Lyophilized DNA Formulation Maintains Supercoiled Structure
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Solution Overview
Problem
There is a need for improved stability, safety, and economic feasibility in formulating naked DNA-based pharmaceutical products for direct therapeutic delivery, with limited research on stability under storage conditions and excipients required for uniform reconstitution and reduced contaminant load.
Innovation Solution
A novel lyophilized pharmaceutical composition that maintains DNA construct stability by reducing conformational changes during lyophilization, allowing uniform reconstitution and minimizing potency loss, comprising plasmid DNA with specific buffer and excipient concentrations, including potassium phosphate, mannitol, sucrose, and NaCl, to ensure accurate and consistent administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naked DNA constructs are formulated for direct in vivo delivery, then therapeutic efficacy is improved, but stability under storage conditions deteriorates
Solution Approach 1:
The patent applies parameter changes by optimizing the concentrations of excipients (sucrose 0.5-1.1%, mannitol 0-3%, NaCl 0.1-0.9%) and buffer pH (7.0-9.0) to maintain DNA stability during lyophilization and storage. This resolves the contradiction by adjusting formulation parameters to preserve both therapeutic efficacy and storage stability.
Solution Approach 2:
The patent uses composite materials by combining naked DNA constructs with a specific formulation system including sucrose, mannitol, NaCl, and potassium phosphate buffer. This composite formulation protects the DNA during storage while maintaining its therapeutic function, resolving the stability-efficacy contradiction.
2Stability of the object's composition
If lyophilization is used to improve storage stability, then stability is improved, but conformational change of DNA constructs occurs
Solution Approach 1:
The patent changes physical-chemical parameters by controlling lyophilization conditions and formulation composition (sucrose 0.5-1.1%, mannitol 0-3%) to minimize conformational changes. The optimized parameters allow lyophilization to proceed while preserving the supercoiled DNA structure, resolving the contradiction between storage stability and structural integrity.
Solution Approach 2:
The patent applies beforehand cushioning by incorporating protective excipients (sucrose, mannitol) in the formulation before lyophilization. These excipients cushion the DNA during the lyophilization process, preventing conformational changes while enabling storage stability.
3Manufacturing precision
If uniform reconstitution is achieved, then manufacturing precision is improved, but complexity of formulation increases
Solution Approach 1:
The patent achieves uniform reconstitution by optimizing formulation parameters (sucrose 0.5-1.1%, mannitol 0-3%, NaCl 0.1-0.9%, potassium phosphate buffer pH 7.0-9.0). These parameter optimizations ensure complete and uniform reconstitution without requiring overly complex formulation systems.
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 composition achieves high stability and uniform reconstitution of DNA constructs, maintaining at least 90% supercoiled DNA form after storage and reconstitution, ensuring effective and safe therapeutic delivery.
Implementation Method 1
A novel lyophilized pharmaceutical composition that maintains the stability of the DNA construct (e.g., a plasmid) during lyophilization
Data Source
AI summary
The present invention provides a novel lyophilized pharmaceutical composition that maintains the stability of a DNA plasmid while forming a uniform and elegant cake during lyophilization. The novel lyophilization formulation further allows uniform reconstitution of the DNA plasmid in a pharmaceutically acceptable solution, enabling complete recover of the active ingredients, minimizing partial loss of potency and allowing administration of the active ingredients in an accurate and consistent manner. Additionally provided herein include methods of making the lyophilized pharmaceutical composition and methods of administering the composition for treatment of various diseases.