Terminally Sterilized Hydromorphone IV Bags for Long-Term Stability
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Solution Overview
Problem
Current hydromorphone hydrochloride formulations are not available in larger volumes and require compounding, which introduces errors, stability issues, and risks contamination and sterility concerns due to dilution and heat-sensitive nature, necessitating a stable, ready-to-administer solution.
Innovation Solution
Development of terminally sterilized hydromorphone hydrochloride formulations in polymeric infusion containers with specific excipients and pH buffering, maintaining stability for long-term storage and avoiding heat-induced degradation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If commercially available hydromorphone hydrochloride products are diluted to prepare larger volumes, then the availability and volume of hydromorphone solutions are improved, but the stability, sterility, and concentration accuracy deteriorate due to water loss, contamination risk, and potential errors in mixing and measuring diluents
Solution Approach 1:
The patent applies preliminary action by pre-formulating hydromorphone hydrochloride in larger volumes (100 mL and 250 mL) with appropriate stabilizers and buffers before storage. This eliminates the need for dilution at the point of use, ensuring that the solution is ready for immediate administration with guaranteed stability and sterility. The formulation includes citrate buffer and sodium chloride to maintain pH and prevent degradation during long-term storage.
Solution Approach 2:
The patent changes the formulation parameters by incorporating specific concentrations of citrate buffer (0.02-0.1% w/v) and sodium chloride (0.85-1.15% w/v) to optimize stability. The pH is adjusted to 3.5-4.5 using citric acid and sodium hydroxide, which prevents hydrolysis and degradation of hydromorphone during storage. These parameter changes enable long-term stability without dilution.
2Reliability
If heat treatment is applied to sterilize diluted hydromorphone solutions, then sterility is improved, but the concentration accuracy and purity deteriorate due to heat-induced degradation of hydromorphone
Solution Approach 1:
The patent applies preliminary action by performing terminal sterilization on the complete formulation (including stabilizers and buffers) before storage, rather than sterilizing after dilution. This ensures sterility is achieved while the formulation components are already in place to protect against heat-induced degradation. The citrate buffer and controlled pH range (3.5-4.5) provide thermal protection during the sterilization process.
Solution Approach 2:
The patent uses citrate buffer as an intermediary substance that mediates between the heat sterilization process and the hydromorphone molecule. The buffer system absorbs and stabilizes the formulation during heat treatment, preventing direct thermal degradation of hydromorphone while allowing effective sterilization to occur.
3Adaptability or versatility
If dilution steps are performed to prepare hydromorphone solutions, then the concentration flexibility is improved, but the time consumption and risk of impurity introduction increase
Solution Approach 1:
The patent applies preliminary action by providing multiple pre-formulated concentration options (0.2 mg/mL, 0.4 mg/mL, 0.8 mg/mL, and 1.6 mg/mL) in ready-to-use volumes. This eliminates the need for time-consuming dilution steps at the point of use, while still providing concentration flexibility to meet different clinical needs. The formulations are prepared in advance with all necessary stabilizers and buffers.
4Duration of action of stationary object
If compounded hydromorphone solutions are stored in PVC bags or CADD reservoirs, then the availability for long-term infusion is improved, but the concentration accuracy deteriorates due to water loss through the container material
Solution Approach 1:
The patent changes the formulation parameters by optimizing the pH range (3.5-4.5) and incorporating citrate buffer to minimize water loss through container materials during long-term storage. The buffered formulation maintains stable osmotic pressure and reduces evaporation, preserving concentration accuracy over extended storage periods in PVC bags and CADD reservoirs.
Data Source
AI summary
The present disclosure relates to a ready-to-administer (RTA), intravenous (IV) bag presentation for hydromorphone. In particular, the present disclosure relates to terminally sterilized liquid formulations comprising hydromorphone hydrochloride in sodium chloride packaged in an RTA IV bag. The present disclosure also relates to methods of treating patients by administration of such formulations and RTA IV bags containing such formulations.