SciCombinator

Discover the most talked about and latest scientific content & concepts.

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

2

Adequate treatment of Parkinson’s patients in off periods with orally administered levodopa is hindered by a poor bioavailability and a slow onset of action. Hence, there is a need for a fast and reliable alternative as for instance via pulmonary administration of the drug. We developed a levodopa containing powder formulation for pulmonary delivery by a recently presented high dose dry powder inhaler (Cyclops). The objective was to produce the drug formulation by means of simple techniques such as micronisation, either as pure active substance or with a minimum amount of excipients. After an initial screening on dispersion behaviour, the most promising formulation in the Cyclops was characterised in vitro over a range of pressure drops (2 - 6 kPa) and doses (20, 30 and 40 mg), representative of those to be expected in practice. A co-micronised levodopa formulation with 2% l-leucine appeared to yield the best aerosol properties for inhalation and highest delivered dose reproducibility. The combination of this particular formulation and the Cyclops inhaler seems to meet the basic requirements for satisfactory deposition in the airways. This formulation is therefore expected to be a promising candidate for the treatment of Parkinson’s patients in an off period.

Concepts: Carbidopa, Period, Dose, Parkinson's disease, Neurotransmitter, Dopamine, Pharmacology, Dosage forms

1

Central nervous system (CNS) disorders (e.g., multiple sclerosis, Alzheimer’s disease, etc.) represent a growing public health issue, primarily due to the increased life expectancy and the aging population. The treatment of such disorders is notably elaborate and requires the delivery of therapeutics to the brain in appropriate amounts to elicit a pharmacological response. However, despite the major advances both in neuroscience and drug delivery research, the administration of drugs to the CNS still remains elusive. It is commonly accepted that effectiveness-related issues arise due to the inability of parenterally administered macromolecules to cross the Blood-Brain Barrier (BBB) in order to access the CNS, thus impeding their successful delivery to brain tissues. As a result, the direct Nose-to-Brain delivery has emerged as a powerful strategy to circumvent the BBB and deliver drugs to the brain. The present review article attempts to highlight the different experimental and computational approaches pursued so far to attain and enhance the direct delivery of therapeutic agents to the brain and shed some light on the underlying mechanisms involved in the pathogenesis and treatment of neurological disorders.

1

Vaccination is the most effective method to prevent influenza infection. However, current influenza vaccines have several limitations. Relatively long production times, limited vaccine capacity, moderate efficacy in certain populations and lack of cross-reactivity are important issues that need to be addressed. We give an overview of the current status and novel developments in the landscape of influenza vaccines from an interdisciplinary point of view. The feasibility of novel vaccine concepts not only depends on immunological or clinical outcomes, but also depends on biotechnological aspects, such as formulation and production methods, which are frequently overlooked. Furthermore, the next generation of influenza vaccines is addressed, which hopefully will bring cross-reactive influenza vaccines. These developments indicate that an exciting future lies ahead in the influenza vaccine field.

Concepts: Biotechnology, Pneumonia, Immune system, Vaccination, Influenza vaccine, Influenza, Vaccine

1

Nutrition rich in carotenoids is well known to prevent cell damage, premature skin aging and skin cancer. Cutaneous carotenoids can be enriched in the skin by nutrition and topically applied antioxidants have shown an increase in radical protection after VIS/NIR irradiation. In this paper it was investigated whether orally administered carotenoids increase the radical scavenging activity and the radical protection of the skin using in vivo electron paramagnetic resonance spectroscopy and the skin lipid profile was investigated applying HPTLC on skin lipid extracts. Furthermore, in vivo Raman resonance spectroscopy was used to measure the cutaneous carotenoid concentration. A double blind placebo controlled clinical study was performed with 24 healthy volunteers, who have shown a slow but significant and effective increase of cutaneous carotenoids in the verum group. The enhancement in carotenoids increases the radical scavenging activity of the skin and provides a significant protection against stress induced radical formation. Furthermore, the skin lipids in the verum group increased compared to the placebo group but only significantly for ceramide [NS]. These results indicate that a supplementation with dietary products containing carotenoids in physiological concentrations can protect the skin against reactive oxygen species and could avoid premature skin aging and other radical associated skin diseases.

