Pharmaceutical formulations for subcutaneous administration of furosemide
Inventors
Michaels, Scott A. • Muntendam, Pieter • Larsen, Glenn R.
Assignees
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Publication Number
US-10272064-B2
Publication Date
2019-04-30
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 document describes liquid pharmaceutical formulations comprising furosemide, or a pharmaceutically acceptable salt, hydrate or ester thereof, with tris(hydroxymethyl)aminomethane (Tris/THAM). The formulation includes water and hydrochloric acid or sodium hydroxide or combinations thereof, and sodium chloride, with furosemide at about 2 mg/mL to about 20 mg/mL and THAM at about 50 mM to about 500 mM.
The formulation is characterized by a molar ratio of THAM to furosemide greater than one, and in specific embodiments greater than or equal to two, with pH between about 7 and about 8.5 or between about 7.2 and about 8, and isosmotic character. The document states that unbuffered furosemide solutions in this pH range are unstable and precipitate, while Tris buffer unexpectedly improves pH control and solubility, including increased solubility up to about 32 mg/mL.
The document further reports improved pH/API stability compared with formulations having a 1:1 Tris:furosemide ratio, under room temperature and various storage and accelerated conditions. It also describes integration with subcutaneous administration using pre-loaded device formats, including micropumps and patch devices, where the formulation is loaded into a pump device.
Claims Coverage
The independent claims define 4 inventive features centered on THAM-buffered liquid pharmaceutical formulations with furosemide, specified concentration ranges, an isosmotic formulation, a defined pH range, and a THAM-to-furosemide molar ratio condition.
Tris-buffered isosmotic THAM-to-furosemide formulation
A liquid pharmaceutical formulation consisting of furosemide (or a pharmaceutically acceptable salt, hydrate or ester), tris(hydroxymethyl)aminomethane at about 50 mM to about 500 mM, water, hydrochloric acid or sodium hydroxide or combinations thereof, and sodium chloride, wherein the molar ratio of tris(hydroxymethyl)aminomethane to furosemide is greater than one and the formulation is isosmotic and has a pH between about 7 to about 8.5.
Greater-than-or-equal-to-two THAM-to-furosemide isosmotic pH window
A liquid pharmaceutical formulation consisting of furosemide (or a pharmaceutically acceptable salt, hydrate or ester) at about 2 mg/mL to about 20 mg/mL, tris(hydroxymethyl)aminomethane at about 50 mM to about 500 mM, water, hydrochloric acid or sodium hydroxide or combinations thereof, and sodium chloride, wherein the molar ratio of tris(hydroxymethyl)aminomethane to furosemide is greater than or equal to two and the formulation is isosmotic and has a pH between about 7.2 to about 8.
Concentrated THAM sub-range with isosmotic pH window
A liquid pharmaceutical formulation consisting of furosemide (or a pharmaceutically acceptable salt, hydrate or ester) at about 2 mg/mL to about 20 mg/mL, tris(hydroxymethyl)aminomethane at about 50 mM to about 250 mM, water, hydrochloric acid or sodium hydroxide or combinations thereof, and sodium chloride, wherein the molar ratio of tris(hydroxymethyl)aminomethane to furosemide is greater than one and the formulation is isosmotic and has a pH between about 7.2 to about 8.
Sole therapeutically active furosemide with fixed THAM ratio and pH
A liquid pharmaceutical formulation comprising furosemide where furosemide is the sole therapeutically active agent and the amount of furosemide is about 8 mg/mL, and a pharmaceutically acceptable buffer comprising tris(hydroxymethyl)aminomethane at about 50 mM, wherein the molar ratio of tris(hydroxymethyl)aminomethane to furosemide is about two and the formulation is isosmotic and has a pH of about 7.4.
Across the independent claims, the formulations share a THAM-buffered, isosmotic liquid containing furosemide with specified furosemide and THAM concentration ranges, a THAM-to-furosemide molar ratio condition greater than one, greater than or equal to two, or about two, and pH ranges of about 7 to about 8.5, about 7.2 to about 8, or about 7.4. One claim further narrows the composition by specifying furosemide as the sole therapeutically active agent and fixing the furosemide amount, THAM concentration, ratio, and pH.
Stated Advantages
Improved pH control and solubility compared with unbuffered furosemide solutions that are unstable or precipitate in the stated pH range.
Improved pH/API stability at room temperature and under storage and accelerated conditions versus a 1:1 Tris:furosemide ratio.
Isosmotic character is associated with enabling subcutaneous use in pre-loaded device formats, including micropumps and patch devices, in the described embodiments.
Documented Applications
Subcutaneous administration of liquid furosemide formulations loaded into a pump device, including pre-loaded micropump and patch device formats.
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