Abstract
Background: A novel co-encapsulated nanoparticle (NP) system using the anti-asthmatic drugs theophylline and budesonide and the biodegradable polymer poly (lactic acid)(PLA) was synthesised using a modified double emulsification solvent diffusion (DESD) method. The aim was to develop a NP system that is suitable for pulmonary drug delivery, using either a nebuliser or a dry powder inhaler, for the treatment of asthma and COPD.
Methods: NPs were synthesised using a DESD method where the organic phase (acetone and dichloromethane containing budesonide and PLA) was emulsified with the aqueous phase (PVA solution containing theophylline) and the organic phase evaporated to form the NP suspension. Freeze dried NPs were characterised for physical and chemical properties as well as cellular toxicity and permeability using 16HBE14o-airway epithelial cells. NPs were formulated as DPIs using different grades of lactose and a nebuliser solution using deionised water and characterised for drug deposition using a multi-stage liquid impinger.
Results: NPs containing both the drugs were successfully prepared at a size range of 350-400nm, surface charge of-12mV and drug loading of 41.7% for budesonide and 26.1% for theophylline. At the highest concentration of NP suspension, cell viability was reduced to approximately 70% of controls (MTT assay)(p< 0.05). Permeability of the drugs across the cellular tight junctions as free drug solutions was more than drug permeability from nebulised NP suspension or DPI. Initial studies indicated that the transport rate of theophylline and budesonide across 16HBE14o-cells was less when delivered using co-encapsulated NPs than from their respective drug solutions at equivalent concentrations over a period of 24 hours. DPIs showed large nanoparticle deposition in the upper airway and nebulized NP suspensions showed deposition in upper and lower airways.
Conclusions: Theophylline and budesonide PLA NPs were successfully formulated, with the desired physicochemical properties. Low toxicity of NPs to the cells was observed over a 24-hour period, albeit with low drug permeability. Future work involving in-vivo response measurement such as changes in the airway diameter when NPs are delivered via inhalation and measurement of biomarkers in the bronchial alveolar lavage fluid needs to be performed to determine drug efficacy.
Methods: NPs were synthesised using a DESD method where the organic phase (acetone and dichloromethane containing budesonide and PLA) was emulsified with the aqueous phase (PVA solution containing theophylline) and the organic phase evaporated to form the NP suspension. Freeze dried NPs were characterised for physical and chemical properties as well as cellular toxicity and permeability using 16HBE14o-airway epithelial cells. NPs were formulated as DPIs using different grades of lactose and a nebuliser solution using deionised water and characterised for drug deposition using a multi-stage liquid impinger.
Results: NPs containing both the drugs were successfully prepared at a size range of 350-400nm, surface charge of-12mV and drug loading of 41.7% for budesonide and 26.1% for theophylline. At the highest concentration of NP suspension, cell viability was reduced to approximately 70% of controls (MTT assay)(p< 0.05). Permeability of the drugs across the cellular tight junctions as free drug solutions was more than drug permeability from nebulised NP suspension or DPI. Initial studies indicated that the transport rate of theophylline and budesonide across 16HBE14o-cells was less when delivered using co-encapsulated NPs than from their respective drug solutions at equivalent concentrations over a period of 24 hours. DPIs showed large nanoparticle deposition in the upper airway and nebulized NP suspensions showed deposition in upper and lower airways.
Conclusions: Theophylline and budesonide PLA NPs were successfully formulated, with the desired physicochemical properties. Low toxicity of NPs to the cells was observed over a 24-hour period, albeit with low drug permeability. Future work involving in-vivo response measurement such as changes in the airway diameter when NPs are delivered via inhalation and measurement of biomarkers in the bronchial alveolar lavage fluid needs to be performed to determine drug efficacy.
| Original language | English |
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| Pages | PO4-5-20 |
| DOIs | |
| Publication status | Published - 1 Jul 2018 |
| Event | The 18th World Congress of Basic and Clinical Pharmacology - Kyoto International Conference Center, Kyoto, Japan Duration: 1 Jul 2018 → 6 Jul 2018 Conference number: 18th |
Conference
| Conference | The 18th World Congress of Basic and Clinical Pharmacology |
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| Abbreviated title | WCP2018 |
| Country/Territory | Japan |
| City | Kyoto |
| Period | 1/07/18 → 6/07/18 |