Shaheen Sultana1, Rashid Ali2, Sushama Talegaonkar3, Farhan Jalees Ahmad4, Gaurav Mittal5, Aseem Bhatnagar6. 1. Jamia Hamdard, Faculty of Pharmacy, Department of Pharmaceutics, Delhi 110062, India. Electronic address: shaheen634@yahoo.co.uk. 2. Institute of Nuclear Medicine and Allied Sciences, Department of Nuclear Medicine, DRDO, Brig. S K Mazumdar Marg, Delhi 110054, India. Electronic address: rashidinmas@gmail.com. 3. Jamia Hamdard, Faculty of Pharmacy, Department of Pharmaceutics, Delhi 110062, India. Electronic address: stalegaonkar@gmail.com. 4. Jamia Hamdard, Faculty of Pharmacy, Department of Pharmaceutics, Delhi 110062, India. Electronic address: farhanja_2000@yahoo.com. 5. Institute of Nuclear Medicine and Allied Sciences, Department of Nuclear Medicine, DRDO, Brig. S K Mazumdar Marg, Delhi 110054, India. Electronic address: gauravmittal23@gmail.com. 6. Institute of Nuclear Medicine and Allied Sciences, Department of Nuclear Medicine, DRDO, Brig. S K Mazumdar Marg, Delhi 110054, India. Electronic address: dr.aseembhatnagar@gmail.com.
Abstract
INTRODUCTION: Alendronate sodium is a bisphosphonate agent used for the treatment of osteoporosis and other bone diseases. It has a strong chelating property to bind or, to some extent, counteract the effects of substances, such as magnesium, calcium citrate, ferrous fumarate, carbonyl iron, as well as the zinc gluconate, sulfate and acetate salts. The objective of the present study was to evaluate lung deposition and sub-acute inhalation toxicity of the alendronate sodium respiratory formulation. METHODS: Particle dimension of aerosols of alendronate was measured using a particle size analyzer. Alendronate was radiolabeled using Technetium-99m for in vitro and in vivo biodistribution studies. Alendronate at doses, 0.5%, 1.0%, and 1.5% in ethanol-saline respiratory formulation was inhaled twice a day up to 5 weeks for inhalation toxicity investigations. Hematological, biochemical and lung toxicity biomarkers in bronchoalveolar lavage (BAL) fluid were determined at the end of the experiment. Histopathological analysis of lung tissues was carried out to observe any microscopic changes RESULTS: Particle size analysis revealed the size within 300-500nm. Anderson cascade impactor results showed that the particles exhibited higher respirable fraction (55.52%) with MMAD of 4.66μm. Hematology, serum biochemistry and lung toxicity biomarkers in BAL fluid performed in the sub-acute toxicity studies indicated no adverse effects of alendronate sodium inhalation except for a significant increase in cholesterol levels and marginal increase in BAL fluid protein. At autopsy, no histopathological changes in major organs were observed. CONCLUSIONS: The lung deposition and safety evaluation data observed from these studies suggested that aerosolized nanosized alendronate sodium by the inhalation route could be a new and promising route of administration as an antidote to radioactive substances through an increase in the bioavailability of the drug as well as a decrease in side effects on systemic delivery.
INTRODUCTION:Alendronate sodium is a bisphosphonate agent used for the treatment of osteoporosis and other bone diseases. It has a strong chelating property to bind or, to some extent, counteract the effects of substances, such as magnesium, calcium citrate, ferrous fumarate, carbonyl iron, as well as the zinc gluconate, sulfate and acetate salts. The objective of the present study was to evaluate lung deposition and sub-acute inhalation toxicity of the alendronate sodium respiratory formulation. METHODS: Particle dimension of aerosols of alendronate was measured using a particle size analyzer. Alendronate was radiolabeled using Technetium-99m for in vitro and in vivo biodistribution studies. Alendronate at doses, 0.5%, 1.0%, and 1.5% in ethanol-saline respiratory formulation was inhaled twice a day up to 5 weeks for inhalation toxicity investigations. Hematological, biochemical and lung toxicity biomarkers in bronchoalveolar lavage (BAL) fluid were determined at the end of the experiment. Histopathological analysis of lung tissues was carried out to observe any microscopic changes RESULTS: Particle size analysis revealed the size within 300-500nm. Anderson cascade impactor results showed that the particles exhibited higher respirable fraction (55.52%) with MMAD of 4.66μm. Hematology, serum biochemistry and lung toxicity biomarkers in BAL fluid performed in the sub-acute toxicity studies indicated no adverse effects of alendronate sodium inhalation except for a significant increase in cholesterol levels and marginal increase in BAL fluid protein. At autopsy, no histopathological changes in major organs were observed. CONCLUSIONS: The lung deposition and safety evaluation data observed from these studies suggested that aerosolized nanosized alendronate sodium by the inhalation route could be a new and promising route of administration as an antidote to radioactive substances through an increase in the bioavailability of the drug as well as a decrease in side effects on systemic delivery.