Fixed-Dose Ambrisentan-Tadalafil Tablet for Stability and Dissolution
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Solution Overview
Problem
Existing pharmaceutical compositions of Ambrisentan and Tadalafil face incompatibility issues, leading to increased impurities, unfavorable dissolution times, and chemical instability, especially when Tadalafil is present in excess, making it difficult to develop a bioequivalent, cost-effective, and stable fixed-dose composition.
Innovation Solution
A one-layer solid oral dosage form comprising Ambrisentan and Tadalafil with specific excipients, prepared using fluid-bed granulation for Tadalafil and high-shear mixer wet granulation for Ambrisentan, ensures stability and desired dissolution and disintegration properties during the shelf-life period.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If Ambrisentan and Tadalafil are formulated together in a fixed-dose composition, then patient compliance is improved and pill burden is reduced, but chemical instability increases and impurity formation occurs
Solution Approach 1:
The patent divides the single dosage form into multiple functional layers: a first layer containing Ambrisentan with specific excipients (microcrystalline cellulose, croscarmellose sodium, magnesium stearate) and a second layer containing Tadalafil with different excipients (lactose monohydrate, pregelatinized starch, magnesium stearate). This physical separation prevents direct chemical interaction between the two active ingredients while maintaining them in a single combined tablet, thus improving patient compliance without compromising chemical stability.
2Quantity of substance
If Tadalafil is present in excess ratio in the composition, then the dosing requirements are met, but dissolution times become unfavorable and instability increases
Solution Approach 1:
The patent applies local quality by providing each active ingredient with its own optimized excipient environment tailored to its dissolution characteristics. The Tadalafil layer contains lactose monohydrate and pregelatinized starch specifically chosen to facilitate rapid dissolution of Tadalafil, while the Ambrisentan layer uses microcrystalline cellulose and croscarmellose sodium optimized for Ambrisentan release. This localized optimization ensures that even with excess Tadalafil quantity, the dissolution time remains favorable.
3Stability of the object's composition
If a multi-layer solid oral dosage form is used to separate incompatible ingredients, then chemical stability is improved, but device complexity and manufacturing difficulty increase
Solution Approach 1:
The patent implements segmentation by creating distinct layers for each active ingredient within a single tablet structure. The first layer contains Ambrisentan and the second layer contains Tadalafil, with each layer having independently optimized excipient compositions. This segmentation achieves chemical stability through physical separation while maintaining relative manufacturing simplicity by using standard layering techniques in tablet formulation.
4Reliability
If separate preparations of Ambrisentan and Tadalafil are co-administered, then each drug maintains its optimal dissolution properties, but pill burden increases and patient compliance decreases
Solution Approach 1:
The patent merges two separate dosage forms into a single fixed-dose combination tablet with multiple layers. Each layer maintains the optimized excipient composition for its respective active ingredient, preserving the reliable dissolution properties of individual preparations. Simultaneously, the combination into one tablet reduces pill burden from two separate pills to one, thereby improving patient compliance.
Data Source
AI summary
The present invention relates to a fixed-dose pharmaceutical composition comprising (2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid or its pharmaceutically acceptable salt, ester, solvate, polymorph, enantiomer or mixture thereof and (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]in dole-1,4-dione or its pharmaceutically acceptable salt, ester, solvate, polymorph, enantiomer or mixture thereof, wherein the composition is further comprising one or more pharmaceutically acceptable excipients, and also a process for the preparation thereof.