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EP-4360621-B1 - FORMULATIONS OF BENDAMUSTINE

EP4360621B1EP 4360621 B1EP4360621 B1EP 4360621B1EP-4360621-B1

Inventors

  • SUNDARAM, Srikanth

Dates

Publication Date
20260506
Application Date
20130315

Claims (7)

  1. A liquid composition containing: a) from 0.5 to 5.6 mg/ml of bendamustine hydrochloride; b) a solubilizer comprising polyethylene glycol and propylene glycol, wherein the weight ratio of polyethylene glycol to propylene glycol is 90:10 to 85:15; c) an antioxidant; and d) about 50mL of a parenterally acceptable diluent selected from the group consisting of water for injection, 0.9% saline (normal saline), 0.45% saline (half normal saline), and 2.5 dextrose/0.45% saline; for use in a method of treating or preventing cancer or malignant disease in a human, comprising parenterally administering said liquid composition over a substantially continuous period of less than or equal to about 10 minutes to a human in need thereof, as part of an intravenous infusion, wherein: (i) the cancer or malignant disease is chronic lymphocytic leukemia and the amount of bendamustine administered to the human is about 100 mg/m 2 body surface area; or (ii) the cancer or malignant disease is indolent B-cell non-Hodgkin's lymphoma and the amount of bendamustine administered to the human is about 120 mg/m 2 body surface area.
  2. The liquid composition for use of claim 1, wherein the amount of solubilizer is from 2.0 to 22.4% vol.
  3. The liquid composition for use of claim 1, where the polyethylene glycol is PEG 400.
  4. The liquid composition for use of claim 1, wherein the weight ratio of polyethylene glycol to propylene glycol is 90:10, or the weight ratio of polyethylene glycol to propylene glycol is 85:15.
  5. The liquid composition for use of claim 1, wherein the antioxidant is monothioglycerol.
  6. A liquid composition comprising 25 mg/ml of bendamustine hydrochloride in a solubilizer comprising polyethylene glycol and propylene glycol, wherein the weight ratio of polyethylene glycol to propylene glyco1 is 90:10 to 85:15; for use in a method of treating or preventing cancer or malignant disease in a human according to any of claims 1-5; wherein the method comprises diluting the liquid composition comprising 25 mg/ml of bendamustine hydrochloride in 50 mL of a parenterally acceptable diluent to form the liquid composition according to any of claims 1-5 comprising about 0.5 mg/ml to about 5.6 mg/ml of bendamustine hydrochloride and parenterally administering said liquid composition according to any of claims 1-5.
  7. A concentrated, ready to use liquid formulation containing 25 mg/ml bendamustine HCl and admixed with sufficient solubilizer comprising polyethylene glycol and propylene glycol, wherein the weight ratio of polyethylene glycol to propylene glyco1 is 90:10 to 85:15, for use in a method of treating or preventing cancer or malignant disease in a human according to any of claims 1-5; wherein the method comprises transferring the liquid formulation to a suitable fixed volume diluent container; and wherein the method comprises parenterally administering a liquid composition according to any of claims 1-5.

Description

BACKGROUND OF THE INVENTION Bendamustine is used in the treatment of a number of cancers including leukemias, Hodgkin's disease and multiple myelomas. Bendamustine (present as the HCl salt) is the active ingredient of the commercial product Treanda™, a lyophilized powder for reconstitution. Current labeling requirements call for the reconstituted product to be immediately (within 30 minutes) diluted into 500 mL of parenterally acceptable diluents such as 0.9% saline (normal saline) or 2.5% dextrose/0.45% saline and administered as part of an intravenous infusion delivering 100 mg/m2 over 30 minutes or 120 mg/m2 over 60 minutes. The diluted admixture may be stored at 2-8°C for up to 24 hours, or 3 hours at room temperature (15-30°C); administration must be completed within this period due to limited chemical stability in aqueous solutions. Solubility limitations at 2-8°C with currently approved and/or available formulations are believed to prevent current formulations from being administered in smaller more concentrated infusion volumes up to about 150 ml; at volumes below 150 ml, solubility is not sufficient even at 25°C. Side effects associated with extravasation and local erythema, swelling and pain at the injection site also dictate that the infusion be as dilute as possible. Therefore, precautions are taken to avoid extravasation, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of bendamustine. Higher infusion volume and longer infusion times, however, are associated with many drawbacks. For example, after reconstitution, the current product has a short period of stability, degradation of the drug occurs from the time of reconstitution until the entire large volume infusion has been completely administered. The current label for Treanda™ therefore instructs that the admixture should be prepared as close as possible to the time of patient administration, and that administration of Treanda™ must be completed within the durations indicated above. From patient comfort and nursing administration points of view, higher infusion volumes and long infusion times are undesirable. Higher infusion volumes may be associated with higher likelihood of weight gain and edema. Shorter infusion times and smaller infusion volumes result in a better quality of life experience for the patient by reducing the overall "stress" to the patient and reducing the time spent in the infusion clinic. Shorter infusion times (and smaller volumes) also reduce the potential extravasation (and shorten the patient monitoring time required). It would be advantageous if the drug could be administered in smaller volumes and over shorter times. The present invention addresses these needs. SUMMARY OF THE INVENTION The invention is defined by the appended claims. In a first aspect of the invention there are provided liquid compositions for use in methods of treating or preventing cancer or malignant disease in a human. The methods include parenterally administering the liquid composition containing: a) from 0.5 to 5.6 mg/ml of bendamustine hydrochloride;b) a solubilizer comprising polyethylene glycol and propylene glycol, wherein the weight ratio of polyethylene glycol to propylene glycol is 90:10 to 85:15;c) an antioxidant; andd) about 50mL of a parenterally acceptable diluent selected from the group consisting of water for injection, 0.9% saline (normal saline), 0.45% saline (half normal saline), and 2.5 dextrose/0.45% saline; over a substantially continuous period of less than or equal to about 10 minutes to a human in need thereof, as part of an intravenous infusion, wherein: (i) the cancer or malignant disease is chronic lymphocytic leukemia and the amount of bendamustine administered to the human is about 100 mg/m2 body surface area; or(ii) the cancer or malignant disease is indolent B-cell non-Hodgkin's lymphoma and the amount of bendamustine administered to the human is about 120 mg/m2 body surface area. The invention provides liquid compositions for use in methods of treating or preventing a bendamustine-responsive condition in a human, as more specifically defined herein. In one disclosed embodiment (not claimed) the methods include administering less than or equal to 325 ml of a liquid composition which contains IngredientConcentration Range (mg/ml)Bendamustine HCl0.05 to 1.6Solubilizer 1 propylene glycol0.30 to 6.5Solubilizer 2 PEG 4003.3 to 65Monothioglycerol0.02 to 0.35NaOH0.0 to 0.01 over a substantially continuous period of less than or equal to about 30 minutes to a subject in need thereof. Also disclosed (not claimed) are liquid compositions for use in methods include administering less than or equal to 325 ml of a liquid composition which contains IngredientConcentration Range (mg/ml)Bendamustine HCl1.1 to 12.5Solubilizer 1 propylene glycol4.5 to 51Solubilizer 2 PEG 40045 to 500Monothioglycerol0.2 to 2.5NaOH0.0 to 0.04 over a substantiall