Intradermal powder immunization with protein-containing vaccines.

The central importance for global public health policy of delivering life-saving vaccines for all children makes the development of efficacious and safe needle-free alternatives to hypodermic needles, preferably in a thermostable form, a matter of pressing urgency. This paper comprehensively reviews past in vivo studies on intradermal powder immunization with vaccine formulations that do not require refrigeration. Particular emphasis is given to the immune response in relation to antigen adjuvantation. While needle-free intradermal delivery of vaccines induces a predominantly Th2-type immune response, adjuvants powerfully enhance and modulate the magnitude and nature of the elicited immune response at various effector sites

The influence of polymer excipients on the dissolution and recrystallization behavior of ketoconazole: Application, variation and practical aspects of a pH shift method

The formulation of amorphous solid dispersions (ASDs) is an effective way to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). The combination of an amorphous state of the drug and the presence of crystallization-inhibiting polymers retains a high amount of dissolved API over time. ASDs with ketoconazole and different polymers were manufactured by spray drying and their characteristics as well as performance were analyzed. Dissolution tests with a change of the dissolution medium from 0.1 M HCl to phosphate buffer at pH 6.8 to simulate pH conditions for instant release formulations, and a direct dissolution of the ASDs in phosphate buffer pH 6.8 to simulate conditions for an enteric formulation, were performed. All ASDs with API contents between 25 and 50% by weight were completely X-ray amorphous. Varying dissolution behaviors between medium change and direct dissolution occurred. It was possible to identify the superior ASD-compositions for both types of tests. The acidic polymers methacrylic acid-ethyl acrylate copolymer, hypromellose acetate succinate and the solubilizer macrogolglycerol hydroxystearate showed the best performances. The combination of the acidic polymers with macrogolglycerol hydroxystearate showed an improved dissolution behavior at higher API contents. The optimization of such formulations with different release-patterns plays an important role for the enhancement of the oral bioavailability of poorly water-soluble drugs

Exploitation of acoustic cavitation-induced microstreaming to enhance molecular transport

Ultrasound (US) exposure of soft tissues, such as the skin, has been shown to increase permeability, enhancing the passage of drug molecules via passive processes such as diffusion. However, US regimes have not been exploited to enhance active convective transport of drug molecules from a donor layer, such as a gel, into another medium. A layered tissue-mimicking material (TMM) was used as a model for a drug donor layer and underlying soft tissue to test penetration of agents in response to a range of US parameters. Influence of agent molecular mass (3-2000 kDa), US frequency (0.256/1.1 MHz) and US pressure (0-10 MPa) on transport was characterised. Agents of four different molecular sizes were embedded within the TMM with or without cavitation nuclei (CN) and US applied to achieve inertial cavitation. Post-insonation, samples were analysed to determine the concentration and penetration distance of agent transported. US exposure substantially enhanced transport. At both US frequencies, enhancement of transport was significantly higher (p < 0.05) above the cavitation threshold, and CN reduced the pressure at which cavitation, and therefore transport, was achieved. Acoustic cavitation activity and related phenomena was the predominant transport mechanism, and addition of CN significantly enhanced transport within a range of clinically applicable acoustic pressures. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

Exploitation of acoustic cavitation-induced microstreaming to enhance molecular transport

Ultrasound (US) exposure of soft tissues, such as the skin, has been shown to increase permeability, enhancing the passage of drug molecules via passive processes such as diffusion. However, US regimes have not been exploited to enhance active convective transport of drug molecules from a donor layer, such as a gel, into another medium. A layered tissue-mimicking material (TMM) was used as a model for a drug donor layer and underlying soft tissue to test penetration of agents in response to a range of US parameters. Influence of agent molecular mass (3-2000 kDa), US frequency (0.256/1.1 MHz) and US pressure (0-10 MPa) on transport was characterised. Agents of four different molecular sizes were embedded within the TMM with or without cavitation nuclei (CN) and US applied to achieve inertial cavitation. Post-insonation, samples were analysed to determine the concentration and penetration distance of agent transported. US exposure substantially enhanced transport. At both US frequencies, enhancement of transport was significantly higher (p < 0.05) above the cavitation threshold, and CN reduced the pressure at which cavitation, and therefore transport, was achieved. Acoustic cavitation activity and related phenomena was the predominant transport mechanism, and addition of CN significantly enhanced transport within a range of clinically applicable acoustic pressures. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

An acoustic microscopy technique to assess particle size and distribution following needle-free injection.

Needle-free injection is a novel technique for transdermal drug and vaccine delivery, the efficacy of which depends on the number density and mean penetration depth of particles beneath the skin. To date, these parameters have been assessed optically, which is time-consuming and unsuitable for use in vivo. The present work describes the development of a scanning acoustic microscopy technique to map and size particle distributions following injection. Drug particles were modeled using a polydisperse distribution of polystyrene spheres, mean diameter 30.0 mum, and standard deviation 16.7 mum, injected into agar-based tissue-mimicking material, and later, as polydisperse stainless steel spheres, mean diameter 46.0 mum, and standard deviation 13.0 mum, injected both into agar and into porcine skin. A focused broadband immersion transducer (10-75 MHz), driven in pulse-echo mode, was scanned over the surface of the injected samples. Recorded echo signals were post-processed to deduce particle penetration depth (30-300 mum). Furthermore, post-injection size distribution of the spheres was calculated using a novel, automated spectral analysis technique. Experimental results were validated optically and found to predict penetration depth and particle size accurately. The availability of simultaneous particle penetration depth and particle size information makes it possible for the first time to optimize particle design for specific drug delivery applications

Molten salt synthesis of potassium-containing hydroxyapatite microparticles used as protein substrate

The bioactivity of a material may be favorably altered by exerting control over its protein sorption propensity. Spheroidal potassium-containing calcium phosphate bioceramic microparticles were manufactured by molten salt synthesis. The effects on particle characteristics and adsorption of bovine serum albumin (BSA) of different hydroxyapatite (HA, Ca10(PO4) 6(OH)2) to salt flux (K2SO4) ratios were investigated. X-ray diffraction (XRD) patterns showed the emergence of minor phases in addition to the HA major phase with increased salt flux. Synthesized particles were found to increase in potassium content with increasing HA:K2SO4 ratio. Conversely, the amount of BSA adsorption onto microparticles, normalized for surface area, decreased with excess K2SO4. The results indicate that K 2SO4 content can impact the morphology, composition, and BSA adsorption propensity of the resultant bioceramic microparticles. © 2014 Elsevier Inc. All rights reserved

Molten salt synthesis of potassium-containing hydroxyapatite microparticles used as protein substrate

The bioactivity of a material may be favorably altered by exerting control over its protein sorption propensity. Spheroidal potassium-containing calcium phosphate bioceramic microparticles were manufactured by molten salt synthesis. The effects on particle characteristics and adsorption of bovine serum albumin (BSA) of different hydroxyapatite (HA, Ca10(PO4) 6(OH)2) to salt flux (K2SO4) ratios were investigated. X-ray diffraction (XRD) patterns showed the emergence of minor phases in addition to the HA major phase with increased salt flux. Synthesized particles were found to increase in potassium content with increasing HA:K2SO4 ratio. Conversely, the amount of BSA adsorption onto microparticles, normalized for surface area, decreased with excess K2SO4. The results indicate that K 2SO4 content can impact the morphology, composition, and BSA adsorption propensity of the resultant bioceramic microparticles. © 2014 Elsevier Inc. All rights reserved