Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

• Bendamustine is used in the treatment of a number of cancers including leukemias, Hodgkin's disease and multiple myelomas.
• Bendamustine (present as the HC1 salt) is the active ingredient of the commercial product TreandaTM, 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/m 2 over 30 minutes or 120 mg/m 2 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.
• a solubilizer comprising polyethylene glycol and propylene glycol; and optionally
• the methods include administering less than or equal to 325 ml of a liquid composition which contains
• the methods include administering less than or equal to 325 ml of a liquid composition which contains
• the methods of the present invention take advantage of the fact that the concentration of the bendamustine HCl is below the room temperature solubility limit of the vehicle into which it is placed. As a result, the bendamustine does not precipitate during administration to the patient thereby substantially avoiding the side effects which would otherwise occur during small volume administration of therapeutic doses of the drug. In addition, patients or subjects with bendamustine-responsive conditions can be treated using substantially smaller parenteral volumes which are well below the standard 500 ml administration volume. [0009] DETAILED DESCRIPTION OF THE INVENTION
• a first aspect of the invention there are provided methods of treating or preventing cancer or malignant disease in a subject or patient who is preferably a human.
• the methods generally include parenterally administering a volume of about 325 ml or less of a liquid composition containing:
• a solubilizer comprising polyethylene glycol and propylene glycol; and optionally
• the solubilizer portion of the formulation preferably includes from about 0.3 to about 45 % volume polyethylene glycol (PEG) and from about 0.03 to about 5% volume propylene glycol (PG), as calculated on the basis of the total or final volume administered.
• PEG polyethylene glycol
• PG propylene glycol
• the final concentration of the PEG generally ranges from about 3 to about 500 mg/ml
• the final concentration of the PG generally ranges from about 0.5 to about 51 mg/ml.
• certain aspects of the invention include concentration ranges for the PEG of from about 45 to about 500 mg/ml or from about 3.3 to about 63.3 mg/ml; and for the PG ranges of from about 4.7 to about 50.6; or from about 0.02 to about 6.5 mg/ml.
• the bendamustine is administered intravenously as part of an intravenous infusion.
• Contemplated infusion volumes are preferably less than 325 ml with volumes such as about 250 ml, 100 ml, and 50 ml, with each volume varying about +/- 10% or +/-15% being preferred in some embodiments.
• the intravenous administration volume is suitable for IV bolus administration and may also include an amount of pharmaceutically acceptable diluent such as normal saline or one of the other diluents described herein which does not cause the solubility of the vehicle to fall below the concentration of the bendamustine.
• the final concentration of the bendamustine will be below the solubility of the combination vehicle containing the mixture of propylene glycol and PEG and diluent. While most aspects of the invention are described in the context of administering less than about 325 ml including all vehicle ingredients, excipients, etc., it should be appreciated that volumes as low as a few milliliters, e.g. about 2, can be used so long as the vehicle includes sufficient solubilizers to preserve the solubility of the bendamustine therein during administration to the patient.
• the word "about” when used to modify infusion volumes or concentrations shall be understood to include values which may vary by amounts of about +/- 10% or 15%.
• the concentration of the bendamustine HC1 or other pharmaceutically acceptable salt thereof is preferably from about 0.5 to about 5.6 mg/ml.
• the concentration of the bendamustine HC1 or other pharmaceutically acceptable salt thereof can be preferably from about 0.1 to about 3.2 mg/ml.
• the concentration of the bendamustine HC1 or other pharmaceutically acceptable salt thereof is from about 0.05 to about 1.4 mg/ml.
• the solubilizer is preferably a mixture of polyethylene glycol, hereinafter
• the solubilizer can also optionally include an antioxidant such as monothioglycerol.
• the amount of antioxidant included is a formulation stabilizing amount, which, in the case of monothioglycerol ranges from about 2 to about lOmg/ml.
• the PEG preferably has a molecular weight of about 400, i.e. PEG 400. Other molecular weight PEG's known to those of ordinary skill can be included if desired in alternative embodiments.
• Certain aspects of the invention call for the ratio of the PEG to PG found in the solubilizer to be about 90: 10. In alternative aspects, the ratio of the PEG to PG is about 85: 15.
