Evaluation of sildenafil pressurized metered dose inhalers as a vasodilator in umbilical blood vessels of chicken egg embryos |
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| Affiliation: | 1. Department of Pharmaceutical Technology, Prince of Songkla University, Songkhla, Thailand;2. Department of Physiology, Prince of Songkla University, Songkhla, Thailand;3. Technical Service Department, Interthai Pharmaceutical Manufacturing Limited, Bangkok, Thailand;4. Nanotec-PSU Excellence Center on Drug Delivery System, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Thailand;1. Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore;2. Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore;3. Department of Laboratory Medicine, National University Hospital, Singapore, Singapore;4. School of Materials Science and Engineering, Nanyang Technological University, Singapore, Singapore;5. Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, Singapore;1. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China;2. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;3. National Experimental Teaching Demonstration Center of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China;1. Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun 130012, China;2. National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun 130012, China;3. School of Life Sciences, Jilin University, Changchun 130012, China;1. Servicio de Reumatología, Hospital Universitario La Paz, IdiPAZ, Madrid, España;2. Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, España;3. Servicio de Reumatología, Hospital Universitario Virgen de Valme, Sevilla, España;4. Servicio de Reumatología, Hospital Universitario Virgen Macarena, Sevilla, España;5. Servicio de Reumatología, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, A Coruña, España;6. Departamento de Medicina, Universidad de Santiago de Compostela, Santiago de Compostela, A Coruña, España;7. Servicio de Reumatología, Hospital Universitario de la Princesa, IIS Princesa, Madrid, España;8. Servicio de Reumatología, Hospital Universitario y Politécnico La Fe, Valencia, España;9. Instituto de Salud Musculoesquelética, Madrid, España |
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| Abstract: | Sildenafil citrate is a selective phosphodiesterase-5 inhibitor used for the treatment for erectile dysfunction and pulmonary hypertension. The delivery of sildenafil directly to the lung could have several advantages over conventional treatments for pulmonary hypertension because of the local delivery, a more rapid onset of response, and reduced side effects. The major problem of sildenafil citrate is its limited solubility in water. Sildenafil citrate was complexed with cyclodextrins (CDs) to enhance its water solubility prior to development as an inhaled preparation. Four sildenafil citrate inhaled formulations were prepared with the aid of HP-β-CD (#1), α-CD (#2) and γ-CD (#3) and their effects were compared with the formulations without CDs (#4). The sildenafil citrate pressurized metered dose inhalers (pMDI) used ethanol as a solvent, PEG400 as a stabilizing agent, sorbitan monooleate as a surfactant and HFA-134a as a propellant. All formulations consisted of sildenafil citrate equivalent to a sildenafil content of 20 μg/puff. These products were evaluated according to a standard guideline of inhalation products. Vasodilation testing was performed to investigate the efficacy of sildenafil pMDIs in relieving a vasoconstricted umbilical blood vessel of the chicken egg embryo. The sildenafil contents of the pMDI formulations #1–#3 were within the acceptance criteria (80–120%). The emitted doses (ED) were 102.3 ± 11.5%, the fine particle fractions (FPF) were 60.5 ± 5.6% and the mass median aerodynamic diameters (MMAD) were 2.3 ± 0.3 μm. The vasodilatory activity of those formulations reduced umbilical blood pressure by 67.1–73.7% after treatment by intravenous injection whereas only a 50.1–58.0% reduced blood pressure was obtained after direct spraying of the sildenafil pMDI containing CDs. With sildenafil formulations of a pMDI without CD the blood pressure was reduced by only 39.0% (P-value < 0.05). The available sildenafil in the blood vessels of chicken egg embryos after spraying sildenafil-CDs pMDIs was within the range of 751–825 ng/mL which was much higher than that of a sildenafil only pMDI. |
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| Keywords: | Sildenafil citrate Cyclodextrin Development Pressurized metered dose inhalers Vasodilation Chicken egg embryo |
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