Tenecteplase Formulation for Acute Ischemic Stroke
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Solution Overview
Problem
Current treatments for acute ischemic stroke using tenecteplase (TNK) lack conclusive evidence on safe and effective dosing, and existing formulations are not approved as safe and efficacious by drug regulators, necessitating the development of improved pharmaceutical compositions with specific amounts of TNK for effective and safe administration.
Innovation Solution
The production of TNK using recombinant DNA technology in a perfusion-based continuous fermentation system in Chinese Hamster Ovary (CHO) cells, followed by chromatographic steps to achieve high purity, and formulation with specific excipients to identify safe and effective doses through clinical trials.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TNK is used for treatment of acute ischemic stroke, then fibrinolytic efficacy is improved, but safety and effective dosing remains undetermined
Solution Approach 1:
The patent applies parameter changes by modifying the concentration and dosage parameters of TNK in pharmaceutical formulations. Different formulations contain specific concentrations (e.g., 0.25 mg/mL, 0.50 mg/mL, 1.00 mg/mL) to optimize both efficacy and safety. This systematic variation of dosage parameters enables precise dosing determination through clinical trials, resolving the contradiction between achieving reliable fibrinolytic effect and determining precise safe dosing.
2Ease of operation
If existing TNK formulations are used, then treatment is available, but they are not approved as safe and efficacious by drug regulators
Solution Approach 1:
The patent applies preliminary action by conducting comprehensive preclinical studies and formulation optimization before regulatory submission. Multiple formulations are prepared and characterized in advance with defined pharmacokinetic and pharmacodynamic properties. Clinical trials are designed with predetermined dosing regimens based on preliminary data, enabling systematic evaluation of safety and efficacy to achieve regulatory approval.
3Duration of action of moving object
If natural human TPA is used, then plasma half-life is 8-10 minutes, but this short half-life limits effective administration in short period
Solution Approach 1:
The patent applies parameter changes by modifying the molecular structure of TPA to create tenecteplase with altered pharmacokinetic parameters. Six amino acid substitutions in the TPA sequence result in extended plasma half-life (20-24 minutes compared to 8-10 minutes for natural TPA). This parameter change in the protein structure directly addresses the limitation of short half-life, allowing effective administration within the critical time window for stroke treatment.
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 method provides safe and effective TNK formulations for acute ischemic stroke treatment, with clinical trials determining the optimal dose and demonstrating improved efficacy and safety compared to existing treatments, as evidenced by significant improvement in NIH-SS scores and reduced incidence of adverse events.
Implementation Method 1
The production of TNK was done by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells in a perfusion-based continuous fermentation system
Implementation Method 2
The production of TNK was done by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells in a perfusion-based continuous fermentation system
Implementation Method 3
followed by chromatographic steps to achieve high purity
Data Source
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AI summary
Pharmaceutical compositions of tenecteplase that are safe and effective in the treatment of acute ischemic stroke compared with the known compositions are disclosed. The compositions of the invention are invented based on a series of testing trials on the different amounts of the TNK and isolating specific amount that is optimally suitable in terms of desired effects of TNK in the treatment of acute ischemic stroke.