• PEG and PG included in infusion volumes of about 100 - 115 ml is from about 0.5 to about 26.5% vol.; while amounts of from about 0.2 to about 5% vol. for the solubilizer are preferably included in infusion volumes of about 250-265 ml; with solubilizer amounts of from about 2.0 to about 22.4% vol. included in infusion volumes of about 50-65 ml.
• the solubilizer is a blend
• the amount of PEG and PG in various volumes (calculated as %> vol.) can be as follows:
• the methods of the invention are advantageously carried out using bendamustine HCl containing compositions administered as small volume infusions with volumes of about 50 ml or about 100 ml or about 250 ml.
• Such smaller volumes allow the drug to be administered over a time period of about 10 minutes or less as part of an intravenous infusions containing a volume of about 50 ml; about 15 minutes or less as part of an intravenous infusions containing a volume of about 100 ml or when volumes of about 250 ml are infused, the IV infusion is administered over a time period of about 30 minutes or less.
• the IV bolus volumes containing sufficient amount of the drug will be less than 50 ml, with amounts of about 10 or 15 to 30 ml being sufficient.
• compositions in many aspects of the invention will also preferably include the parenterally acceptable diluents such as water for injection (WFI), 0.9% saline (normal saline, preferred), 0.45% saline (half normal saline) or 2.5 % dextrose/0.45%) saline.
• WFI water for injection
• 0.9% saline normal saline, preferred
• 0.45% saline half normal saline
• 2.5 % dextrose/0.45% saline
• some preferred bendamustine formulations can also include a minor amount of a pH adjuster such as sodium formate, sodium phosphate, potassium hydroxide, phosphoric acid or, preferably, sodium hydroxide.
• a pH adjuster such as sodium formate, sodium phosphate, potassium hydroxide, phosphoric acid or, preferably, sodium hydroxide.
• formulations used in the methods described herein can be one or more of those described in US Patent Nos. 8,344,006 and 8,076,366; and US Patent Application Nos. 2013/0041004; 2012/0071532; 2010/0216858; 2006/0159713; and 2013/0041003, the contents of each of which are incorporated herein by reference. It being understood that the vehicle into which the bendamustine HCl is placed will have sufficient bendamustine solubility which exceeds the concentration of the drug included therein.
• a sufficient amount of a concentrated, ready to use liquid formulation such one containing 25 mg/ml bendamustine HCl and already admixed with sufficient solubilizers can be transferred to a suitable fixed volume diluent container such as a bag containing 50, 100, 250 ml normal saline or the like.
• a suitable fixed volume diluent container such as a bag containing 50, 100, 250 ml normal saline or the like.
• lyophilized bendamustine HC1 can be reconstituted, combined with sufficient solubilizer blends as described herein and administered in accordance with the inventive methods.
• the actual amount delivered to the patient will be slightly more than the diluent amount so as to allow for the addition of the drug/ solubilizer vehicle.
• CLL chronic lymphocytic leukemia
• compositions described herein can be administered as part of a poly-pharmaceutical treatment regimen according to known protocols with the exception that the concentrated bendamustine compositions described herein are administered in smaller infusion volumes over significantly shorter administration periods.
• some CLL treatment regimens can include administering the compositions described herein intravenously as part of about 100 ml infusions in about 20 minutes or less and more preferably in about 15 minutes or less on days 1 and 2 of a 28 day cycle and repeating the cycle up to 6 times or longer if clinically appropriate. If 250 ml volumes are used to deliver the bendamustine, the time of administration is preferably about 30 minutes or less. If 50 ml volumes are used to deliver the bendamustine, the time of administration is preferably about 10 minutes or less.
• the amount of bendamustine HC1 administered to the patient in need thereof per dose (infusion or otherwise) in some preferred embodiments is about 100 mg/m 2 .
• the amount of bendamustine HC1 administered to the patient in need thereof as part of the 50, 100 or 250 ml infusion is an amount sufficient to provide a dosage of 50 or 25 mg/m 2 . Additional administration dosages will be apparent to those of ordinary skill based upon clinical experience, patient need without undue experimentation.
• the composition is administered intravenously as a 100 ml infusion in less than 20 minutes and more preferably in about 15 minutes or less on days 1 and 2 of a 21 day cycle for up to 8 cycles or longer if clinically appropriate. If 250 ml volumes are used to deliver the bendamustine, the time of administration is preferably about 30 minutes or less. If 50 ml volumes are used to deliver the bendamustine, the time of administration is preferably about 10 minutes or less.
