Prodrug to probe solution HFA pMDI formulation and pulmonary esterase activity

Area of Science:

• Pharmaceutical Chemistry
• Drug Delivery Systems
• Respiratory Medicine

Background:

• Salbutamol is a widely used bronchodilator for asthma and COPD.
• Current salbutamol formulations face challenges with solubility and delivery efficiency.
• Development of novel prodrugs can improve drug solubility and pharmacokinetic profiles.

Purpose of the Study:

• To synthesize and characterize a novel salbutamol prodrug.
• To evaluate the solubility of the prodrug in HFA-134a, a common propellant for metered-dose inhalers.
• To assess the in vitro hydrolysis of the prodrug by esterases in rat lung homogenate, blood, and plasma.

Main Methods:

• Synthesis of a novel salbutamol prodrug.
• Solubility testing in HFA-134a.
• In vitro hydrolysis studies using rat lung homogenate, plasma, and blood esterases.
• Quantification of released salbutamol over time.

Main Results:

• The novel salbutamol prodrug exhibited complete miscibility in HFA-134a, contrasting with salbutamol's low solubility.
• The prodrug underwent hydrolysis in rat lung homogenate with a half-life of 45 minutes.
• Approximately 17% of the expected salbutamol was regenerated after 8 hours of incubation in lung homogenate.

Conclusions:

• The synthesized salbutamol prodrug demonstrates favorable solubility properties for use in solution propellant formulations.
• In vitro hydrolysis suggests the prodrug can be effectively cleaved by lung esterases, releasing active salbutamol within the lungs.
• This novel prodrug holds promise for improved pulmonary delivery of salbutamol via a solution pressurized metered-dose inhaler (pMDI).