Pharmaceutical formulations for subcutaneous administration of furosemide
Inventors
Michaels, Scott A. • Muntendam, Pieter • Larsen, Glenn R.
Assignees
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Publication Number
US-9884039-B2
Publication Date
2018-02-06
Expiration Date
Abstract
The present teachings relate to liquid pharmaceutical formulations of furosemide, where the pharmaceutical formulations include a molar excess of tris(hydroxymethyl)aminomethane to furosemide, have a pH in the range of 7 to 8.5, and a concentration of tris(hydroxymethyl)aminomethane greater than or equal to about 50 mM. The present teachings can improve the stability of liquid pharmaceutical formulations including furosemide and the suitability of such pharmaceutical formulations for subcutaneous administration or delivery.
Core Innovation
The invention relates to liquid pharmaceutical formulations of furosemide for subcutaneous delivery, and methods of treating a patient with or exhibiting the symptoms of edema, hypertension or heart failure. The liquid pharmaceutical formulation contains furosemide, or a pharmaceutically acceptable salt, hydrate or ester thereof, with furosemide as the sole therapeutically active agent. The formulation is liquid, isosmotic, and is buffered with tris(hydroxymethyl)aminomethane (tris/THAM/Tris).
The formulations use a molar excess of tris(hydroxymethyl)aminomethane over furosemide, with a molar ratio of tris(hydroxymethyl)aminomethane to furosemide greater than or equal to two, and in other claim language greater than or equal to 1.5. The tris(hydroxymethyl)aminomethane concentration is defined within ranges that include about 50 mM to about 250 mM, and the pH is defined within ranges including about 7.2 to about 8 or about 7 to about 8.5.
The problem being addressed is poor solubility and stability of unbuffered furosemide and the need to enable near-physiologic pH and osmolality to reduce pain and support use in pre-loaded devices. The description reports that buffer studies show tris improves pH maintenance and enables higher solubility versus phosphate buffers, and that stability studies indicate no change under non-accelerated conditions and increased degradation under accelerated conditions depending on tris and pH.
Claims Coverage
The independent claims cover treating edema, hypertension or heart failure by administering a liquid pharmaceutical formulation in which furosemide is the sole therapeutically active agent and the formulation is tris-buffered, isosmotic, with defined pH and a tris-to-furosemide molar ratio. The claim set includes three inventive features, with subcutaneous delivery and device use also recited in the claim coverage.
Tris-buffered liquid furosemide with isosmotic pH and molar excess
Administering to a patient a liquid pharmaceutical formulation comprising furosemide as the sole therapeutically active agent and a pharmaceutically acceptable buffer comprising tris(hydroxymethyl)aminomethane, where the formulation is isosmotic and has a pH between about 7.2 to about 8, the furosemide amount is between about 2 mg/mL to about 15 mg/mL, the tris(hydroxymethyl)aminomethane concentration is about 50 mM to about 250 mM, and the molar ratio of tris(hydroxymethyl)aminomethane to furosemide is greater than or equal to two.
Subcutaneous tris-buffered liquid furosemide with fixed concentrations and molar ratio
Administering subcutaneously to a patient a liquid pharmaceutical formulation comprising about 8 mg/mL of furosemide as the sole therapeutically active agent and tris(hydroxymethyl)aminomethane at about 50 mM, where the molar ratio of tris(hydroxymethyl)aminomethane to furosemide is about 2, the liquid pharmaceutical formulation has a pH of about 7.4 and is isosmotic.
Subcutaneous liquid furosemide with tris buffer, isosmotic pH range, and molar ratio threshold
Administering subcutaneously to a patient a liquid pharmaceutical formulation comprising furosemide as the sole therapeutically active agent at an amount between about 2 mg/mL to about 20 mg/mL and tris(hydroxymethyl)aminomethane at a concentration greater than or equal to about 50 mM, where the liquid pharmaceutical formulation is isosmotic and has a pH between about 7 to about 8.5, and the molar ratio of tris(hydroxymethyl)aminomethane to furosemide is greater than or equal to 1.5.
Across the independent claims, coverage centers on liquid, isosmotic furosemide formulations buffered with tris(hydroxymethyl)aminomethane using defined tris concentrations and a tris-to-furosemide molar excess or threshold. The claims further specify pH ranges and furosemide concentration ranges, and include subcutaneous administration with dependent refinements for use with a pump device and patch device.
Stated Advantages
Tris improves pH maintenance.
Tris enables higher solubility versus phosphate buffers.
Stability under non-accelerated conditions is indicated.
Near-physiologic pH and osmolality are enabled to reduce pain.
Enables use in pre-loaded devices.
Documented Applications
Subcutaneous delivery of liquid furosemide formulations using micropump/patch device concepts.
Compatibility with pre-loaded devices is discussed.
Dry-heat sterilization feasibility is discussed.
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