Current Pharmaceutical Design - Volume 21, Issue 19, 2015

Pulmonary drug delivery (PDD) with dry powder inhaler (DPI) has rapidly developed for the treatment of local and systemic diseases, which targets the delivery of fine drug particles into the deep lung surface by combining technologies of fine drug particle formulation, small dose packaging and suitable inhaler, where by each contributes to the overall aerodynamic performance. The basic requirements of DPI formulation are an excellent aerodynamic performance, including particle size distribution within 1-5 μm, suitable morphology and electrostatic charge, low surface energy, high deposition rate and long shelf life stability. The strategy of DPI formulation is shifting from carrier-based to carrier free, from single drug to drug combination, from microparticles to nanoparticles and from small molecules to biomacromolecules. Making such DPI formulation is a big challenge for conventional pharmaceutical techniques. Fortunately, an emerging technology of supercritical fluid particle design (SCF PD) provides a powerful platform for DPI formulation since it runs single step operation at near ambient temperature to minimize the potential damage of delicate active ingredients and to ensure the consistency of the DPI formulation. Combining with our research experiences in DPI formulation of budesonide and recombinant human insulin, this review focus on the most recent development of DPI formulation using SCF PD technology, which can well control and tune the particle size, morphology and surface properties through different design routes (nanoparticles or microparticles, polymorphic particles, composite particles and bio-drug particles), and hence enable prominent enhancement aerodynamic performance and pulmonary deposition of such inhaled dry powders. Also considered within this review is the progress of the industrialization of SCF PD processes for DPI formulation.

Strategies for a particular drug delivery are always of great interest to the pharmaceutical industry, and efficient methods of preparing products with controlled particle microstructures are fundamental for the development and application of drug delivery. Supercritical fluid particle design (SCF PD) processes, as a green and effective alternative to traditional methods, have been effectively employed to produce particles with designated microstructures. Combining with research experiences in our research group, this review aims to provide a roadmap of SCF PD for particular drug delivery. For any drug delivery formulations, macroscopic properties (administration methods, drug release behaviour and targeting) are directly influenced by the particle microstructures (morphology, particle size, particle size distribution, crystal form, drug loading, encapsulation efficiency, etc). “Inverse” strategies are introduced at first to obtain the necessary particle microstructures for a particular drug delivery in this paper. Then, how to produce particles with designated microstructures via SCF PD processes is discussed, mainly focusing on the screening and selection of operating parameters according to thermodynamic and fluid dynamic studies. Recent examples of SCF micronization and co-precipitation/encapsulation processes are also summarized with an emphasis on how to tailor the particle microstructures by controlling the operating parameters. Finally, challenges and issues needing further study are briefly suggested for SCD PD.

Biodegradable particles have important applications in Drug Delivery Systems (DDS) of protein/peptide drugs. And recently, particle systems have also showed to be powerful for vaccine delivery (adjuvant) in order to solve the difficulties when conventional Alum adjuvant was used. However, in above applications, the problems of broad size distribution and poor reproducibility of particles, and deactivation of protein during the preparation, storage and release, are still big challenges. Furthermore, particle should be designed specially according to antigen type and purpose in vaccine delivery. In this article, the techniques to control the diameter of microparticle (MP) will be introduced at the first, and then the strategies about how to maintain the bioactivity of protein drugs during preparation and drug release will be reviewed. Furthermore, particle application specially designed for vaccine delivery to enhance both humoral response and cellular response, will be described.

Biopharmaceuticals including recombinant proteins, monoclonal antibody and nucleic acid based therapeutics have become more and more important to improve the quality of life of patients. However, the administration of biopharmaceuticals was mainly limited to parenteral routes and their delivery remains the most significant challeng to their clinical adoption due to their unfavorable intrinsic physicochemical properties. Among noninvasive administration routes the lung has been attempted intensively to be an alternative to injection to deliver the biopharmaceuticals, and has shown to be promising. In this review we discussed the formulation strategies and particle engineering technologies to improve the efficiency of pulmonary delivery of biopharmaceutical, with a focus on systemic therapy of pharmaceutical proteins/peptides and local delivery of siRNA via the lung administration.

