Pharmaceutical formulations for subcutaneous administration of furosemide
Inventors
Michaels, Scott A. • Muntendam, Pieter • Larsen, Glenn R.
Assignees
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Publication Number
US-11433044-B2
Publication Date
2022-09-06
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 provides stable liquid pharmaceutical formulations comprising furosemide as the sole therapeutically active agent and tris(hydroxymethyl)aminomethane in molar excess relative to furosemide. The formulations include tris(hydroxymethyl)aminomethane at a concentration in a range of about 50 mM to about 500 mM, with a pH between about 7 and about 8.5, and are isosmotic.
The disclosed tris(hydroxymethyl)aminomethane-containing systems address poor stability of furosemide in liquid formulations, including pH instability and API instability when compared to unbuffered or phosphate-buffered systems. The formulations are described as improving pH/API stability and solubility.
The compositions are used for treating a human with or exhibiting the symptoms of edema, hypertension or heart failure by administering the liquid pharmaceutical formulation subcutaneously. The subcutaneous administration is described using delivery options including a patch device and a pump device, and the formulation is discussed in relation to compatibility with sterilization and device reservoir formulations.
Claims Coverage
Two independent claims are directed to methods of treating a human with edema, hypertension or heart failure by subcutaneous administration of an isosmotic liquid pharmaceutical formulation. The claims recite two inventive features centered on the furosemide formulation and delivery device, with different minimum furosemide concentration and pH language in the patch-device claim.
Subcutaneous furosemide formulation with tris(hydroxymethyl)aminomethane molar excess
A method administering subcutaneously a liquid pharmaceutical formulation comprising furosemide as the sole therapeutically active agent, wherein the amount of furosemide is about 5 mg/mL or greater, and tris(hydroxymethyl)aminomethane at a concentration in a range of about 50 mM to about 500 mM, wherein 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 about 1.5.
Patch device subcutaneous furosemide formulation with tris(hydroxymethyl)aminomethane molar excess
A method administering subcutaneously using a patch device a liquid pharmaceutical formulation comprising furosemide as the sole therapeutically active agent, wherein the amount of furosemide is about 15 mg/mL or greater, and tris(hydroxymethyl)aminomethane at a concentration in a range of about 50 mM to about 500 mM, wherein the liquid pharmaceutical formulation is isosmotic and has a pH between about 7.2 to about 8, and the molar ratio of tris(hydroxymethyl)aminomethane to furosemide is greater than or equal to 1.5.
Across the independent claims, the inventive coverage centers on an isosmotic liquid formulation where furosemide is the sole therapeutically active agent and tris(hydroxymethyl)aminomethane is present at about 50 mM to about 500 mM with a defined tris(hydroxymethyl)aminomethane-to-furosemide molar ratio greater than about 1.5 or greater than or equal to 1.5, together with a specified pH window. The claim set additionally differentiates subcutaneous delivery using a pump device versus a patch device and specifies different minimum furosemide amounts in the independent claims.
Stated Advantages
Improved pH/API stability versus unbuffered or phosphate-buffered systems.
Improved solubility.
Stability demonstrated with measurements including HPLC, pH, and osmolality under room and cold/accelerated temperature conditions.
Documented Applications
Treating a human with or exhibiting the symptoms of edema by subcutaneous administration of the disclosed liquid pharmaceutical formulation.
Treating a human with or exhibiting the symptoms of hypertension by subcutaneous administration of the disclosed liquid pharmaceutical formulation.
Treating a human with or exhibiting the symptoms of heart failure by subcutaneous administration of the disclosed liquid pharmaceutical formulation.
Use of the disclosed liquid pharmaceutical formulation with a pump device for subcutaneous administration.
Use of the disclosed liquid pharmaceutical formulation with a patch device for subcutaneous administration.
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