Current Pharmaceutical Design - Volume 21, Issue 27, 2015

Nucleic acid therapeutics has huge potential for the treatment of a wide range of diseases including respiratory diseases. Plasmid DNA (pDNA) and small interfering RNA (siRNA) are the two most widely investigated nucleic acids for therapeutic development. However, efficient and safe delivery of nucleic acids is still a major hurdle in translating nucleic acid therapy into clinical practice. For the treatment of respiratory diseases, administration via inhalation is the most direct and effective way to deliver therapeutic nucleic acids to the lungs. Although liquid aerosol formulation is investigated in most of the studies, it is not desirable in terms of maintaining the stability of nucleic acid especially during long-term storage. This problem could be circumvented by formulating the therapeutic nucleic acids into dry powder for inhalation, and should be considered as the future direction of developing inhalable nucleic acids. In this review, the three major particle engineering methods investigated for the preparation of inhalable pDNA and siRNA formulations, including spray drying (SD), spray freeze drying (SFD) and supercritical fluid (SFC) drying, are discussed and compared. Moreover, common assessment methods and the challenges of evaluating the biological activities of inhalable nucleic acid powders are also reviewed.

The pulmonary dosing route has been advocated as an attractive alternative to injection and oral administration for the systemic delivery of therapeutic peptides and proteins. The lung possesses many favorable physiological characteristics for systemic absorption of inhaled peptides/proteins, so inhalable formulation systems of these drugs have generated considerable interest as a valid and non-invasive dosing approach. A major obstacle to the widespread use of inhalation therapies for many peptides/proteins is the limited bioavailability and thereby insufficient therapeutic outcomes because of biopharmaceutical challenges such as rapid pulmonary clearance, limited pulmonary deposition, delayed dissolution in lung environment, poor membrane permeability, and low metabolic stability. A better understanding of the biopharmaceutical properties of inhaled peptides/proteins would be indispensable to overcome these drawbacks with the aid of strategic drug delivery systems and chemical synthesis of new derivatives based on structure-activity relationship information, possibly leading to improved therapeutic potential of pharmaceutical products. The present paper reviews biopharmaceutical properties of inhaled peptides/proteins, with a focus on the pharmacokinetic fate of inhaled peptides/proteins and critical determinants of therapeutic potential. The emphasis in this mini-review will also be on viable formulation approaches for breakthroughs beyond the biopharmaceutical limitations of inhalation therapy with peptides/proteins.

Lung infections may be bacterial, viral or fungal and they are typically treated with oral or parenteral antibiotics. Inhaled dry powder formulations offer unique opportunities for treating lung infections with enhanced effectiveness and stability. Since drug delivery to the lungs requires chronic and repeated administration of larger amounts of therapeutics, dry powder formulations are attractive alternatives to deliver drugs directly to the lungs as they are not limited by solubility issues and they are regarded as being more stable than liquid dosage forms. This state-of-the-art review presents the use of inhaled formulations for tuberculosis as a main focus, but also for other diseases such as bronchiectasis, chronic obstructive pulmonary disease (COPD), pneumonia and respiratory infections occurring as complications during lung transplants. Opportunities for the use of inhaled therapies and other respiratory diseases or as prevention or antidotes against warfare agents are offered. Typical and novel inhaled formulations that have been used as well as preclinical and clinical studies and evaluation of these inhaled therapies are discussed for each disease state. Lastly, the use of inhaled therapies as an alternative to end the emergence of drug resistant strains is discussed along with the risks of increasing these resistant strains if the inhaled therapy is not designed based on dosing regimens established by wellplanned pharmacokinetic and pharmacodynamic studies.

