Tenapanor Bis-HCl Tablet Composition for Dissolution and Stability
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Solution Overview
Problem
Existing formulations of tenapanor exhibit unsatisfactory dissolution and stability, particularly at varying pH levels and under accelerated stability conditions, which affects its efficacy as a locally acting NHE3 inhibitor for treating gastrointestinal conditions and hyperphosphatemia.
Innovation Solution
A pharmaceutical formulation comprising greater than 6% w/w of tenapanor bis-HCl with a chloride content greater than 5.82% w/w, incorporating propyl gallate and tartaric acid, and using hydroxypropyl cellulose as a disintegrant, along with specific excipients, to enhance dissolution and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing formulations of tenapanor are used, then the drug can be administered, but dissolution and stability are unsatisfactory
Solution Approach 1:
The patent modifies the chemical parameters of tenapanor by converting it to the bis-HCl salt form, which fundamentally changes its dissolution characteristics and stability profile. This parameter change enables the drug to achieve satisfactory dissolution across varying pH levels and maintain stability under accelerated conditions, directly resolving the reliability issues of existing formulations
Solution Approach 2:
The patent creates a composite pharmaceutical formulation by combining tenapanor bis-HCl with specific excipients including hydroxypropyl cellulose, propyl gallate, and tartaric acid. This composite material approach synergistically enhances both dissolution performance and stability, addressing the reliability-deficiency of previous single-component or simpler formulations
2Reliability
If tenapanor is used as a locally acting NHE3 inhibitor, then therapeutic effects are achieved, but dissolution variability at different pH levels reduces efficacy
Solution Approach 1:
The conversion to bis-HCl salt form fundamentally alters the drug's ionization state and solubility characteristics, enabling it to maintain consistent dissolution across the wide pH range encountered in the gastrointestinal tract. This parameter modification allows tenapanor to adapt to varying pH conditions while maintaining reliable therapeutic efficacy
Solution Approach 2:
The patent optimizes the local chemical properties of tenapanor at the molecular level by using the bis-HCl salt form, which provides enhanced local solubility and stability characteristics. This local quality enhancement ensures consistent drug release and absorption regardless of the pH environment in different GI regions
3Reliability
If phosphate binders are used for hyperphosphatemia, then phosphate levels can be managed, but 70% of CKD patients continue to experience elevated phosphorus levels
Solution Approach 1:
The patent positions tenapanor bis-HCl as an intermediary mechanism that addresses phosphate control through a different pathway than traditional binders. By inhibiting NHE3 and reducing paracellular phosphate uptake, tenapanor acts as a mediator that achieves phosphate level control without the limitations of binder-based approaches, improving treatment effectiveness for CKD patients
Data Source
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AI summary
The present invention provides a pharmaceutical tablet formulation of tenapanor that is chemically stable and soluble comprising greater than about 6% w/w of amorphous tenapanor in its bis-HCl form, an acidifying agent, an antioxidant, a disintegrant, a lubricant, a glidant, a filler, and an immediate release coating, wherein the total chloride content of the active ingredient is greater than 5.82% and the particle diameter distribution D50 is from about from about 18μm to about 22μm.