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.
Highlights
A number of biologics including peptides, proteins, antibodies, and nucleic acids, have been developed as pharmaceutical candidates for new modalities [1], since they can act on targeted molecules that cannot be controlled by small molecule drugs in providing greater safety, potency, and target specificity [2,3]
To extend the duration of the pharmacological action of salmon calcitonin (sCT), Poly (lactic-co-glycolic) acid (PLGA) was selected as a biodegradable sustained-release carrier for preparing sCT/SR
For the steady production of sCT/SR, the temperature of air flow was set at 25 ◦ C to avoid the aggregation of PLGA microparticles during the drying process because the glass transition point of PLGA is relatively low, possibly resulting in improved yield of PLGA
Summary
A number of biologics including peptides, proteins, antibodies, and nucleic acids, have been developed as pharmaceutical candidates for new modalities [1], since they can act on targeted molecules that cannot be controlled by small molecule drugs in providing greater safety, potency, and target specificity [2,3]. A size range of particles from 1 μm to 5 μm is considered to be appropriate to deposit in the deep lung for drug absorption from alveolar sites [14] Despite these attractive aspects of pulmonary delivery for biologics, it is still challenging to strictly control the aerodynamic properties of drug-loaded powders at a single micron scale by conventional powderization technology to achieve efficient pulmonary delivery of drugs. The fine droplet drying (FDD) process, a new powderization technique employing an ink jet head used in the printing industry, was developed by our group and firstly applied to the production of pharmaceutical formulations [18]. The inkjet head is a scalable atomizer, possibly leading to high throughput production of powders These characteristics of FDD process would be desirable for particle design and control aerodynamic properties of DPIs, far less is known about the applicability of the FDD process to particle design for inhalation. To evaluate in vivo efficacy and prolongation of the pharmacological action, the hypocalcemic effect of sCT was measured after the insufflation of sCT samples (40 μg-sCT/kg) in rats
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