Design and development of novel mitochondrial targeted nanocarriers, DQAsomes for curcumin inhalation.

Curcumin has potent antioxidant and anti-inflammatory properties but poor absorption following oral administration owing to its low aqueous solubility. Development of novel formulations to improve its in vivo efficacy is therefore challenging. In this study, formulation of curcumin-loaded DQAsomes (vesicles formed from the amphiphile, dequalinium) for pulmonary delivery is presented for the first time. The vesicles demonstrated mean hydrodynamic diameters between 170 and 200 nm, with a ζ potential of approximately +50 mV, high drug loading (up to 61%) and encapsulation efficiency (90%), resulting in enhanced curcumin aqueous solubility. Curcumin encapsulation in DQAsomes in the amorphous state was confirmed by X-ray diffraction and differential scanning calorimetry analysis. The existence of hydrogen bonds and cation-π interaction between curcumin and vesicle building blocks, namely dequalinium molecules, were shown in lyophilized DQAsomes using FT-IR analysis. Encapsulation of curcumin in DQAsomes enhanced the antioxidant activity of curcumin compared to free curcumin. DQAsome dispersion was successfully nebulized with the majority of the delivered dose deposited in the second stage of the twin-stage impinger. The vesicles showed potential for mitochondrial targeting. Curcumin-loaded DQAsomes thus represent a promising inhalation formulation with improved stability characteristics and mitochondrial targeting ability, indicating a novel approach for efficient curcumin delivery for effective treatment of acute lung injury and the rationale for future in vivo studies.

A poly(vinyl alcohol) nanoparticle platform for kinetic studies of inhaled particles.

The lack of a well defined nanosystem that retains its physicochemical properties and can be tracked in complex biological environments is one reason why the study of NP transport across biological barriers is currently so difficult. As a result, surprisingly little is known about the fate of sub-micron particles once they deposit in the airways of the lung. The aim of this study was to design and manufacture a novel nanoparticle (NP) core that would be physically stable, i.e., not aggregate in biological fluids, and act as a tracking system to investigate NP distribution in the lung. Accordingly, covalent fluorescent labeling (to allow particle tracking) of 40% hydrolyzed poly(vinyl alcohol) was undertaken by inducing dissociation of the carboxylic acid group (ArCOO(-)) of 5(6)-carboxyfluorescein (CF) which then reacted with the hydroxyl group of poly(vinyl alcohol) (PVA) to produce a covalently linked PVA-CF ester. Polymer purification was followed by NP manufacture and characterization in biological media. In contrast to commercial latex particles which aggregated in both cell culture medium and Hank's balanced salt solution (HBSS), the PVA nanoparticles retained their original size (ca. 220 nm), maintained a neutral surface charge in cell culture medium for 24 h and were not acutely toxic to respiratory cells in vitro.

Challenges to optimal medicines use in people living with dementia and their caregivers: A literature review.

Dementia is fast becoming a global concern due to a demographic shift towards an older population. Many studies have shown that caring for a family member or friend has a profound and negative impact on the physical, emotional and psychosocial aspects of the caregivers' life. One significant activity that a family caregiver undertakes is assistance with the management of medicines. This review was undertaken to ascertain what the issues are that affect optimal medicines use from the perspectives of people living with dementia and their caregivers, both in the community and care home settings. A literature search was conducted using electronic databases, employing a combination of search terms. A total of 16 studies met the inclusion criteria. Six broad themes were identified, together with some recommendations to improve medicines use in people with dementia. Challenges to medicines use centred on medicines management and administration, the impact on the caregiver and care recipient, their partnership and interface with formal care. Future research should focus on developing targeted interventions that can overcome these challenges to achieve optimal medicines use.

Effect of formulation variables on oral grittiness and preferences of multiparticulate formulations in adult volunteers.

Multiparticulate formulations are composed of multiple solid dosage units which can be administered directly to the mouth or sprinkled on food. Oral grittiness (i.e. rough mouthfeel) may arise from the presence of particles in the mouth, limiting palatability. In this work, multiparticulate formulations were prepared by dispersion of spherical granules into orange flavoured vehicles thickened with hypromellose (HPMC) at different viscosities in order to assess oral perception of grittiness by a panel of thirty adults through direct scaling on a 100mm visual analogue scale. The effect of formulation factors such as particle size (90, 127, 263µm), amount of particles per 10ml (0.25, 0.50, 1.00g) and viscosity of the vehicle (0.08, 0.43, 2.80Pas) were investigated. Grittiness was increasingly perceived with increasing amount and size of particles. Increasing viscosity of the administration media had a masking effect on the perception of particles. Less gritty samples were generally regarded as 'more pleasant' by the participants of the study. However, samples dispersed in thickened vehicles seemed to be less preferred despite being less gritty; which could be ascribed to an unpleasant mouthfeel of the vehicle. In the design of multiparticulate formulations acceptable for a targeted patient group all these formulation factors will need to be considered and optimised.

