Effervescent Pharmaceutical Formulations for High-Loading Dissolution
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Solution Overview
Problem
Current pharmaceutical formulations of Compound I, used to treat diseases like lymphoma, immune thrombocytopenia purpura, and rheumatoid arthritis, face issues with unsatisfactory and variable dissolution and bioavailability at increased active ingredient loadings, particularly above 12.5% w/w, leading to inconsistent drug delivery.
Innovation Solution
Formulations containing greater than 15% w/w of Compound I, combined with effervescent agents such as sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium carbonate, calcium carbonate, or potassium carbonate, which enhance dissolution at low pH by changing the disintegration mechanism from swelling to erosion, allowing for rapid disintegration and improved bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If the percent loading of Compound I is increased to reduce the number of tablets, then the dosage convenience is improved, but the dissolution and bioavailability become unsatisfactory and variable
Solution Approach 1:
The patent changes the pH parameter of the dissolution environment by incorporating effervescent agents that generate CO2 and lower pH in the gastrointestinal tract. This parameter change enables high loading formulations (100mg tablets with 25% w/w Compound I) to dissolve effectively by creating acidic conditions that enhance the dissolution rate and consistency of Compound I, thereby maintaining reliability while improving dosage convenience.
Solution Approach 2:
The effervescent agents (sodium bicarbonate, potassium bicarbonate, or citric acid) act as intermediaries that mediate between the high loading of Compound I and the dissolution process. These agents generate CO2 bubbles that create mechanical agitation and lower pH, facilitating the dissolution of Compound I without requiring multiple tablets, thus resolving the contradiction between high loading and consistent dissolution.
2Productivity
If the percent loading of Compound I is increased to 25% w/w in 100mg tablets, then the productivity is improved, but the dissolution at low pH becomes unsatisfactory and variable
Solution Approach 1:
The patent deliberately changes the pH parameter by incorporating effervescent agents that create acidic conditions in the gastrointestinal tract. This parameter change transforms the dissolution environment from neutral to acidic, enabling high loading formulations (25% w/w Compound I) to achieve satisfactory and consistent dissolution at low pH, thereby improving productivity without sacrificing reliability.
Solution Approach 2:
The patent converts the potential harm of low pH (which normally causes unsatisfactory dissolution) into a benefit by using effervescent agents to generate acidic conditions that enhance Compound I dissolution. The CO2 generation and pH lowering, which could be considered harmful to dissolution, are instead utilized to improve the dissolution performance of high loading formulations, enabling 100mg tablets with 25% w/w Compound I to dissolve reliably.
3Reliability
If effervescent agents are added to enable high loading formulations, then the dissolution at low pH is improved, but the device complexity increases
Solution Approach 1:
The patent uses effervescent agents to change the pH parameter, which improves dissolution reliability. While this adds formulation complexity, the complexity is managed by selecting from a limited set of well-characterized effervescent agents (sodium bicarbonate, potassium bicarbonate, citric acid) and optimizing their concentrations to achieve the desired pH change without excessive complexity.
Solution Approach 2:
The effervescent agents function as disposable components that are consumed during the dissolution process. They generate CO2 and pH change temporarily to facilitate dissolution, then are metabolized or excreted. This approach accepts temporary formulation complexity as a trade-off for achieving reliable dissolution, with the effervescent agents serving as transient, consumable elements that enable high loading formulations to perform reliably.
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 use of effervescent agents in pharmaceutical compositions with higher loadings of Compound I results in tablets that exhibit satisfactory dissolution and bioavailability, overcoming the limitations of variable performance seen in lower loading formulations.
Implementation Method 1
effervescent agents such as sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium carbonate, calcium carbonate, or potassium carbonate, which enhance dissolution at low pH by changing the disintegration mechanism from swelling to erosion
Implementation Method 2
enhance dissolution at low pH
Data Source
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AI summary
There are provided pharmaceutical compositions comprising greater than 15% w/w of a compound of Formula (I) as defined herein and/or hydrate thereof and an amount of one or more effervescent agents that is sufficient to provide satisfactory in vitro dissolution; and further comprising one or more pharmaceutically acceptable ingredients; and to processes for obtaining them.