• the amount of bendamustine administered to the subject is preferably about 120 mg/m 2 , although in alternative embodiments, the amount administered ranges from about 90 or 60 mg/m 2 . As will be appreciated, further alternative dosage amounts will be apparent to those of ordinary skill based upon clinical experience, patient need without undue experimentation.
• the above-mentioned dosages calculated in mg/m 2 for purposes of body surface area (BSA) are consistent with the bendamustine HC1 concentrations also described herein, e.g. 0.5 to 5.6 mg/ml.
• the invention also contemplates IV bolus administration of bendamustine- containing formulations in volumes which can be administered via syringe, e.g. from a few milliliters up to about 50 milliliters, with therapeutic amounts of the drug in a concentration which does not exceed the vehicle solubility for the drug therein.
• Further embodiments of the invention include methods of treating or preventing a bendamustine-responsive condition in a subject such as a human.
• the methods include administering less than or equal to 325 ml of a liquid composition which contains
• the administration time is well below 30 minutes and the administration time will decrease as the volume administered decreases.
• Bendamustine formulations containing the above ingredients are capable of delivering approximately 25 mg of the drug as the HC1 salt in volumes of pharmaceutically acceptable diluent ranging from about 325 ml down to about 15 ml.
• NaOH 0.08 is combined with 300 ml of a normal saline diluent to provide a final IV infusion containing 301 ml and a bendamustine final concentration of 0.08 mg/ml.
• a normal saline diluent 300 ml
• a bendamustine final concentration 0.08 mg/ml.
• One ml of the 25 mg/ml Eagle bendamustine HC1 is diluted into additional diluent volumes as shown below:
• the measured solubility of the bendamustine HC1 in the diluent/solubilizer combination (50 ml diluent plusl ml of 25 mg/ml bendamustine HC1 and solubilizers, etc.) at room temperature was 10.5 mg/ml using normal saline and 14.2 mg/ml using half normal saline/dextrose.
• the solubility of the diluent/solubilizer combination far exceeded the bendamustine concentration, thus assuring the avoidance of precipitated drug prior to or during administration.
• the concentration of solubilizers increases with respect to the total volume in small administration doses, the solubility of the bendamustine is maintained.
• the methods include administering less than or equal to 325 ml of a liquid composition which contains Ingredient Concentration Range (mg/ml)
• Solubilizer 1 propylene glycol 4.5 to 51
• Bendamustine formulations containing the above ingredients are capable of delivering approximately 360 mg of the drug as the HC1 salt in volumes of pharmaceutically acceptable diluent ranging from about 325 ml down to about 15 ml.
• the measured solubility of the bendamustine HC1 in the diluent/solubilizer combination (1 ml drug + solubilizers, etc. and 50 ml diluent) at room temperature was 10.5 mg/ml using normal saline and 14.2 mg/ml using half normal saline/dextrose.
• 0.9% saline and 0.9% saline containing from different amounts of a non-aqueous solubilizer comprising a mixture of polyethylene glycol 400 and propylene glycol (in the volume proportion of 90: 10) with and without 5 mg/ml monothioglycerol was determined at both room temperature (22-23°C) and at refrigerated temperature (5°C).
• a non-aqueous solubilizer comprising a mixture of polyethylene glycol 400 and propylene glycol (in the volume proportion of 90: 10) with and without 5 mg/ml monothioglycerol was determined at both room temperature (22-23°C) and at refrigerated temperature (5°C).
• an excess of bendamustine HCl was added to solvents comprising of various volume percent of the non-aqueous solubilizer in 0.9%> saline, and allowed to equilibrate with shaking for 30 minutes at room temperature, or for 24 hours at refrigerated temperature.
• the suspensions were filtered through a 0.2 micron filter to remove undissolved bendamustine, and the filtrate solutions analyzed for bendamustine HCl content using a HPLC assay; quantification was performed against a bendamustine HCl reference standard.
• the solubility data are presented in Table 1.
