Natural and bioinspired excipients for dry powder inhalation formulations

A DPI formulation should meet several requirements to serve its purpose. First and foremost, the DPI formulation should consist of drug-containing particles with aerodynamic diameters roughly in the range of 1-5 μm in order to achieve deep lung deposition, often referred to as the fine particle fraction (FPF) [1,5]. Particles larger than 5 μm generally impact on the oropharynx and are subsequently swallowed, while the bulk of particles smaller than 1 μm does not deposit at all and is exhaled (Fig. 1). In addition to a suitable particle size distribution, DPI formulations should have good physical and chemical stability and a relatively low retention in the DPI device (i.e., a high emitted dose (ED)). Furthermore, a DPI formulation should have satisfactory dose reproducibility, by ensuring powder flowability and dispersibility [1]. Meeting these requirements is far from trivial, because micron-sized particles are generally very cohesive and adhesive, which results in poor flow properties and poor aerosolization performance. Consequently, development of a DPI formulation is typically a delicate process, in respect to particle generation as well as balanced use of excipients.

To generate particles in the desired size range, several preparation techniques can be applied, of which milling and spray-drying are most commonly used. Milling is usually the first technique that is attempted due to its low costs, reproducibility, and ease of use. With milling, larger particles are mechanically broken up into smaller particles in the desirable size range by, for instance, particle-particle collisions. However, milling does not enable much control over the shape, density, and surface properties of the resulting particles. By contrast, more control over these particle characteristics can be achieved by spray-drying. With spray-drying, a solution, suspension, or colloidal dispersion is atomized after which the formed droplets are dried by a hot gas. Typically, spray-drying produces spherical or raisin-like particles [6]. Spray-drying is highly suitable for so-called ‘particle engineering’, because its various process parameters such as solute concentration, droplet size, and feed rate, strongly affect the particle characteristics and can be easily controlled.

The performance of dry powder formulations can be further improved by the incorporation of excipients. Typically, excipients are added to DPI formulations for four main purposes: (1) to enhance physical and chemical stability of the active pharmaceutical ingredient (API); (2) to enhance mechanical properties of the API; (3) to modify API pharmacokinetics and/or -dynamics; (4) and to improve API dosing reproducibility by functioning as a bulking agent and powder flow enhancer. However, an excipient should be inactive and exert no therapeutic effect at the used dosage[2,7]. Notwithstanding, pulmonary toxicity of excipients that could successfully fulfil one or more of these functions is a common challenge in DPI formulation development, partly due to the limited buffering capacity of the lungs[5]. Furthermore, as toxicity studies are typically very costly and pulmonary drug delivery is a nonconventional delivery method, knowledge on excipient toxicity is generally lacking. This is reflected by the fact that only a limited number of compounds are included in the inactive ingredient list of the Food and Drug Administration (FDA) for inhalation purposes. Consequently, potential excipients for DPI formulations are preferably natural and bioinspired compounds that are biocompatible and can easily be metabolized and cleared.

The main aim of this manuscript is to review the use of natural and bioinspired excipients (NBEs) for the preparation of inhalation dry powders by using mainly literature published in the previous two years (January 2019 to January 2021). In the context of this review, NBEs are compounds from natural sources or excipients inspired by or based on such compounds. It should be noted that our goal is not to give an extensive list of all NBEs that have been used in this period, but to discuss fundamental and applied research on NBEs frequently used for the preparation of inhalation dry powders. For an extensive list of excipients that have been used in approved pulmonary drug products, we kindly refer the reader to the Food and Drug Administration’s (FDA) list of inactive ingredients [8]. The NBEs we reviewed are divided into four main categories, namely: amino acids, sugars, lipids, and biodegradable polymers. Salts and buffers are also important excipients in dry powder inhalation formulations, but they have been scarcely studied during the period covered by this review and are, therefore, not further discussed.

Article information: Daan Zillen, Max Beugeling, Wouter L.J. Hinrichs, Henderik W. Frijlink, Floris Grasmeijer, Natural and bioinspired excipients for dry powder inhalation formulations, Current Opinion in Colloid & Interface Science, 2021. https://doi.org/10.1016/j.cocis.2021.101497.