Oral drug delivery is a preferred route because of good patient compliance. However, most peptide/ protein drugs are delivered via parenteral routes because of the absorption barriers in the gastrointestinal (GI) tract such as enzymatic degradation by proteases and low permeability acrossthe biological membranes. To overcome these barriers, different formulation strategies for oral delivery of biomacromolecules have been proposed, including lipid based formulations and polymer-based particulate drug delivery systems (DDS). The aim of this review is to summarize the existing knowledge about oral delivery of peptide/protein drugs and to provide an overview of formulationand characterization strategies. For a better understanding of the challenges in oral delivery of peptide/protein drugs, the composition of GI fluids and the digestion processes of different kinds of excipients in the GI tract are summarized. Additionally, the paper provides an overview of recent studies on characterization of solid drug carriers for peptide/protein drugs, drug distribution in particles, drug release and stability in simulated GI fluids, as well as the absorption of peptide/protein drugs in cell-based models. The use of biorelevant media when applicable can increase the knowledge about the quality of DDS for oral protein delivery. Hopefully, the knowledge provided in this review will aid the establishment of improved biorelevant models capable of forecasting the performance of particulate DDS for oral peptide/protein delivery.

Dendrimers are emerging as potential novel nano-scaled material in drug delivery applications. An interesting area of application is oral drug delivery. In oral drug delivery, many drugs suffer from low bioavailability due to the presence of various biological barriers. Dendrimers have been shown to modulate tight junctions and the integrity of cellular membranes. This effect gives hope for dendrimer to be applied in oral drug delivery. Based on such properties, dendrimers are further surface-modified so that the system will be more suitable for oral delivery applications. Cationic dendrimers are commonly conjugated with neutral or negatively charged ligands, such as polyethylene glycol (PEG), to reduce potential toxicity in gastrointestinal (G.I.) tract. Dendrimers are also surfacemodified to inhibit the efflux effect of P-glycoprotein, which is one of the major drug efflux pumps in G.I. tract. Another interesting strategy is to directly conjugate or mix dendrimer with drugs either to form a dendrimer-drug conjugation or complex to deliver the drug. In this review, application of dendrimers in oral drug delivery will be discussed. The main focus is on the various surface modification strategies to design a more desirable dendrimer-based delivery system that fits the need in oral drug delivery.

Several immune disorders may occur in the skin, such as psoriasis, atopic dermatitis and vitiligo. As the largest organ in the human body, skin provides a unique and non-invasive platform to deliver active pharmaceutical ingredients into superficial lesions or even circulations. In recent years, novel pharmaceutical particles were applied in the topical treatment for skin-related immune disorders to keep the stability, improve the bioactivity, as well as reduce the toxicity of APIs, or even provide a targeting property for the agents. As the pathogenesis of these diseases is increasingly highlighted, the target site and function of topical delivery of particles become more clear and specific. Therefore, diversified surface engineering of vehicles has gradually gained more attention. Appropriate size, charge and surface modification of API-loaded particles can bring out a favorable effect for skin disorders. In this review, comparison of normal and pathological skin structure, penetration route of various drug particles, nano- and micro- particles applied for skin-related immune disorders are summarized. In-vitro and in-vivo evaluation methods for topical therapy of immune disorders will be discussed. Moreover, recent applications of particles loaded with active ingredients from herbal medicines or biological agents for skin immune disorders are also highlighted.

Solid dosage forms are better than liquid dosage forms in many ways, such as improved physical and chemical stability, ease of storage and transportation, improved handling properties, and patient compliance. Therefore, it is required to transform dosage forms of liquid origins into solid dosage forms. The functional approaches are to absorb the liquids by solid excipients or through drying. The conventional drying technologies for this purpose include drying by heating, vacuum-, freeze- and spray-drying, etc. Among these drying technologies, fluidbed drying emerges as a new technology that possesses unique advantages. Fluid-bed drying or coating is highly efficient in solvent removal, can be performed at relatively low temperatures, and is a one-step process to manufacture formulations in pellet forms. In this article, the status of the art of manufacturing solid dosage forms from bulk liquids by fluid-bed drying technology was reviewed emphasizing on its application in solid dispersion, inclusion complexes, self-microemulsifying systems, and various nanoscale drug delivery systems.

During the past 10 years particle engineering in the pharmaceutical industry has become a topic of increasing importance. Engineers and pharmacists need to understand and control a range of key unit manufacturing operations such as milling, granulation, crystallisation, powder mixing and dry powder inhaled drugs which can be very challenging. It has now become very clear that in many of these particle processing operations, the surface energy of the starting, intermediate or final products is a key factor in understanding the processing operation and or the final product performance. This review will consider the surface energy and surface energy heterogeneity of crystalline solids, methods for the measurement of surface energy, effects of milling on powder surface energy, adhesion and cohesion on powder mixtures, crystal habits and surface energy, surface energy and powder granulation processes, performance of DPI systems and finally crystallisation conditions and surface energy. This review will conclude that the importance of surface energy as a significant factor in understanding the performance of many particulate pharmaceutical products and processes has now been clearly established. It is still nevertheless, work in progress both in terms of development of methods and establishing the limits for when surface energy is the key variable of relevance.