• Table 1 Solubility of bendamustine HC1 in 0.9% saline with various amounts of non-aqueous solubilizer (90:10 PEG400:PG with and without 5 mg/mL monothioglycerol (MTG))
• Bendamustine-containing compositions are prepared by adding 5 mg/ml of thioglycerol to a mixture containing 90% polyethylene glycol 400 and 10% propylene glycol. As indicated in the Table 2 below, NaOH may be added to the PEG in an amount sufficient to get apparent pH of greater than or equal to 6.5 as measured using the pH method outlined in the USP monograph for polyethylene glycol (PEG). Bendamustine (BDM) is then added to the sample to a concentration of 10 mg/ml. [0042] Table 2
• compositions are then admixed with normal saline based on the total dose of bendamustine HC1, which in turn is based on the patient body surface area (BSA) and the dosing regimen (100 mg/m 2 for CLL and 120 mg/m 2 for NLL; although dose modifications of 90, 60, 50, and 25 mg/m 2 are possible, only the highest two dosing regimens are considered for illustrative purposes, as these result in the highest concentration of bendamustine during infusion).
• BSA patient body surface area
• the 100 ml infusion is then made by admixing the dose appropriate volume of the lOmg/ml solution with a 100 ml portion of normal saline to provide an infusible composition containing the appropriate dose of bendamustine (as the HC1 salt) in the final admixture, which can be administered intravenously over about 15 minutes to a patient in need thereof.
• bendamustine as the HC1 salt
• Table 3 the concentrations of bendamustine (as HC1 salt) and the corresponding volume percent of non-aqueous component are well below the corresponding solubilities at both room temperature and refrigerated temperature as detailed in Table 1.
• the final concentration of bendamustine HC1 in a 100 ml admixture is 1.94 mg/mL.
• This is above the solubility of bendamustine HC1 at refrigerated storage conditions in the absence of any non-aqueous components (1.175 mg/ml as shown in Table 1 for 100% normal saline), as would be the case with the currently approved TreandaTM product, thereby precluding preparation and storage of a 100 ml admixture volume at refrigerated conditions.
• the use of the non-aqueous bendamustine formulation described in this example results in the presence of 19.4% of the non-aqueous component in the final admixture, which improves the solubility to about 3.8 mg/mL (solubility of 3.824 mg/mL at 2-8°C with 20% non-aqueous component, as shown in Table 1). Therefore, the solubility with the non-aqueous formulation is well above the final concentration (of bendamustine HC1) of 1.94 mg/mL, allowing preparation and storage of the 100 ml admixture at refrigerated conditions.
• the room temperature solubilities in 100% normal saline and 80% normal saline (with 20%) non-aqueous component) are about 3.3 mg/ml and 8.5 mg/ml, respectively (see Table 1), which are also well above the final concentration of 1.94 mg/ml. Therefore, 100 ml admixtures of the non-aqueous formulation described in the example may also be prepared and stored at room temperature.
• the non-aqueous formulation of bendamustine described in this example at Table 2 may be diluted into smaller infusion volumes ranging from 250 ml or less, and stored at either room temperature or refrigerated temperature, with bendamustine continuing to remain in solution for extended periods of time as compared to currently available formulations.
• Example 4 The procedures of Example 2 are repeated except that the dose appropriate volume of the 10 mg/ml bendamustine solution is diluted into 250 ml of normal saline. The final concentration of bendamustine in the 250 ml volume container ranges from about 0.05 mg/ml to about 1.3 mg/ml. [0048] Example 4
• Example 2 The approximately 100 ml bendamustine HC1 infusion of Example 2 is administered to a patient in about 15 minutes.
• Bendamustine-containing compositions may be prepared by adding 5 mg/ml of thioglycerol to 90% polyethylene glycol 400 and 10% propylene glycol. As indicated in the Table 4 below, NaOH may be added in an amount sufficient to get apparent pH of greater than or equal to 6.5 as measured using the pH method outlined in the USP
• compositions are then admixed with normal saline based on the total dose of bendamustine HC1, which in turn is based on the patient body surface area (BSA) and the dosing regimen (100 mg/m 2 for CLL and 120 mg/m2 for NLL; although dose modifications of 90, 60, 50, and 25 mg/m 2 are possible, only the highest two dosing regimens are considered for illustrative purposes, as these result in the highest concentration of bendamustine during infusion).
• BSA patient body surface area
• Table 5 provides the final concentration of bendamustine (as the HC1 salt) in the final admixture, for volumes ranging from 250 ml to 50 ml.