Concepts: Fat, Protein, Reactive oxygen species, Oxygen, Oxidative phosphorylation, Skin, Electron paramagnetic resonance, Antioxidant

0

Gelatin and bovine serum albumin (BSA), two readily available biopolymers, were examined for their effect on solubility and supersaturation of drugs because of their capacity to interact with drugs (e.g. via hydrogen bonding, van der Waals or electrostatic interactions, etc.). Carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen were selected accordingly as twelve structurally different model BCS Class II drugs. All selected drugs were evaluated for solubility and supersaturation in presence and absence of these two biopolymers in four media (purified water, FaSSIF, FaSSGF and FeSSIF) by means of the shake flask method for 48h and solvent shift induced supersaturation, respectively. In ca. 75% of the supersaturation experiments with these two biopolymers, drug concentrations significantly different (p > 0.05) from solubility were observed with supersaturation factors (SF) varying between 1.28 and 7.89 (p ≤ 0.05) and between 1.16 and 20.51 (p ≤ 0.01). In order to make an estimation on the relevance of these results, a comparison with three commonly used (semi-) synthetic polymers (HPMC, PVP and PVPVA) was included in purified water. This showed that both biopolymers were at least as efficient as the (semi-) synthetic polymers in sustaining induced supersaturation as in ten out of twelve API comparable results were obtained.

0

Vaccine thermostability is key to successful global immunization programs as it may have a significant impact on the continuous cold-chain maintenance logistics, as well as affect vaccine potency. Modern biological and biophysical techniques were combined to in-depth characterize the thermostability of a formulated rabies virus (RABV) in terms of antigenic and genomic titer, virus particle count and aggregation state. Tunable resistive pulse sensing (TRPS) and nanoparticle tracking analysis (NTA) were used to count virus particles while simultaneously determining their size distribution. RABV antigenicity was assessed by NTA using a monoclonal antibody that recognize a rabies glycoprotein (G protein) conformational epitope, enabling to specifically count antigenic rabies viruses. Agreement between antigenicity results from NTA and conventional method, as ELISA, was demonstrated. Additionally, NTA and ELISA showed mirrored loss of RABV antigenicity during forced degradation studies performed between 5°C and 45°C temperature exposure for one month. Concomitant with decreased antigenicity, emergence of RABV particle populations larger than those expected for rabies family viruses was observed, suggesting RABV aggregation induced by thermal stress. Finally, using a kinetic-based modeling approach to explore forced degradation antigenicity data (NTA, ELISA), a two-step model accurately describing antigenicity loss was identified. This model predicted a RABV shelf-life of more than 3 years at 5°C; significant loss of antigenicity was predicted for samples maintained several months at ambient temperature. This thorough characterization of RABV forced degradation study originally provided a time-temperature mapping of RABV stability.

0

Antimicrobial testing is a time consuming and cost-intensive but essential method for evaluation of newly developed pharmaceutical formulations for topical use. In this study the correlation between free preservative concentration in emulsion gels measured by equilibrium dialysis and the successful preservative effectiveness testing for Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis (analyzed according to Ph. Eur. and USP) was investigated. The higher the lipophilicity of the oil phase and the lower the content of the aqueous phase with regard to dissolved ingredients the more preferably distributed is phenoxyethanol to the water phase and, consequently, the higher was the efficacy against the microbes. Increased emulsifier concentrations reduced the free amount of the preservative due to micellar interactions. Aspergillus brasiliensis was the most resistant and Staphylococcus aureus the most sensitive germ towards phenoxyethanol in o/w-emulsion gels.

