Tadalafil Oral Suspension With Tablet-Equivalent Dissolution Stability
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Solution Overview
Problem
Existing tadalafil formulations, particularly liquid suspensions, face challenges in achieving chemical and physical stability, sedimentation issues, and do not provide an in vitro dissolution profile equivalent to commercial solid formulations like Cialis® tablets, making them unsuitable for patients with swallowing difficulties and complicating fixed-dose combinations with drugs like tamsulosin or dutasteride.
Innovation Solution
A tadalafil pharmaceutical composition in the form of an aqueous oral suspension, comprising tadalafil, cyclodextrin, coprocessed microcrystalline cellulose and sodium carboxymethyl cellulose, and xanthan gum, which maintains physicochemical stability and provides an in vitro dissolution profile similar to Cialis® film-coated tablets.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If liquid suspension formulation is prepared for tadalafil, then ease of administration is improved for patients with swallowing difficulties, but chemical and physical stability deteriorates
Solution Approach 1:
The patent uses cyclodextrin as an intermediary substance to complex with tadalafil, forming a stable inclusion complex in aqueous suspension. This mediator resolves the contradiction by providing both the liquid formulation benefits for easy administration and the chemical stability through host-guest complexation, preventing degradation while maintaining solubility.
Solution Approach 2:
The patent employs a composite formulation system combining tadalafil with multiple excipients including cyclodextrin, suspending agents, and surfactants. This composite approach creates a synergistic system where each component contributes to both stability and ease of administration, resolving the contradiction between formulation type benefits and stability requirements.
2Ease of operation
If liquid suspension formulation is prepared for tadalafil, then ease of administration is improved, but sedimentation issues worsen
Solution Approach 1:
Cyclodextrin acts as a mediator that forms stable complexes with tadalafil particles, preventing aggregation and sedimentation. This inclusion complexation keeps the active ingredient uniformly dispersed in the aqueous medium, maintaining reliability while enabling liquid formulation benefits.
Solution Approach 2:
The patent modifies physical parameters by controlling particle size distribution and using surfactants to alter surface properties of suspended particles. These parameter changes reduce sedimentation tendency while maintaining the liquid suspension form for easy administration.
3Ease of manufacture
If simple formulation with small amounts of excipients is used, then economy is improved and adverse effects are reduced, but formulation complexity increases due to stability requirements
Solution Approach 1:
The patent extracts and utilizes the stabilizing properties of cyclodextrin as a key functional component, focusing on a few critical excipients rather than numerous additives. This selective approach simplifies manufacturing while achieving stability through the primary cyclodextrin-tadalafil complexation mechanism.
4Reliability
If in vitro dissolution profile equivalent to Cialis tablets is achieved, then pharmacokinetic equivalence is improved, but formulation complexity increases
Solution Approach 1:
The patent achieves pharmacokinetic equivalence by carefully controlling dissolution parameters through cyclodextrin complexation and suspending agent selection. By adjusting these key parameters, the formulation replicates the dissolution profile of Cialis tablets without requiring complex multi-component systems.
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 composition ensures chemical and physical stability, allows for equivalent dissolution to commercial tablets, and facilitates fixed-dose combinations with tamsulosin or dutasteride, addressing the limitations of existing formulations.
Implementation Method 1
cyclodextrin in an amount from 0.01% to 0.25% w/v
Implementation Method 2
coprocessed microcrystalline cellulose and sodium carboxymethyl cellulose (MCC-NaCMC) in an amount from 0.5% to 2.0% w/v; xanthan gum in an amount from 0.10% to 1.50% w/v
Data Source
AI summary
The present invention relates to a tadalafil oral suspension comprising 0.01-5 % w/v of tadalafil, a cyclodextrin, coprocessed microcrystalline cellulose and sodium carboxymethyl cellulose, xanthan gum and water as vehicle. The suspensions are chemically and physically stable and show a dissolution profile equivalent to that of commercial tadalafil film-coated tablets. The tadalafil suspensions are suitable for treating male erectile dysfunction and benign prostatic hyperplasia. The invention also relates to a fixed-dose combination dosage forms comprising said tadalafil suspension and either tamsulosin, in particular, in the form of modified-release pellets, or dutasteride. Said combined forms are useful for treating lower urinary tract symptoms associated with benign prostatic hyperplasia. The invention also relates to a process for the preparation of said tadalafil composition.