• the concentrations of bendamustine (as HC1 salt) and the corresponding volume percent of non-aqueous component are well below the corresponding solubilities at room temperature as detailed in Table 1, for all admixture volumes up to 50 ml.
• the final concentration of bendamustine HC1 in a 50 ml admixture is 4.03 mg/ml.
• the use of the non-aqueous bendamustine formulation described in this example results in the presence of 16.1% of the non-aqueous component in the final admixture, which improves the room temperature solubility to about 6.5 mg/ml (solubility of 6.554 mg/ml and 7.012 mg/ml with 15% non-aqueous component, as shown in Table 1). Therefore, the solubility with the non-aqueous formulation is well above the final concentration (of bendamustine HC1) of 4.03 mg/mL, allowing preparation and storage of the 100 ml admixture at room temperature conditions.
• the non-aqueous formulation of bendamustine described in this example may be diluted into smaller infusion volumes ranging from 250 ml or less, with bendamustine continuing to remain in solution if maintained at room temperature.
• concentrations of bendamustine (as HC1 salt) and the corresponding volume percent of non-aqueous component exceed the corresponding solubilities as detailed in Table 1 , for all admixture volumes equal to or below 150 ml.
• the solubility at refrigerated conditions with 15% non-aqueous component has improved to 2.9 mg/ml but is still below the final concentration of 4.03 mg/ml.
• the nonaqueous formulation of bendamustine described in this example may be diluted into smaller infusion volumes ranging from 250 ml to 50 ml, and stored at only room temperature (but not refrigerated temperature), with bendamustine continuing to remain in solution.
• the minimum admixture volume that can be used is 150 ml or higher.
• BSA Admix Volume 150 mL Admix. Vol ume 100 mL (m 2 ) 100 mg/m 2 dose 120 mg/m 2 dose 100 mg/m 2 dose 120 mg/m 2 dose
• bendamustine HCl solutions at 1.4 mg/ml or 3.2 mg/ml at blood to drug solution volumetric ratios of 1 :2 and 1 : 1, respectively. These volumetric ratios correspond to infusion times of 15 minutes and 10 minutes, respectively, for the 250 ml and 100 ml admixture volumes.
• a placebo of the bendamustine formulation was also evaluated at these concentrations and volumetric ratios.
• a positive control 1% saponin solution
• a negative control normal saline
• TreandaTM diluted in normal saline to the highest concentration stated in the prescribing information 0.6 mg/ml
• Test Article A 25 mg/mL, diluted to 3.2 mg/mL with saline - 100 ml admixture
• Test Article A 25 mg/mL, diluted to 1.4 mg/mL with saline - 250 ml admixture
• Test Article A Vehicle (Placebo, diluted with 100 ml saline)
• Test Article A Vehicle (Placebo, diluted with 250 ml saline)
• TreandaTM (5 mg/mL, diluted to 0.6 mg/mL with saline)
• Saponin is a hemolytic agent used to lyse erythrocytes.
• TreandaTM reconstituted and admixed with normal saline to a final concentration of 0.6 mg/ml (the highest concentration stated in the label) was also studied either as a 30 minute IV infusion (the shortest infusion time stated in the label), as well as perivascular injection (250 ⁇ ). Animals were held for a 96 hour (post-dose) observation period. During the observation period, dermal scores were recorded for all administration sites. At the end of the observation periods, animals were euthanized and a macroscopic and microscopic examination of both ears was performed. Parameters evaluated during the study were: viability, clinical observations, body weights, macroscopic observations and microscopic pathology.
• the tested minimum and maximum concentrations are about 0.25 mg/ml and 3.2 mg/ml, respectively.
• the chemical stability of TreandaTM was also determined at the lowest (0.2 mg/ml) and the highest (0.6 mg/ml) admixed
• TreandaTM when prepared as directed in the label shows total degradation of about 5-6% in 3 hours at room temperature (corresponding to the room temperature stability claim in the label); monohydroxy bendamustine is the main degradant.
• the non-aqueous bendamustine formulations admixed in either 50 ml or 100 ml saline show total degradation of less than 5-6% over 6 hours at the lowest concentrations tested, indicating that these admixtures are significantly less prone to degradation. This stabilizing effect is particularly pronounced at the higher concentrations (which are more typical), with chemical stability evident for 24 hours at these concentrations.
• bendamustine thus offer better chemical stability than TreandaTM when admixed into smaller volumes.

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