Sprayable Glyceryl Trinitrate Aqueous Formulation
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Solution Overview
Problem
Current pharmaceutical preparations of glyceryl trinitrate (GTN) for topical use, such as sprays, face challenges with low water solubility and viscosity issues, leading to ineffective absorption and rapid loss when applied sublingually or dermally, necessitating higher concentrations to achieve therapeutic plasma levels quickly in emergency situations.
Innovation Solution
A pharmaceutical preparation comprising 0.15 to 3 weight percent GTN, 40 to 95 weight percent water, and 2 to 10 weight percent of a water-soluble polymer, like tyloxapol or poloxamer, which maintains low viscosity and stability, enabling sprayable and effective topical application.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GTN concentration is increased to achieve therapeutic plasma levels, then absorption effectiveness is improved, but viscosity increases making the formulation unsprayable
Solution Approach 1:
A water-soluble polymer is introduced as an intermediary substance to enhance GTN solubility in aqueous formulations. The polymer acts as a solubilizing agent that allows higher GTN concentrations to be achieved without proportionally increasing viscosity, thereby maintaining sprayability while improving absorption effectiveness.
Solution Approach 2:
The formulation changes the solvent system from pure water or simple alcohol-based solutions to a complex aqueous polymer solution. This parameter change in the solvent composition allows the formulation to dissolve higher concentrations of GTN while the polymer structure prevents excessive viscosity increase, resolving the contradiction between concentration and sprayability.
2Speed
If GTN concentration is increased to ensure rapid onset of action, then therapeutic effectiveness is improved, but formulation stability deteriorates
Solution Approach 1:
The water-soluble polymer serves as a stabilizing intermediary that prevents precipitation and degradation of GTN at higher concentrations. By forming a stable complex or solution matrix, the polymer enables the formulation to maintain both high GTN concentration (for rapid onset) and long-term stability.
Solution Approach 2:
The formulation creates a composite aqueous system combining GTN, water, and water-soluble polymer. This composite structure leverages the solubilizing and stabilizing properties of the polymer to enable high GTN concentrations while maintaining formulation stability, achieving both rapid onset and reliability.
3Object-affected harmful factors
If water content is increased to improve safety profile, then patient safety is improved, but GTN solubility decreases
Solution Approach 1:
The water-soluble polymer acts as a mediating agent that enables GTN to remain soluble in high-water-content formulations. The polymer provides hydrophobic interaction sites for GTN while being fully water-soluble itself, thus maintaining both high water content (for safety) and adequate GTN solubility.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The preparation ensures stable, clinically effective GTN concentrations are achieved with improved absorption and reduced loss, allowing rapid onset of action for treating angina pectoris and other arterial insufficiencies without intolerable viscosity increases, thus addressing the limitations of existing formulations.
Implementation Method 1
GTN containing sprays may be formulated with or without the addition of a propellant... GTN is a medium polarity liquid with limited water solubility, but it dissolves easily in a plurality of other solvents
Implementation Method 2
GTN is quickly absorbed from the mucosa and can act within seconds
Data Source
AI summary
The present application relates to a pharmaceutical preparation comprising (a) from 0.15 to 3 weight percent of glyceryl trinitrate, (b) from 40 to 95 weight percent water, and (c1) from 2 to 10 weight percent of at least one water soluble polymer, or (c2) from 1 to 10 weight percent of at least one water soluble polymer and 5 to 20 weight percent of ethanol.