Improving sublingual delivery of weak base compounds using pH(max) concept: application to propranolol

Area of Science:

• Pharmaceutical Sciences
• Pharmacokinetics
• Drug Delivery Systems

Background:

• Sublingual drug delivery offers rapid absorption but can be limited by drug properties.
• Optimizing the micro-environmental pH at the absorption site is crucial for enhancing the absorption of weak base compounds like propranolol.

Purpose of the Study:

• To provide theoretical and experimental validation for an optimal pH (pHmax) to enhance sublingual absorption of propranolol.
• To demonstrate the utility of the pHmax concept in improving sublingual drug delivery.

Main Methods:

• Derivation and experimental validation of pH-solubility and pH-permeability equations for propranolol.
• In vitro assessment of solubility and permeability profiles.
• A pharmacokinetic study comparing a pHmax-targeted buffered propranolol tablet with a marketed product (Inderal) in healthy subjects.

Main Results:

• Excellent correlation (R(2)=0.999) between theoretical and experimental solubility profiles.
• Permeability profiles predicted an optimal pH (pHmax) for mucosal permeation.
• Significantly higher plasma propranolol concentrations (AUC) within the first 30 minutes were observed with the buffered tablet compared to Inderal (p<0.05).

Conclusions:

• The pHmax concept was experimentally confirmed for propranolol sublingual delivery.
• A buffered tablet designed to achieve pHmax significantly enhanced early plasma propranolol concentrations.
• The pHmax approach holds potential for improving sublingual delivery of other weak base compounds.