Formulations of terlipressin
Inventors
Markham, Penelope • Adams, Jonathan • Smith, Denise • Bacardit Cabado, Jorge
Assignees
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Publication Number
US-12156898-B2
Publication Date
2024-12-03
Expiration Date
Abstract
The disclosure provides pharmaceutical compositions comprising terlipressin having increased concentration with long term storage stability.
Core Innovation
The invention relates to an aqueous composition comprising terlipressin acetate or a pharmaceutically acceptable salt thereof, with terlipressin acetate present at about 0.5 to about 1.0 mg/mL and aspartic acid present at about 0.1 to 1 mg/mL. The composition is defined to have a pH from about 3.4 to about 5.0 and a sum of impurities of less than 5.0% of the total weight of the impurities and terlipressin in the composition.
The aqueous terlipressin acetate formulations are optimized to provide stable, higher-concentration room temperature storage. Stability is described using experimental evidence including HPLC and label strength and purity assessments across temperature conditions including 2–8°C, 25°C, and 40°C, with aspartic acid versus acetic acid stabilization and with and without nitrogen protection.
Delivery embodiments described include pre-filled syringe and kit/container formats for terlipressin acetate. The document describes use scenarios including outpatient or rapid-use settings, including continuous infusion and bolus administration via an ambulatory pump and diluent options, and long-term syringe storage data including clear colorless appearance and trends in impurity and label strength over time.
Claims Coverage
The independent claim covers an aqueous terlipressin acetate formulation defined by specific concentration ranges, acidic pH range, and a low sum of impurities. Across the dependent claims associated with the independent claim, six inventive features refine impurity limits, pH, stability conditions, pH adjusting agents, and kit instructions for administration modes.
Aspartic-acid aqueous terlipressin acetate with acidic pH and low impurities
An aqueous composition comprising terlipressin acetate (or a pharmaceutically acceptable salt) with terlipressin acetate at about 0.5 to about 1.0 mg/mL, aspartic acid at about 0.1 to 1 mg/mL, pH about 3.4 to about 5.0, and a sum of impurities of less than 5.0% of the total weight of the impurities and terlipressin.
Tighter impurity limit
The aqueous composition has a sum of impurities of less than 4.5% of the total weight of the impurities and terlipressin in the composition.
Narrower pH range
The pH of the composition is from about 4.0 to about 5.0.
Defined stability durations under storage conditions
The composition is stable at about 25°C for at least 24 months and at 30°C and about 75% relative humidity for at least six months.
Specific pH adjusting agents
The composition includes a pH adjusting agent selected from hydrochloric acid, potassium hydroxide, acetic acid, sodium hydroxide, or potassium hydroxide.
Kit instructions for administration by continuous infusion or bolus intravenous dose
A kit includes instructions for administering the composition by continuous infusion or as a bolus intravenous dose.
Overall, the claim set is centered on an aspartic-acid-containing aqueous terlipressin acetate formulation with an acidic pH and low sum of impurities, further refined by tighter impurity and pH ranges, defined stability conditions, specific pH adjusting agents, and kit embodiments providing instructions for continuous infusion or bolus intravenous administration.
Stated Advantages
Provides stable, higher-concentration aqueous terlipressin acetate formulations for long-term room temperature storage.
Supports delivery using pre-filled syringe/kit formats for rapid-use/outpatient settings.
Enables administration by continuous infusion or bolus intravenous dose via an ambulatory pump with diluent options.
Documented Applications
Outpatient/rapid-use settings using pre-filled syringe or kit/container delivery of the aqueous terlipressin acetate formulation.
Continuous infusion administration and bolus intravenous dose administration via an ambulatory pump, with options involving diluent containers.
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