Design and Characterizations of Inhalable Poly(lactic-co-glycolic acid) Microspheres Prepared by the Fine Droplet Drying Process for a Sustained Effect of Salmon Calcitonin

Abstract

The present study aimed to develop inhalable poly (lactic-co-glycolic acid) (PLGA)-based microparticles of salmon calcitonin (sCT) for sustained pharmacological action by the fine droplet drying (FDD) process, a novel powderization technique employing printing technologies. PLGA was selected as a biodegradable carrier polymer for sustained-release particles of sCT (sCT/SR), and physicochemical characterizations of sCT/SR were conducted. To estimate the in vivo efficacy of the sCT/SR respirable powder (sCT/SR-RP), plasma calcium levels were measured after intratracheal administration in rats. The particle size of sCT/SR was 3.6 µm, and the SPAN factor, one of the parameters to present the uniformity of particle size distribution, was calculated to be 0.65. In the evaluation of the conformational structure of sCT, no significant changes were observed in sCT/SR even after the FDD process. The drug release from sCT/SR showed a biphasic pattern with an initial burst and slow diffusion in simulated lung fluid. sCT/SR-RP showed fine inhalation performance, as evidenced by a fine particle fraction value of 28% in the cascade impactor analysis. After the insufflation of sCT samples (40 µg-sCT/kg) in rats, sCT/SR-RP could enhance and prolong the hypocalcemic action of sCT possibly due to the sustained release and pulmonary absorption of sCT. From these observations, the strategic application of the FDD process could be efficacious to provide PLGA-based inhalable formulations of sCT, as well as other therapeutic peptides, to enhance their biopharmaceutical potentials.

Protein Binding and Differential Distribution of Calcitonin in the Sub-compartments of Blood: An in vitro Study

“…Our observation of relatively higher affinity of sCT compared to hCT towards calcitonin receptor and its signalling is consistent with previous reports. 2,5,13 In contrast to the general assumption of higher binding of calcitonin to albumin in plasma, 2,5,13 we observed that both hCT and sCT had weaker affinity to albumin compared to its affinity to other plasma proteins. In the plasma both hCT and sCT were observed to have superior affinity to beta-2-microglobulin's, although the physiological significance of this is unknown.…”

“…12 Several attempts are also being made to enhance the pharmacokinetics of CT to further increase its bioavailability and achieve sustained delivery. 13,14 The sustained pharmacodynamic effects of CT despite the limitations with its pharmacokinetics calls to question if such attempts to further improve the pharmacokinetics of CT are necessary especially when this can lead to several undesirable pharmacodynamic and adverse effects. Further the variability observed between the pharmacokinetics vs pharmacodynamic effects of CT may paraphs indicate a unique compartmentalization of CT in the blood.…”

Recent Advances in Formulations for Long-Acting Delivery of Therapeutic Peptides

“…Another category of strategies for efficient, improved, and long-acting administration of peptides is based on the encapsulation and delivery of peptides using advanced formulations and materials such as micro/nanoparticles, − hydrogels, − particle/hydrogel composites, , polymeric and naturally derived scaffolds, − and stimuli-responsive materials − (Figure ). Such platforms are anticipated to overcome major hurdles that therapeutic peptide delivery has been encountered and illustrate great potential for sustained and controlled delivery of peptides .…”

Poly(Lactic Acid)-Based Microparticles for Drug Delivery Applications: An Overview of Recent Advances

“…Concerning the administration of biologics, parenteral routes, such as intravenous and/or intramuscular injections, have been mostly used due to their low oral bioavailability and stability in the gastrointestinal tract, which can negatively affect patient compliance. As an alternative non-invasive route for the administration of pharmaceutical ingredients, recently pharmaceutical researchers have focused their studies on pulmonary delivery [76]. The pulmonary route is an attractive target for both local and systemic drug delivery due to benefits, such as rich blood supply, large surface area, and absence of firstpass metabolism.…”