Rapamycin Formulation Stability via Nitrogen Blanketing
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Solution Overview
Problem
Existing pharmaceutical formulations, particularly those containing rapamycin, are unstable due to sensitivity to air components like oxygen, requiring additional preservatives that can be toxic to eye tissues, and lack stability over time.
Innovation Solution
Development of stable liquid formulations with elevated nitrogen levels and reduced oxygen levels, packaged in sealed vessels to minimize exposure to air, which maintains the therapeutic agent's potency without toxic preservatives, including self-emulsifying and in situ gelling formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If antioxidants such as BHT or ascorbyl palmitate are added to stabilize formulations, then stability is improved, but toxicity to eye tissues increases
Solution Approach 1:
The patent removes harmful antioxidants (BHT, ascorbyl palmitate) from the formulation entirely and replaces them with nitrogen gas sparging and headspace nitrogen blanketing. This extraction of toxic substances while maintaining stability through inert atmosphere protection resolves the contradiction between stability and toxicity.
Solution Approach 2:
The patent uses nitrogen gas to create an inert atmosphere by sparging the formulation and filling the headspace with nitrogen. This inert environment prevents oxidation of rapamycin without introducing toxic preservatives, simultaneously achieving stability while eliminating toxicity concerns.
2Ease of operation
If formulations are exposed to air during storage, then ease of operation is improved, but stability deteriorates due to oxygen sensitivity
Solution Approach 1:
The patent seals formulations in vessels with nitrogen-filled headspaces, creating a portable inert atmosphere that maintains stability during storage and transport without requiring special handling conditions. This resolves the contradiction by making the formulation both easy to store and stable against oxidation.
Solution Approach 2:
The formulation is prepared in advance with nitrogen sparging and headspace nitrogen filling before sealing. This preliminary action of removing oxygen and replacing it with nitrogen ensures stability is established before storage begins, allowing convenient long-term storage without degradation.
3Ease of operation
If head space volume is increased relative to fill volume, then ease of operation is improved, but stability worsens due to increased oxygen exposure
Solution Approach 1:
The patent fills the headspace with nitrogen gas after sealing, converting the potentially harmful oxygen-rich environment into a protective inert atmosphere. This allows flexible headspace volumes for manufacturing convenience while maintaining formulation stability through the nitrogen barrier.
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 formulations retain at least 60% to 90% of their initial strength for extended periods, including up to 24 months, without the need for toxic preservatives, ensuring effective and safe delivery of rapamycin for ocular treatments.
Implementation Method 1
The liquid formulations are prepared by a process including sparging with nitrogen one or more components of the liquid formulation with nitrogen
Implementation Method 2
sealed vessels comprising a liquid formulation comprising an immunophilin binding compound, wherein the liquid formulation is in contact with a head space gas having greater than 80% nitrogen gas
Data Source
AI summary
Described herein are formulations comprising therapeutic agents, including but not limited to formulations comprising rapamycin, pharmaceutical formulations, unit dose forms, kits, methods of preparing formulations, and methods of using formulations. Such formulations and methods have increased stability.