Dry powder inhalers have become increasingly attractive for pulmonary delivery of locally and systemically effective medications. In comparison to the liquid counterparts, such as nebulisation and pressurised metered dose inhalers, the powder form generally offers better chemical stability, improved portability and potentially superior patient adherence. Currently, the aerosol performance between dry powder inhalers varies to a large extent due to differences in the design of inhaler device and formulation. The particulate properties have a significant influence on the inter-particle interactions, which impacts on the aerosolisation of the inhaled powder. In this review, critical particulate properties that affect aerosol performance are discussed. Recent advances in powder production and particle engineering techniques are also assessed, aiming to develop new inhaled powder formulations or improve the aerosolisation efficiency of existing products.

Chinese medicine (CM) in inhalation therapy has a long history of applications since ancient China in the forms of smoke, steam vapor, medicated pillows and aromatic sachets. Over the years, thousands of clinical treatments involving the inhalation of CMs have been reported for the treatment of respiratory disease. Shuanghuanglian, Yuxingcao and Qingkailing are primarily applied in pneumonia and bronchitis. At present, metered dose inhalation (MDI), aromatic inhalation and nebulized inhalation are used extensively in practice. In particular, nebulized CM for the treatment of respiratory diseases has been applied as a noninvasive route with reduced serious adverse reactions and is equivalent to or more efficacious than its intravenous counterparts. Although nebulized CM is widely used in clinical practice, only three MDI and five aromatic inhalations of CM products have been approved by the China Food and Drug Administration (CFDA), and no products in the form of a dry powder inhaler (DPI) or in dosage forms intended for nebulization have been reported. The development of formulations for CM has focused on improving the aerodynamic performance of the particles prepared by spray drying, enhancing the bioavailability and local concentration in the respiratory tract, and increasing the mucoadhesion and sustained release of the CM upon the incorporation of novel excipients. New devices, including MDI and nebulizer devices, have been developed for the delivery of the above-mentioned particles to the pulmonary system. Although the development of CM inhalation products to meet the international quality standards is facing a number of challenges, the inhalation of CMs show great potential for further exploration, particularly as an alternative route to IV infusion for the treatment of respiratory diseases.

Dry powder inhalers (DPIs) usually contain drug particles <6 μm which agglomerate and/ or adhere on the surfaces of large carriers particles. The detachment of drug particles from carriers and de-agglomeration of drug particles into primary particles is essential for drug deposition in the deep lung. These processes are influenced by the surface energy of particles. Inverse gas chromatography (IGC) has been used to determine the surface energy of powder particles used in DPI to characterize materials and to understand aerosolization behaviour. Early studies used an infinite dilution technique to determine nonpolar surface energy and free energy of adsorption for polar interactions separately. Although some correlations were observed with the change in nonpolar surface energy before and after micronization, milling and storage, a lack of consistency in the change of free energy of adsorption was common. Moreover, a consistent relationship between complex de-agglomeration behaviour and surface energy has not been established and there are even some examples of negative correlation. In fact, nonpolar surface energy at infinite dilution is an incomplete representation of powder surface characteristics. The techniques for measuring polar surface energy, total surface energy and surface energy distribution have provided more revealing information about surface energetics of powders. Surface energy distributions determined by IGC or surface energy analyser have been successfully used to understand energetic heterogeneity of surfaces, characterize different polymorphs and understand changes due to micronization, structural relaxation, dry coating and storage. Efforts have been made to utilize surface energy distribution data to calculate powder strength distribution and to explain complex de-agglomeration behaviour of DPI formulations.

