TH-302 Freeze-Dried Formulation With High Drug Loading
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Solution Overview
Problem
Existing freeze-dried formulations of TH-302 have low drug loading capacity, requiring multiple vials for administration and posing high medication costs, while high-concentration injections with adjuvants like dimethylacetamide cause adverse reactions.
Innovation Solution
A high-concentration solution for TH-302 is developed using tert-butanol and water as solvents, with suitable excipients like sucrose or mannitol, to create a freeze-dried formulation with increased drug loading capacity and avoid adverse reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional freeze-dried formulations of TH-302 are used, then the formulation can be prepared with simple excipients, but the drug loading capacity is low requiring multiple vials for administration
Solution Approach 1:
The patent changes the solvent system parameters from conventional aqueous solutions to a mixed solvent system comprising water, tert-butanol, and ethanol. This parameter change enables the formulation to achieve high drug loading capacity (up to 500 mg/mL) while maintaining freeze-dried formulation stability, thereby reducing the number of vials needed for administration.
2Quantity of substance
If high-concentration injections with adjuvants like dimethylacetamide are used, then the drug loading capacity is improved, but adverse reactions occur
Solution Approach 1:
The patent extracts and removes the harmful adjuvant dimethylacetamide from the formulation while replacing it with a safe mixed solvent system of water, tert-butanol, and ethanol. This extraction eliminates the cause of adverse reactions while maintaining the high drug loading capacity through the optimized solvent system and excipient combination.
Solution Approach 2:
The patent introduces tert-butanol and ethanol as intermediary substances that facilitate high drug solubility and formulation stability without causing adverse reactions. These intermediary solvents act as safe alternatives to dimethylacetamide, enabling high-concentration formulations (up to 500 mg/mL) with improved safety profile.
3Quantity of substance
If multiple vials are used to achieve required dosage, then the total drug amount is sufficient, but the medication cost increases
Solution Approach 1:
The patent merges multiple low-concentration vials into a single high-concentration freeze-dried formulation containing up to 500 mg/mL TH-302. This merging approach consolidates the total drug amount required for administration into one vial, eliminating the need for multiple vials and thereby reducing medication costs while maintaining sufficient total dosage.
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 enables a freeze-dried formulation with improved drug loading, reducing the number of vials needed and minimizing adverse reactions, enhancing clinical convenience and safety.
Implementation Method 1
A solution (20 mL) of TH-302 (100 mg) and sucrose (1 g) was added to a freeze-dried vial and freeze-dried to produce a freeze-dried unit dosage form
Implementation Method 2
The follow-up dose regimen for the human patients in the Phase I clinical trial of TH-302 uses a freeze-dried formulation. The TH-302 freeze-dried formulation for injection is prepared in a 100 mL glass vial
Data Source
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AI summary
Provided are a TH-302 solution, a freeze-dried formulation, a freeze-dried formulation unit package, an injection, and an injection preparation method. The solution for preparing a freeze-dried formulation having high drug loading capacity contains TH-302, water, tert-butyl alcohol, and mannitol; the water and the tert-butyl alcohol are used as a mixed solvent, the volume percentage of the tert-butyl alcohol relative to the solution is (30±3)% or the mass percentage is (24±2.4)%, or the content of the tert-butyl alcohol in the solution is (235.5±23.55) mg/mL; the content of TH-302 in the solution is (8.16±0.82) mg/g or (8.00±0.80) mg/mL; the mannitol is used as an excipient, the mass percentage of the mannitol in the solution is (7.14±0.71)% or the content of the mannitol in the solution is (70±7) mg/mL; and the pH value of the solution is 4-9. The freeze-dried formulation contains TH-302 and mannitol; the drug loading capacity of TH-302 in the freeze-dried formulation is (8.00±0.80) mg/cm3 or the mass percentage of TH-302 in the freeze-dried formulation is (10.23±1.02)%; and the content of the mannitol in the freeze-dried formulation is (70±7) mg/cm3, or the content of the mannitol in the freeze-dried formulation is the percentage balance of the mass percentage, (10.23±1.02)%, of TH-302.