The Effects of Excipients and Particle Engineering on the Biophysical Stability and Aerosol Performance of Parathyroid Hormone (1-34) Prepared as a Dry Powder for Inhalation

Abstract

Abstract. Pulmonary delivery of therapeutic peptides and proteins has many advantages including high relative bioavailability, rapid systemic absorption and onset of action and a non-invasive mode of administration which improves patient compliance. In this study, we investigated the effect of spraydrying (SD) and spray freeze-drying processes on the stability and aerosol performance of parathyroid hormone (PTH) (1-34) microparticles. In this study, the stabilisation effect of trehalose (a non-reducing sugar) and Brij 97 (a non-ionic surfactant) on spray-dried PTH particles was assessed using analytical techniques including circular dichroism (CD), fluorescence spectroscopy, modulated differential scanning calorimetry and an in vitro bioactivity assay. Physical characterisation also included electron microscopy, tap density measurement and laser light diffraction. The aerosol aerodynamic performance of the formulations was assessed using the Andersen cascade impactor. Based on these studies, a formulation for spray freeze-drying was selected and the effects of the two particle engineering techniques on the biophysical stability and aerosol performance of the resulting powders was determined. CD, fluorescence spectroscopy and bioactivity data suggest that trehalose when used alone as a stabilising excipient produces a superior stabilising effect than when used in combination with a non-ionic surfactant. This highlights the utility of CD and fluorescence spectroscopy studies for the prediction of protein bioactivity post-processing. Therefore, a method and formulation suitable for the preparation of PTH as a dry powder was developed based on spray-drying PTH with trehalose as a stabiliser with the bioactivity of SD PTH containing trehalose being equivalent to that of unprocessed PTH.

Dry powder inhalation: past, present and future

“…One of the most successful technologies in this respect is PulmoSphere ™ (Novartis, developed by Nektar Therapeutics) [95]. Particle engineering is also needed to achieve stabilization of large molecules (biopharmaceuticals) in the dry state with sugar glasses (cryoprotectants) [97][98][99][100][101], prolonged drug release or therapeutic effect (e.g. by mucoadhesion) [102][103][104][105][106][107], and enhanced drug absorption [106,108].…”

“…The formulation has to contain the drug particles in the desired aerodynamic size distribution for deposition in the target area. Formulation design may be needed to achieve previously mentioned effects [97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116] or a better product stability. DPI devices need to disperse the formulation effectively into this size distribution, preferably at the lowest possible flow rate within the first 0.5 L (children) or 1 L (adults) of inhaled air to achieve drug distribution over the entire lung.…”

The effect of excipients on the stability and aerosol performance of salmon calcitonin dry powder inhalers prepared via the spray freeze drying process

“…Tween-free powders produced higher FPF values than formulations containing Tween. This could be a result of increased agglomeration in the particles containing Tween, which limits dispersion (24).…”

Bone anabolics in osteoporosis: Actuality and perspectives

“…To improve the rhPTH safety profile some attractive options for the alternative delivery have been tested. One is transdermal self-administration using coated microneedle patches [27] whereas other are inhaled and oral delivery [28] . In the first case PTH interestingly showed an increased of trabecular bone to the same extent whereas the gain of total hip BMD was much greater than those obtained with sc administered rhPTH 1-34 [27] .…”