Controlled-release formulations comprising Torsemide
Inventors
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Publication Number
US-10154963-B2
Publication Date
2018-12-18
Expiration Date
Abstract
Disclosed herein are controlled-release (GR, e.g., extended-release (ER) or prolonged-release (PR)) oral dosage formulation comprising an effective amount of Torsemide or a pharmaceutically acceptable salt thereof and at least one sustained release excipient comprising a polymer, wherein the at least one matrix component is selected from the group consisting of: hydroxy propyl cellulose (HPC), hydroxpropyl methyl cellulose (HPMC), glyceryl behenate, and a polyethylene glycol glyceride. Torsemide may be present in the formulation in a range of about 1 wt % to about 20 wt %, or about 5 wt % to about 10 wt % and the matrix component is present in the formulation in a range of about 5 wt % to about 50 wt %, or about 15 wt % to about 35 wt %. The formulation may further comprise at least one binder, lactose, talc and magnesium stearate. Methods of making and using the controlled-release oral dosage Torsemide formulation are also disclosed. A novel mechanism for Torsemide action in diuresis is further disclosed.
Core Innovation
The invention provides an extended-release oral dosage formulation manufactured by wet granulation for torsemide or a pharmaceutically acceptable salt thereof. The formulation is based on matrix sustained-release excipients including hydroxypropyl methyl cellulose and high density microcrystalline cellulose, together with lactose monohydrate, and uses defined wt % composition ranges to form an extended-release structure intended to achieve a target dissolution profile over about 12 hours.
The invention describes extended-release performance through pharmacokinetic comparisons with a corresponding immediate-release dosage form. The disclosed formulation is reported to change pharmacokinetic parameters such as reduced Cmax and AUC exposure and increased Tmax and t1/2, while maintaining extended delivery over later time windows.
The invention also states that the extended-release profile is associated with prolonged natriuresis and diuresis, greater fluid and Na+ loss, and mitigation of creatinine clearance reduction, with blood pressure effects reported. The described rationale is that a controlled-release profile reduces plasma fluctuation and may improve tolerability, compliance, and avoidance of night dosing.
Claims Coverage
The document includes three independent claims. Across the independent claims, the inventive features cover wet granulation manufacture, defined extended-release matrix excipient composition ranges for torsemide, and in one claim the co-inclusion of an aldosterone receptor antagonist within the extended release dosage formulation.
Wet-granulation extended-release torsemide formulation with defined HPMC, microcrystalline cellulose and lactose monohydrate
An extended-release oral dosage formulation manufactured by wet granulation comprising torsemide or a pharmaceutically acceptable salt thereof as an active ingredient; 27 wt % to 34 wt % of hydroxypropyl methyl cellulose; 25 wt % to 53 wt % of high density microcrystalline cellulose of nominal particle size of about 100 micrometer; and 6.5 wt % to 8 wt % of lactose monohydrate.
Wet-granulation extended-release torsemide formulation with defined HPMC, microcrystalline cellulose and lactose monohydrate
An extended-release oral dosage formulation manufactured by wet granulation comprising torsemide or a pharmaceutically acceptable salt thereof as an active ingredient; 27 wt % to 34 wt % of hydroxypropyl methyl cellulose; 25 wt % to 53 wt % of high density microcrystalline cellulose of nominal particle size of about 100 micrometer; and 5 wt % to 8 wt % of lactose monohydrate.
Wet-granulation extended-release torsemide formulation co-formulated with an aldosterone receptor antagonist
An extended-release oral dosage formulation manufactured by wet granulation comprising torsemide or a pharmaceutically acceptable salt thereof, 27 wt % to 34 wt % of hydroxypropyl methyl cellulose; 25 wt % to 53 wt % of high density microcrystalline cellulose of nominal particle size about 100 micrometer, 5 wt % to 8 wt % of lactose monohydrate, and an aldosterone receptor antagonist or a pharmaceutically acceptable salt thereof, wherein said torsemide and said aldosterone receptor antagonist are comprised in an extended release dosage formulation.
Overall, the claims are directed to wet-granulated extended-release oral torsemide formulations with specified ranges of hydroxypropyl methyl cellulose, high density microcrystalline cellulose, and lactose monohydrate. One independent claim further requires inclusion of an aldosterone receptor antagonist in the extended-release dosage formulation.
Stated Advantages
Reduced plasma fluctuation.
Improved tolerability and compliance.
Avoidance of night dosing.
Prolonged natriuresis and diuresis.
Greater fluid and Na+ loss.
Mitigated creatinine clearance reduction.
Blood pressure effects are reported.
Improved pharmacokinetic profile with decreased Cmax and AUC and increased Tmax and t1/2.
Documented Applications
Oral extended-release torsemide therapy intended to provide prolonged natriuresis and diuresis and influence renal sodium and potassium-related effects through modulation of renal pathways.
Use of the extended-release torsemide formulation in a setting where avoidance of night dosing and improved compliance/tolerability are relevant.
Use of an extended-release co-formulation including an aldosterone receptor antagonist together with torsemide in an extended-release oral dosage formulation.
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