Manufacturing Man-Made Magnetosomes: High-Throughput In Situ Synthesis of Biomimetic Magnetite Loaded Nanovesicles.

A new synthetic method for the production of artificial magnetosomes, i.e., lipid-coated vesicles containing magnetic nanoparticles, is demonstrated. Magnetosomes have considerable potential in biomedical and other nanotechnological applications but current production methods rely upon magnetotactic bacteria which limits the range of sizes and shapes that can be generated as well as the obtainable yield. Here, electrohydrodynamic atomization is utilized to form nanoscale liposomes of tunable size followed by electroporation to transport iron into the nanoliposome core resulting in magnetite crystallization. Using a combination of electron and fluorescence microscopy, dynamic light scattering, Raman spectroscopy, and magnetic susceptibility measurements, it is shown that single crystals of single-phase magnetite can be precipitated within each liposome, forming a near-monodisperse population of magnetic nanoparticles. For the specific conditions used in this study the mean particle size is 58 nm (±8 nm) but the system offers a high degree of flexibility in terms of both the size and composition of the final product.

Formulation approaches to pediatric oral drug delivery: benefits and limitations of current platforms.

INTRODUCTION: Most conventional drug delivery systems are not acceptable for pediatric patients as they differ in their developmental status and dosing requirements from other subsets of the population. Technology platforms are required to aid the development of age-appropriate medicines to maximize patient acceptability while maintaining safety, efficacy, accessibility and affordability. AREAS COVERED: The current approaches and novel developments in the field of age-appropriate drug delivery for pediatric patients are critically discussed including patient-centric formulations, administration devices and packaging systems. EXPERT OPINION: Despite the incentives provided by recent regulatory modifications and the efforts of formulation scientists, there is still a need for implementation of pharmaceutical technologies that enable the manufacture of licensed age-appropriate formulations. Harmonization of endeavors from regulators, industry and academia by sharing learning associated with data obtained from pediatric investigation plans, product development pathways and scientific projects would be the way forward to speed up bench-to-market age appropriate formulation development. A collaborative approach will benefit not only pediatrics, but other patient populations such as geriatrics would also benefit from an accelerated patient-centric approach to drug delivery.

Ink-jet printing versus solvent casting to prepare oral films: Effect on mechanical properties and physical stability.

The aim of this work was to compare and contrast the mechanical properties and physical stabilities of oral films prepared with either thermal ink-jet printing (TIJP) or solvent casting (SC). Clonidine hydrochloride was selected as a model drug because of its low therapeutic dose and films were prepared using cellulose polymers. Mechanical testing showed that the printed films had Young's moduli and tensile strength values similar to the free film, while casted films were significantly more brittle. The drug also appeared to crystallize out of casted films during stress testing whereas printed films remained unchanged. The dissolution behavior of printed and cast films were similar, because of the rapid disintegration of the polymer. The conclusion is that printing resulted in a better film than casting because the drug resided on the film, rather than in the film where it could exert a plasticizing effect.

Quantifying crystallisation rates of amorphous pharmaceuticals with dynamic mechanical analysis (DMA).

One of the stability concerns for amorphous pharmaceuticals is phase transformation to a crystalline form. Since conversion from an amorphous matrix to a crystalline lattice should result in a change in mechanical modulus of the material dynamic mechanical analysis (DMA) offers potential as a stability-indicating assay for what are often complex formulations. Amorphous indomethacin glasses were used as model samples. Pockets made of a metal weave allowed the glass to be mounted in the instrument while ensuring exposure to RH. Crystallisation was manifest as an increase in the storage modulus signal with time. Conversion of the data to fraction crystallisation allowed quantitative determination of the rate and mechanism of crystallisation by application of the Urbanovici-Segal model. Rates of crystallisation were seen to increase with temperature and humidity while temperature and humidity affected the mechanism of crystallisation. High temperature and humidity resulted in three dimensional crystal growth. Reducing the humidity caused a switch in mechanism to growth from edges. Reducing temperature resulted in a mixed mechanism of growth from surfaces and edges. The DMA was also sensitive to crystallisation of phenobarbital sodium formulated in an oral film, but quantitative analysis was not possible as the onset of crystallisation was not recorded.