Teriparatide Liquid Formulation Stability via pH and Salt Control
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Solution Overview
Problem
Current liquid pharmaceutical preparations containing teriparatide face challenges in inhibiting the formation of deamidated, isomerized, and oxidized products, which affect stability and purity, leading to reduced efficacy over time.
Innovation Solution
A liquid pharmaceutical preparation with a pH range of 3.0 to 5.0, containing inorganic and organic salts, and specific additives like methionine and D-mannitol, which inhibits the formation of deamidated, isomerized, and oxidized products of teriparatide, maintaining high purity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If liquid pharmaceutical preparation is formulated without specific pH control and stabilizers, then manufacturing simplicity is maintained, but teriparatide degrades forming deamidated, isomerized, and oxidized products
Solution Approach 1:
The patent applies parameter changes by optimizing the pH range to 3.0-5.0 and specifying precise concentrations of stabilizers (methionine 0.1-10 mg/mL, D-mannitol 1-100 mg/mL, inorganic salts 1-50 mM). These parameter optimizations inhibit degradation reactions while maintaining formulation simplicity for clinical use.
Solution Approach 2:
The patent uses intermediary substances (methionine, D-mannitol, and inorganic salts) that act as mediators between teriparatide and the aqueous environment. These intermediaries prevent direct harmful interactions by forming protective complexes and controlling the chemical microenvironment, thereby reducing deamidation, isomerization, and oxidation.
2Reliability
If pH is adjusted to 3.0-5.0 with buffer systems, then deamidation and isomerization are inhibited, but oxidation may be promoted
Solution Approach 1:
Methionine serves as a sacrificial intermediary that preferentially undergoes oxidation instead of teriparatide. The patent specifies methionine at 0.1-10 mg/mL to create a protective reducing environment. D-mannitol acts as another intermediary that scavenges reactive oxygen species and metal ions, preventing oxidation at the pH 3.0-5.0 range where deamidation and isomerization are suppressed.
Solution Approach 2:
The patent creates local quality differences by adding inorganic salts (sodium chloride 1-50 mM, potassium chloride 1-50 mM, or calcium chloride 0.1-50 mM) that locally modify the chemical environment around teriparatide molecules. These salts control ionic strength and metal ion availability, creating microenvironments that simultaneously suppress deamidation/isomerization while preventing oxidation through controlled ion interactions.
3Manufacturing precision
If stabilizers and buffers are added to inhibit degradation, then teriparatide purity is maintained, but manufacturing cost and formulation complexity increase
Solution Approach 1:
The patent establishes specific parameter ranges that balance purity with manufacturability: pH 3.0-5.0 (optimizing stability without requiring complex buffer systems), methionine 0.1-10 mg/mL, D-mannitol 1-100 mg/mL, and inorganic salts at defined concentrations. These parameters ensure high purity by inhibiting all major degradation pathways while remaining compatible with standard pharmaceutical manufacturing processes.
Solution Approach 2:
The patent creates a composite formulation system combining multiple stabilizing mechanisms: pH control through weak acid buffers, protein stabilizers (methionine and D-mannitol), and ionic strength control (inorganic salts). This composite approach synergistically addresses deamidation, isomerization, and oxidation simultaneously, achieving high purity while maintaining formulation simplicity through well-established pharmaceutical excipients.
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 solution effectively inhibits the formation of undesirable products, ensuring the stability and high purity of teriparatide, thereby maintaining its efficacy over a long period.
Implementation Method 1
inhibiting the formation of oxidized product of teriparatide or a salt thereof
Implementation Method 2
inhibiting the formation of deamidated product of teriparatide or a salt thereof
Data Source
AI summary
According to the present invention, a liquid pharmaceutical preparation containing teriparatide or a salt thereof having excellent physical properties, the liquid pharmaceutical preparation containing teriparatide or a salt thereof, and at least one or more members of inorganic salts and/or organic salts is provided.