Preparation and in vivo absorption evaluation of spray dried powders containing salmon calcitonin loaded chitosan nanoparticles for pulmonary delivery

Drug Design, Development and Therapy Dovepress open access to scientific and medical research Original Research Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Open Access Full Text Article Preparation and in vivo absorption evaluation of spray dried powders containing salmon calcitonin loaded chitosan nanoparticles for pulmonary delivery This article was published in the following Dove Press journal: Drug Design, Development and Therapy 27 August 2013 Number of times this article has been viewed Chutima Sinsuebpol Jittima Chatchawalsaisin Poj Kulvanich Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand Correspondence: Poj Kulvanich Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, 254 Phayathai Road, Pathumwan, Bangkok 10330, Thailand Tel +66 89 921 2096 Fax +66 2 218 8279 Email Introduction Pulmonary delivery is a potentially non-invasive administration route for peptide and protein drugs for systemic treatments.1 Proteins and macromolecules are absorbed more through this route because the lung possesses a large and highly absorptive surface area, extensive vascularization, and low thickness of the alveolar epithelium. Lung alveolar surface varies between 80–140 m2, larger than that of the nose which is estimated to be about 180 cm2. The distance between epithelial surface and blood 861 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2013:7 861–873 Dovepress © 2013 Sinsuebpol et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Ltd, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Ltd. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/DDDT.S47681 Powered by TCPDF (www.tcpdf.org) Purpose: The aim of the present study was to prepare inhalable co-spray dried powders of salmon calcitonin loaded chitosan nanoparticles (sCT-CS-NPs) with mannitol and investigate pulmonary absorption in rats. Methods: The sCT-CS-NPs were prepared by the ionic gelation method using sodium tripolyphosphate (TPP) as a cross-linking polyion. Inhalable dry powders were obtained by co-spray drying aqueous dispersion of sCT-CS-NPs and mannitol. sCT-CS-NPs co-spray dried powders were characterized with respect to morphology, particle size, powder density, aerodynamic diameter, protein integrity, in vitro release of sCT, and aerosolization. The plasmatic sCT levels following intratracheal administration of sCT-CS-NPs spray dried powders to the rats was also determined. Results: sCT-CS-NPs were able to be incorporated into mannitol forming inhalable microparticles by the spray drying process. The sCT-CS-NPs/mannitol ratios and spray drying process affected the properties of the microparticles obtained. The conformation of the secondary structures of sCTs was affected by both mannitol content and spray dry inlet temperature. The sCT-CS-NPs were recovered after reconstitution of spray dried powders in an aqueous medium. The sCT release profile from spray dried powders was similar to that from sCT-CS-NPs. In vitro inhalation parameters measured by the Andersen cascade impactor indicated sCT-CSNPs spray dried powders having promising aerodynamic properties for deposition in the deep lung. Determination of the plasmatic sCT levels following intratracheal administration to rats revealed that the inhalable sCT-CS NPs spray dried powders provided higher protein absorption compared to native sCT powders. Conclusion: The sCT-CS-NPs with mannitol based spray dried powders were prepared to have appropriate aerodynamic properties for pulmonary delivery. The developed system was able to deliver sCT via a pulmonary route into the systemic circulation. Keywords: Salmon calcitonin, chitosan, nanoparticles, mannitol, spray dried powders, pulmonary delivery Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Sinsuebpol et al circulation is between 0.5 and 1.0 µm, which is much less than the other regions of respiratory tract. In addition, it has low enzymatic action and also avoids hepatic first pass metabolism.1,2 Salmon calcitonin (sCT) is a 32 amino acid cyclic polypeptide with a molecular weight of approximately 3,450 Da, available as a high potency therapeutic agent to treat osteoporosis, hypercalcemia, symptomatic Paget’s disease of bone, and osteoarthritis.3 It has been commercialized in the form of subcutaneous or intramuscular injections and nasal sprays. Injectable dosage form often discourages patients’ usage due to pain experienced during injection and resulting facial flushes and nausea.4 Nasal delivery was established for simple administration. However, some drawbacks of nasal formulations including irritation to nasal mucosa, rhinitis, rhinorrhea, and allergic rhinitis have been reported.5 These drawbacks are unavoidable since the nasal spray formulations inevitably contain absorption enhancers to increase trans-mucosal calcitonin delivery. Many studies also reported a low systemic bioavailability of therapeutic protein administered nasally, requiring a high dose to be taken.6 Nasal bioavailability was particularly restricted by characteristics of the drug molecule, rapid enzyme degradation in nasal cavity, poor membrane penetration, and rapid mucociliar clearance.7 The intranasal sCT bioavailability was very low, approximately 3%, although an absorption enhancer was used in the formulation.8 In addition, the disadvantage is that most commercial sCT products formulated in aqueous solution dosage form are prone to instability, and hence required to be kept under refrigerated conditions. As protein or peptide drugs are more stable in the solid state, dry powders for inhalation have been explored as an alternative delivery system for sCT.9,10 Limitations of nasal delivery regarding low drug bioavailability may be improved by administration through the pulmonary route. Nanoparticles are of interest as a carrier of proteins and macromolecules for pulmonary delivery due to their capacity to penetrate into intracellular compartments and the possibility of avoiding phagocytosis of macrophages. They can also have high drug loading capacity, improved drug absorption, differently targeted deposition, and sustained release property.11 However, the use of nanoparticles itself for delivery to the lung is limited by the low in (...truncated)