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Advanced Drug Delivery Reviews (v.63, #6)
Production methods for nanodrug particles using the bottom-up approach by Hak-Kim Chan; Philip Chi Lip Kwok (pp. 406-416).
This review focuses on bottom-up processes such as precipitation (or crystallisation) and single droplet evaporation to produce nanoparticles containing largely pure therapeutics for pharmaceutical applications. Suitable precipitation techniques involve the use of high-gravity, confined impinging liquid jet mixing, multi-inlet vortex mixing, supercritical fluids, and ultrasonic waves. Droplet evaporation methods are spray-based, including nanospray drying, aerosol flow reactor method, spraying of low-boiling point solvent under ambient conditions and electrospraying of low-electrical conducting solutions. A key to the success of yielding stable nanoparticles in these various techniques is to control the particle growth kinetics through evaporation rate of the droplets or mixing rate during precipitation.Display Omitted
Keywords: Nanoparticle; Precipitation; Crystallisation; Micro-mixing; Particle growth; Hydrosol; Nanosuspension; Drying; Evaporation; Spray
Controlling drug nanoparticle formation by rapid precipitation by Suzanne M. D'Addio; Robert K. Prud'homme (pp. 417-426).
Nanoparticles are a drug delivery platform that can enhance the efficacy of active pharmaceutical ingredients, including poorly-water soluble compounds, ionic drugs, proteins, peptides, siRNA and DNA therapeutics. To realize the potential of these nano-sized carriers, manufacturing processes must be capable of providing reproducible, scalable and stable formulations. Antisolvent precipitation to form drug nanoparticles has been demonstrated as one such robust and scalable process. This review discusses the nucleation and growth of organic nanoparticles at high supersaturation. We present process considerations for controlling supersaturations as well as physical and chemical routes for modifying API solubility to optimize supersaturation and control particle size. We conclude with a discussion of post-precipitation factors which influence nanoparticle stability and efficacy in vivo and techniques for stabilization.Display Omitted
Keywords: Nucleation; Growth; Supersaturation; Antisolvent addition; Flash nanoprecipitation; Nanoparticle; Prodrug
Nanosizing for oral and parenteral drug delivery: A perspective on formulating poorly-water soluble compounds using wet media milling technology by Elaine Merisko-Liversidge; Gary G. Liversidge (pp. 427-440).
A significant percentage of active pharmaceutical ingredients identified through discovery screening programs is poorly soluble in water. These molecules are often difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues, e.g. poor bioavailability, lack of dose proportionality, slow onset of action and other attributes leading to poor patient compliance. In addition, for parenteral products, these molecules are generally administered with co-solvents and thus have many undesirable side effects. Wet media milling is one of the leading particle size reduction approaches that have been successfully used to formulate these problematic compounds. The approach is a water-based media milling process where micron-sized drug particles are shear-fractured into nanometer-sized particles. Nanoparticle dispersions are stable and typically have a mean diameter of less than 200nm with 90% of the particles being less than 400nm. The formulation consists only of water, drug and one or more GRAS excipients. Drug concentrations approaching 300–400mg/g can be targeted with the use of minimal amounts stabilizer. Typically, on average, the drug to stabilizer ratio on a weight basis ranges from 2:1 to 20:1. These liquid nanodispersions exhibit acceptable shelf-life and can be post-processed into various types of solid dosage forms. Nanoparticulate-based drug products have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routes of administration can be identified with milligram quantities of drug substance providing the discovery scientist an alternate avenue for screening and identifying superior leads. In the last few years, formulating poorly water soluble compounds as nanosuspensions has evolved from a conception to a realization. The versatility and applicability of this drug delivery platform are just beginning to be realized.Display Omitted
Keywords: Nanoparticles; Nanosuspensions; Nanomedicine; Poorly-water soluble compounds
Formation, characterization, and fate of inhaled drug nanoparticles by Jian Zhang; Libo Wu; Hak-Kim Chan; Wiwik Watanabe (pp. 441-455).
Nanoparticles bring many benefits to pulmonary drug delivery applications, especially for systemic delivery and drugs with poor solubility. They have recently been explored in pressurized metered dose inhaler, nebulizer, and dry powder inhaler applications, mostly in polymeric forms. This article presents a review of processes that have been used to generate pure (non polymeric) drug nanoparticles, methods for characterizing the particles/formulations, their in-vitro and in-vivo performances, and the fate of inhaled nanoparticles.Display Omitted
Keywords: Inhalation; Nanoparticle; Formation; Performance; In-vivo; In-vitro; Clearance
Physical and chemical stability of drug nanoparticles by Libo Wu; Jian Zhang; Wiwik Watanabe (pp. 456-469).
As nano-sizing is becoming a more common approach for pharmaceutical product development, researchers are taking advantage of the unique inherent properties of nanoparticles for a wide variety of applications. This article reviews the physical and chemical stability of drug nanoparticles, including their mechanisms and corresponding characterization techniques. A few common strategies to overcome stability issues are also discussed.Display Omitted
Keywords: Drug nanoparticles; Nanosuspensions; Physical stability; Chemical stability; Stabilizer
Nanoparticles and microparticles for skin drug delivery by Tarl W. Prow; Jeffrey E. Grice; Lynlee L. Lin; Rokhaya Faye; Margaret Butler; Wolfgang Becker; Elisabeth M.T. Wurm; Corinne Yoong; Thomas A. Robertson; H. Peter Soyer; Michael S. Roberts (pp. 470-491).
Skin is a widely used route of delivery for local and systemic drugs and is potentially a route for their delivery as nanoparticles. The skin provides a natural physical barrier against particle penetration, but there are opportunities to deliver therapeutic nanoparticles, especially in diseased skin and to the openings of hair follicles. Whilst nanoparticle drug delivery has been touted as an enabling technology, its potential in treating local skin and systemic diseases has yet to be realised. Most drug delivery particle technologies are based on lipid carriers, i.e. solid lipid nanoparticles and nanoemulsions of around 300nm in diameter, which are now considered microparticles. Metal nanoparticles are now recognized for seemingly small drug-like characteristics, i.e. antimicrobial activity and skin cancer prevention. We present our unpublished clinical data on nanoparticle penetration and previously published reports that support the hypothesis that nanoparticles >10nm in diameter are unlikely to penetrate through the stratum corneum into viable human skin but will accumulate in the hair follicle openings, especially after massage. However, significant uptake does occur after damage and in certain diseased skin. Current chemistry limits both atom by atom construction of complex particulates and delineating their molecular interactions within biological systems. In this review we discuss the skin as a nanoparticle barrier, recent work in the field of nanoparticle drug delivery to the skin, and future directions currently being explored.Display Omitted
Keywords: Nanoparticle; Drug delivery; Topical; Skin; Percutaneous penetration; Transdermal delivery