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

Abstract

The effect of excipients on the stability and aerosol performance of salmon calcitonin dry powder inhalers prepared via the spray freeze drying processSpray freeze drying was developed to produce dry powders suitable for applications such as inhalation delivery. In the current study, the spray freeze drying technique was employed to produce inhalable salmon calcitonin microparticles. Effects of the carrier type, concentration of hydroxyl propyl-β-cyclodextrin and the presence of Tween 80 on the chemical and structural stability, as well as on the aerosol performance of the particles were investigated. The results indicated that hydroxyl propyl-β-cyclodextrin had the most important effect on the chemical stability of the powder and strongly increased its stability by increasing its concentration in the formulation. Chemically stable formulations (over 90 % recovery) were selected for further examinations. Fluorescence spectroscopy and circular dichroism suggested that the formulations were structurally stable. Aerosol performance showed that the Tween-free powders produced higher fine particle fraction values than the formulations containing Tween (53.7 vs. 41.92 % for trehalose content and 52.85 vs. 43.06 % for maltose content).Keywords: salmon calcitonin, inhalation, spray freeze drying, hydroxypropyl-β-cyclodextrin, fine particle fraction, stabilitySalmon calcitonin (sCT) is a 32-amino acid linear polypeptide hormone with a 1-7 disulfide bridge (1). It has been approved for the treatment of osteoporosis and Paget's disease; its injectable solution (Calcimar, Miacalcin) and nasal spray (Fortical, Miacalcin) are commercially available for this purpose. Parenteral delivery is an inconvenient route, especially for drugs such as sCT that have short half-lives after administration (15-20 min) and require frequent injections to retain a pharmacological effect. The nasal form shows 3 to 5 % efficacy over the parenteral dosage form (2).Pulmonary delivery of peptides and proteins is a noninvasive alternative method (3) and a promising route because the lung has an enormous absorptive surface area, very NARGES POURSINA ALIREZA VATANARA* MOHAMMAD REZA ROUINI KAMBIZ GILANI ABDOLHOSSEIN ROUHOLAMINI NAJAFABADI

Drying Technologies for the Stability and Bioavailability of Biopharmaceuticals

“…In SFD, the liquid solution is sprayed into a vapor via a nozzle using a cryogenic fluid, such as liquid nitrogen [ 43 , 44 , 53 , 54 , 55 ]. The chemical composition, protein solution concentrations, atomization rate, freezing rate, as well as the temperature of cryogenic liquid have key roles in determining the density and particle size distribution of spray freeze-dried powders [ 50 ].…”

“…Maa et al showed that SFD powders of influenza vaccines have superior stability compared with liquid formulations [ 58 ]. Processing other proteins such as rhDNase, anti-IgE monoclonal antibodies [ 21 ], calcitonin [ 53 ], and parathyroid hormone [ 44 ] using SFD provided stable dried powders with appropriate particle sizes and good flow properties.…”

Poly(lactic acid)/poly(lactic-co-glycolic acid) particulate carriers for pulmonary drug delivery

“…Moreover, first-pass metabolism effect can be minimized by pulmonary delivery, which can be a good alternative delivery system for therapeutic peptides and proteins (Rytting et al 2008). The pulmonary delivery of therapeutic proteins and peptides, such as calcitonin (Poursina et al 2016), trastuzumab , and insulin (Exubera ® and Afrezza ® ) (Al-Tabakha 2015), have been investigated for the treatment of osteoporosis, breast cancer, and diabetes, respectively (Table 3). For systemic delivery through the pulmonary route, some specific physical barriers, such as blood proteolytic degradation, renal clearance, and hepatic first-pass metabolism, should be considered, and an effective dosage form of the drug is highly required to be absorbed through the alveolar and bronchial epithelium (Depreter et al 2013).…”

“…After administration, drug distribution in the lung and retention in the appropriate site of the lung is important to achieve effective treatment (Labiris and Dolovich 2003a). A drug formulation designed for systemic delivery needs to be deposited in the lower parts of the lung to provide optimal bioavailability (Poursina et al 2016). However, for the local delivery of antibiotics for the treatment of pulmonary infection, prolonged drug retention in the lungs is required to achieve proper efficacy.…”

Development of β‐carotene aerosol formulations using a modified spray dryer

“…Cyclodextrin is reportedly suitable for encapsulation of carotenoids (Madhavi & Kagan, 2008) in soft gels, providing higher bioavailability. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) is an approved compound for inhalation, and researchers have confirmed that as a coating material, it increases the stability of the core compound (Poursina, Vatanara, Rouini, Gilani, & Rouholamini, 2016). Ungaro et al (2009) developed insulin aerosols using a double emulsion method.…”