Cinacalcet Tablet Binder Optimization for Dissolution
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Solution Overview
Problem
Current pharmaceutical compositions of cinacalcet lack stability, reproducibility, and bioequivalence due to inadequate binder concentrations, with existing formulations either being binder-free or containing excessive amounts that affect dissolution profiles and bioavailability.
Innovation Solution
A pharmaceutical composition comprising cinacalcet or its pharmaceutically acceptable salts with binders in an amount of 0.9% w/w or less, specifically using povidone and pregelatinized starch in amounts not exceeding 0.9% w/w, combined with a process involving wet granulation, dry granulation, direct compression, or compaction methods to ensure stability and bioequivalence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If binder concentration is increased to improve mechanical strength, then tablet strength is improved, but dissolution profile and bioavailability are adversely affected
Solution Approach 1:
The invention changes the binder concentration parameter from conventional high levels (5-10% w/w) to a low level (0.1-0.9% w/w). This parameter change resolves the contradiction by finding an optimal low concentration that provides sufficient mechanical strength without adversely affecting dissolution profile and bioavailability, as demonstrated by in-vitro dissolution studies showing comparable profiles to reference products.
Solution Approach 2:
The invention applies partial action by using only the minimum necessary amount of binder (0.1-0.9% w/w) rather than excessive amounts conventionally used. This partial binding approach is sufficient to maintain tablet mechanical strength during storage and handling while avoiding the harmful effects of excessive binder on dissolution and bioavailability.
2Reliability
If binder concentration is decreased to improve dissolution profile, then bioavailability is improved, but mechanical strength is compromised
Solution Approach 1:
The invention optimizes the binder concentration parameter to a specific low range (0.1-0.9% w/w) that simultaneously satisfies both requirements: maintaining adequate mechanical strength for tablet integrity during storage and handling, while preserving dissolution profile and bioavailability comparable to reference products.
Solution Approach 2:
The invention copies the successful dissolution profile of the reference product (Sensipar®) by using a low binder concentration formulation, demonstrating bioequivalence through comparable in-vitro dissolution profiles across multiple time points, while achieving adequate mechanical strength.
3Reliability
If binder is completely eliminated to improve bioavailability, then dissolution is enhanced, but manufacturing reliability becomes inadequate
Solution Approach 1:
The invention uses a small but non-zero amount of binder (0.1-0.9% w/w), which is partial action compared to conventional formulations. This minimal binder presence is sufficient to ensure manufacturing reliability including adequate tablet mechanical strength and consistent dissolution profiles, while having negligible impact on bioavailability, thus resolving the contradiction between binder-free formulation and manufacturing reliability.
Data Source
AI summary
A pharmaceutical composition containing cinacalcet or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients. A pharmaceutical composition containing cinacalcet or pharmaceutically acceptable salts thereof having a particle size distribution D90 equal to or less than 20 μm, D50 equal to or less than 10 μm, and D10 equal to or less than 5 μm and one or more and binders in an amount of 0.9% w/w or less, relative to the total weight of composition, where the composition is not free of binder and that the total amount of binder does not exceed 0.9% w/w relative to the total weight of the composition.