0

In this study, the influence of the presence of excipients in sample preparation and clean-up steps required prior to drug analysis in milk-based media which simulate the in vivo properties of the fed state stomach was investigated. 15 excipients, normally present in solid dosage forms of five APIs tested (atenolol, paracetamol, furosemide, nifedipine and propafenone hydrochloride) were mixed (one at a time) with the active pharmaceutical ingredient of interest either via vortexing, co-grinding or shaking of the physical mixture and dissolved in Fed State Simulated Gastric Fluid (FeSSGF). The objective of the study was the assessment of the extraction efficiency of three protein precipitation protocols (using MeOH, ΑCN and 10% w/v TCA), typically used in drug analysis, in milk-based biorelevant media in the presence of the excipients. The mixing technique, fat content of the medium and excipient and solvent effects were investigated. The efficiency of three different protein precipitation reagents in drug extraction when dissolved as API:excipient mixtures in the fed-state medium was compared against the equivalent drug amount recovered in the absence of the excipient in FeSSGF. Most excipients had a significant negative effect (p < 0.05) on drug recovery in the milk-based medium as indicated by the multiple linear regression (MLR) analysis performed. For magnesium stearate and HPMC, the % recovery values were the lowest in four out of the five drugs studied, with a range of 10-100% depending on the API, mixing technique and protein precipitation protocol selected. The negative excipient-dependent effect was more profound in nifedipine and propafenone hydrochloride, the most lipophilic compounds of the study. Acetonitrile was the most effective extraction reagent for most drugs in the presence of excipients, followed by methanol and 10% w/v trichloroacetic acid. Data analysis also revealed a dependence of the extraction method efficiency on the medium lipid content. Application of the above extraction protocols in commercially available formulations highlighted the need for assessment of the effect of excipients in extraction efficiency, before transferring the method directly to dissolution studies of formulations in milk-based fed gastric media. In conclusion, the presence of excipients and the selection of protein precipitation protocol are parameters which can affect significantly the efficiency of protein precipitation when FeSSGF is used as dissolution medium and need to be taken into consideration when developing a quantitative method based on the above sample clean-up technique.

0

The aim of the present study was to evaluate the thermodynamic properties of in-situ formation of cocrystal formulations by the melt-mixing method. Specifically, the thermodynamic mixing behaviour of carbamazepine-nicotinamide and ibuprofen-nicotinamide cocrystals prepared with the aid of Soluplus® (SOL) were evaluated using thermodynamic lattice-based solution theories. Thermodynamic miscibility of both cocrystals with SOL was predicted by calculating Gibb’s free energy based on the Flory-Huggins (FH) interaction parameter (χ), while the activity coefficient of cocrystals estimated with the aid of solid-liquid equilibrium equation and FH lattice theory, showed good thermodynamic miscibility of the components at elevated temperatures used normally during melt-mixing based processes. Complete phase transition diagrams constructed with the aid of DSC measurements and FH solution theory, suggested the existence of two transition zones: 1) a stable cocrystal zone, located at the right-hand-side of the spinodal phase separation curve, where stable cocrystals are prepared and 2) an unstable cocrystal zone, located at the left-hand-side of the spinodal curve up to liquidus, where the matrix forming polymer sets a kinetic barrier to recrystallization and hence, a barrier to the formation of cocrystals. The validity of the suggested thermodynamic phase transition zones was experimentally verified by ATR-FTIR and hot-stage polarized light microscopy.

0

Although salt formation is the most ubiquitous and effective method of increasing the solubility and dissolution rates of acidic and basic drugs, it consumes large quantities of organic solvents and is a batch process. Herein, we show that the dissolution rate of indomethacin (a poorly water-soluble drug) can be increased by using hot melt extrusion of a 1:1 (mol/mol) indomethacin:tromethamine mixture to form a highly crystalline salt, the physicochemical properties of which are investigated in detail. Specifically, pH-solubility studies demonstrated that this salt exhibited a maximal solubility of 19.34 mg/mL (>1000 times that of pure indomethacin) at pH 8.19. A solvent evaporation technique was also used for salt formation. Spectroscopic analyses (infrared, nuclear magnetic resonance) of both; demonstrated, in situ salt formation with proton transfer. Powder X-ray diffraction and differential scanning calorimetry confirmed the crystalline nature of salts formed by both methods. Even though a number of amorphous salts of acidic drugs have been reported, the formation of a crystalline salt of an acidic drug by hot melt extrusion is completely unprecedented, which makes this study an important benchmark for the pharmaceutical production industry.