameters were recorded. Still elastic strands were shaped by a rotary fly-cutter type Dynamat 20 from Metzner (Neu-Ulm, Germany). Properties of the final products were analyzed via digital image analysis to point out critical parameters influencing the quality. Important aspects were uniformity of diameter, height, roundness, weight and variations in the cutting angle. Stability of the products was measured by friability tests and by determining the crushing strength of the final products. Drug loading studies up to 70% were performed to evaluate the capacity of the matrix and to prove the technological feasibility. Changes in viscosities during API addition were analyzed by a Haake Minilab capillary rheometer. X-ray studies were performed to investigate molecular structures of the matrices. RESULTS: External shapes of the products were highly affected by die-swelling of the melt. Reliable reproducibility concerning uniformity of mass could be achieved even for high production rates (>2500 cuts/min). Both mechanical strength and die swelling of the products could be linked to the ratio of amylose to amylopectin. Formulations containing up to 70% of API could still be processed. Viscosity measurements revealed the plasticizing effect caused by API addition. Dissolution data proved the suitability of extruded starch matrices as a sustained release dosage form. Monitoring of consumed energies during the cutting process could be linked to changes in viscosity. The established PAT system enables the detection of small variations in material properties and can be an important tool to further improve process stability.

Concepts: Starch gelatinization, Industry, Compressive strength, Rheometer, Work hardening, Extrusion, Viscosity, Strength of materials


The present study was conducted to examine the feasibility of nimodipine loaded PLGA microparticles suspended in Tisseel(™) fibrin sealant as an in situ forming depot system. This device locally placed can be used for the treatment of vasospasm after a subarachnoid hemorrhage. Microparticles were prepared via spray drying by using the vibration mesh spray technology of Nano Spray Dryer B-90. Spherically shaped microparticles with different loadings and high encapsulation efficiencies of 93.3% to 97.8% were obtained. Depending on nimodipine loading (10% - 40%) the particle diameter ranged from 1.9 ± 1.2 μm to 2.4 ± 1.3μm. Thermal analyses using DSC revealed that Nimodipine is dissolved in the PLGA matrix. Also fluorescent dye loaded microparticles were encapsulated in Tisseel(™) to examine the homogeneity of particles. 3D-pictures of the in situ forming devices displayed uniform particle homogeneity in the sealant matrix. Drug release was examined by fluorescence spectrophotometry which demonstrated a drug release proportional to the square root of time. A prolonged drug release of 19.5 h was demonstrated under in vitro conditions. Overall, the Nimodipine in situ forming device could be a promising candidate for the local treatment of vasospasm after a subarachnoid hemorrhage.

Concepts: Scientific method, In situ, Vasospasm, Spray nozzle, Nano spray dryer, In vitro, Spray drying, Subarachnoid hemorrhage


Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have been recognized, among the large number of non-viral vectors for gene transfection, as an effective and safety alternative to potentially treat both genetic and not genetic diseases. A key feature is the possibility to be designed to overcome the numerous challenges for successful gene delivery. Lipid nanoparticles (LNs) are able to overcome the main biological barriers for cell transfection, including degradation by nucleases, cell internalization intracellular trafficking, and selectively targeting to a specific cell type. Additionally, they present important advantages: from a safety point of view LNs are prepared with well tolerated components, and from a technological point of view, they can be easily produced at large-scale, can be subjected to sterilization and lyophilisation, and have shown good storage stability. This review focuses on the potential of SLNs and NLCs for gene therapy, including the main advances in their application for the treatment of ocular diseases, infectious diseases, lysosomal storage disorders and cancer, and current research for their future clinical application.

Concepts: Genetic disorder, DNA, Disease, Gene, Cancer, Molecular biology, Genetics, Cell


Transdermal protein delivery is a useful and attractive method for protein therapy and dermal vaccination. However, this delivery method is restricted by the low permeability of the stratum corneum. The purpose of this study was to develop a transdermal delivery system for enhancement of protein permeability into the skin. First, we prepared a transparent gel patch made of polysaccharides with gold nanorods on the gel surface and fluorescein isothiocyanate-modified ovalbumin (FITC-OVA) inside. Next, the gel patch was placed on mouse skin to allow contact with the coated gold nanorods, and irradiated by a continuous-wave laser. The laser irradiation heated the gold nanorods and the skin temperature increased to 43°C, resulting in enhanced translocation of FITC-OVA into the skin. These results confirmed the capability of the transdermal protein delivery system to perforate the stratum corneum and thus facilitate the passage of proteins across the skin.

Concepts: Polysaccharide, Polymer, Gel electrophoresis, Egg white, Epidermis, Keratin, Skin, Protein


Transdermal drug delivery is an attractive route of drug administration, however there are relatively few marketed transdermal products. To increase delivery across the skin, strategies to enhance skin permeability are widely investigated, with microneedles demonstrating particular promise. Hydrogel-forming microneedles are inserted into the skin, and following dissolution of a drug loaded reservoir and movement of the drug through the created channels, the microneedle array is removed intact, and can then be readily and safely discarded. This study presents the formulation and evaluation of an integrated microneedle patch containing the Alzheimer’s drug, donepezil hydrochloride. The integrated patch consisted of hydrogel-forming microneedles in combination with a donepezil hydrochloride containing film. Formulation and characterisation of plasticised films, prepared from poly(vinylpyrrolidone) or poly (methyl vinyl ether co-maleic anhydride/acid) (Gantrez(®)) polymers, is presented. Furthermore, in vitro permeation of donepezil hydrochloride across neonatal porcine skin from the patches was investigated, with 854.71 μg ± 122.71 μg donepezil hydrochloride delivered after 24 h, using the optimum patch formulation. Following administration of the patch to an animal model, plasma concentrations of 51.8 ± 17.6 ng/mL were obtained, demonstrating the success of this delivery platform for donepezil hydrochloride.

Concepts: Acetylcholine, Alzheimer's disease


Monoclonal antibody and Fc fusion protein drugs are complex heterogeneous mixtures of numerous different protein variants and modifications. N-glycosylation as one of the most complex post-translational modification influences the structural characteristics of the antibodies Fc part thereby potentially modulating effector function and pharmacokinetics. Several investigations on the relationship between N-glycosylation and pharmacokinetics have been published. However, this structure - function relationship is not fully understood. In this review potential alterations with focus on N-glycosylation of mAbs and Fc fusion proteins and the possible effects on the pharmacokinetics are reviewed and the current understandings of the underlying mechanisms are described.

Concepts: Amino acid, Immune system, Immunohistochemistry, Structure, Monoclonal antibodies, Protein