This paper provides a review on key research findings in the rapidly developing area of pharmaceutical aerosol electrostatics. Solids and liquids can become charged without electric fields, the former by contact or friction and the latter by flowing or spraying. Therefore, charged particles and droplets carrying net charges are produced from pharmaceutical inhalers (e.g. dry powder inhalers, metered dose inhalers, and nebulisers) due to the mechanical processes involved in aerosolisation. The charging depends on many physicochemical factors, such as formulation composition, solid state properties, inhaler material and design, and relative humidity. In silico, in vitro, and limited in vivo studies have shown that electrostatic charges may potentially influence particle deposition in the airways. However, the evidence is not yet conclusive. Furthermore, there are currently no regulatory requirements on the characterisation and control of the electrostatic properties of inhaled formulations. Besides the need for further investigations on the relationship between physicochemical factors and charging characteristics of the aerosols, controlled and detailed in vivo studies are also required to confirm whether charges can affect particle deposition in the airways. Since pharmaceutical aerosol electrostatics is a relatively new research area, much remains to be explored. Thus there is certainly potential for development. New findings in the future may contribute to the advancement of pharmaceutical aerosol formulations and respiratory drug delivery.

Advances in particle engineering techniques, such as spray drying, freeze drying and supercritical fluid precipitation, have greatly enhanced the ability to control the structure, morphology, and solid state phase of inhalable sized particles (1 - 5 μm) for formulation in pressurized metered dose inhalers (pMDI). To optimize the properties of these engineered particles for formulation in hydrofluoroalkane propellants (HFA 134a / 227) it is necessary to measure both bulk and individual particle properties before, after, and during formulation. This review examines established and recently developed methods for evaluating a variety of particle properties including but not limited to size, surface and internal morphology, chemical composition, and solid state phase. Novel methods for evaluating particle physical and chemical stability directly in propellant or similar environments are also discussed.

The performance of a dry powder inhaler (DPI) depends on powder properties as well as the air and particle flows in the device. The main principle of powder dispersion is to overcome the inter-particle cohesion using various dispersion/ de-agglomeration forces. While different dispersion mechanisms have been identified, their relative importance under different conditions is less clear. The lack of understanding of these mechanisms is a major obstacle to the advance of pharmaceutical powder aerosol technology. This paper briefly reviews our recent effort in developing a combined computational fluid dynamics (CFD) and discrete element method (DEM) approach to gain such pivotal information. Dispersions under various specifically designed conditions were simulated to exam the role of individual dispersion mechanism. The air and particle flows were analysed at the particle scale and linked to dispersion performance characterised by fine particle fraction (FPF). In addition, the dispersion mechanisms of both drug only and carrier based formulations in a commercial inhaler were studied. Our work shows that the approach has the potential to develop a theoretical framework for designing new DPIs.

Dry powder inhalers are one of the most popular devices for delivering medication directly to the lungs of patients. Both for local action and when using the lungs as a portal of entry into the systemic circulation. Dry powder inhalers rely on the patient’s inspiratory effort to supply the energy for the device to effectively deliver medication. In this respect they are limited by the airway pressures that a patient can generate with their respiratory muscles. In this review we focus on a simple model outlining the variables influencing respiratory pressure and review the literature on inspiratory flow rates in patients with respiratory disease. The main determinants of the capability to generate the pressure necessary to effectively use a dry powder inhaler are shown to be age and gender, not disease or disease severity.

The lung dose of inhaled pharmaceutical aerosol that an individual will receive from an inhaler can now be more accurately estimated in light of recent extrathoracic deposition modeling that has correlated characteristic airway dimensions with deposition. This paper first summarizes the current state of extrathoracic deposition models, including recent developments that have quantified the effects of aerosol electrostatics and inhaler mouthpiece diameter on deposition. A generalized equation for predicting extrathoracic deposition in different subjects is then developed and average characteristic airway dimensions representative of different age groups are indicated. A methodology is then presented to predict the lung dose per unit body surface area individuals will receive from an inhaler. A sample calculation shows that a typical 10-year-old child subject would receive a lower lung dose per unit body surface area than an adult subject inhaling through the same inhaler at the same 90 L min-1 flow rate, due to greater extrathoracic deposition in the child. In order to provide an equivalent lung dose per unit body surface area to the child as to the adult, an inhaler particle size adjustment is specified. Finally, the use of idealized geometries for developing inhaler-specific empirical correlations and improving upon inhaler design is outlined.