Abstract
Amorphous calcium carbonate (ACC) is known to interact with proteins, for example, in biogenic ACC, to form stable amorphous phases. The control of amorphous/crystalline and inorganic/organic ratios in inhalable calcium carbonate microparticles may enable particle properties to be adapted to suit the requirements of dry powders for pulmonary delivery by oral inhalation. For example, an amorphous phase can immobilize and stabilize polypeptides in their native structure and amorphous and crystalline phases have different mechanical properties. Therefore, inhalable composite microparticles made of inorganic (i.e., calcium carbonate and calcium formate) and organic (i.e., hyaluronan (HA)) amorphous and crystalline phases were investigated for peptide and protein pulmonary aerosol delivery. The crystalline/amorphous ratio and polymorphic form of the inorganic component was altered by changing the microparticle drying rate and by changing the ammonium carbonate and HA initial concentration. The bioactivity of the model peptide, salmon calcitonin (sCT), coprocessed with alpha-1-antitrypsin (AAT), a model protein with peptidase inhibitor activity, was maintained during processing and the microparticles had excellent aerodynamic properties, making them suitable for pulmonary aerosol delivery. The bioavailability of sCT after aerosol delivery as sCT and AAT-loaded composite microparticles to rats was 4-times higher than that of sCT solution.
Highlights
Polypeptides and proteins the lung is an attractive route into the bloodstream, owing to the high and thin surface area of the alveolar epithelium and due to lower metabolic activity compared to the gastrointestinal tract.[1,2] Peptide deposition within the lung can be controlled by the development of peptide-loaded microparticles with suitable aerodynamic properties that allow them reach the distal lungs, where the absorption capacity is higher
We hypothesise that inhalable microparticles could be made of Amorphous calcium carbonate (ACC), crystalline CaCO3 and biopolymer (HA), enabling their properties to be adapted in terms of aerodynamic characteristics, drug release profile, mechanical strength and protein stability
We investigated the possibility of pulmonary delivery of salmon calcitonin and alpha-1-antitrypsin (AAT), chosen as a model polypeptide and model protein, respectively, by way of inhalable composite microparticles made of HA and CaCO3.37
Summary
Polypeptides and proteins the lung is an attractive route into the bloodstream, owing to the high and thin surface area of the alveolar epithelium and due to lower metabolic activity compared to the gastrointestinal tract.[1,2] Peptide deposition within the lung can be controlled by the development of peptide-loaded microparticles with suitable aerodynamic properties that allow them reach the distal lungs, where the absorption capacity is higher. Negatively charged carboxylic groups from HA could be used to interact with Ca2+ and control the nucleation of CaCO3.32 HA is a ubiquitous anionic polysaccharide that is part of the extracellular lung matrix and has already been investigated as an inhalable therapeutic agent for lung diseases.[33,34,35] For example, inhaled HA prevents the side effects of hypertonic saline inhalation alone, which is used to treat bronchiolitis and patients with cystic fibrosis.[34, 36] We hypothesise that inhalable microparticles could be made of ACC, crystalline CaCO3 and biopolymer (HA), enabling their properties to be adapted in terms of aerodynamic characteristics, drug release profile, mechanical strength and protein stability In particles of this type, the properties could be tuned by controlling the organic:inorganic materials ratio and by controlling the solid state nature of the inorganic components. We investigated the possibility of pulmonary delivery of salmon calcitonin (sCT) and alpha-1-antitrypsin (AAT), chosen as a model polypeptide and model protein, respectively, by way of inhalable composite microparticles made of HA and CaCO3.37
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