Bendamustine hydrochloride liquid injection pumps

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This application is a Non-provisional application which claims priority to and the benefit of Italian Application No. MA filed on Jun. Bendamustine hydrochloride is an active ingredient which is used in the treatment of chronic lymphocytic leukemia and non-Hodgkin's lymphoma, whose chemical structure is represented by the following formula I.

This drug belongs to the class of nitrogen mustards and acts as anti-tumoral agent thank to the active part of the molecule constituted by the bis-chloroethylamino group, that under physiological conditions forms, through an internal replacement of the amino nitrogen on one of the two chlorine atoms, a highly reactive and electrophilic aziridine-type structure that is able to effectively react with the nitrogen bases of the nucleic acids causing serious changes of cellular replication and reparation that lead to apoptosis.

The synthesis of bendamustine was reported for the first time in W. Furthermore, the document discloses that after the reconstitution of the product lyophilized from water, microparticles are formed contributing to the instability of the system. In the document it is observed that a way to overcome the disadvantage of the hygroscopicity of the lyophilized product seems to be represented by the addition of mannitol to the mixture to be lyophilized; however it is reported that such addition does not solve the problem of the remarkable decomposition of the active ingredient and the formation of microparticles after reconstitution.

Such instability increases with the increasing of the temperature: The paper also discloses the mechanism of the formation of the main degradation product of bendamustine in water, named HP1, which is generated according to the mechanism reported in the following scheme 1. The same paper also discloses the inhibition effect exerted by sodium chloride on the degradation of the active ingredient in aqueous solution.

WO discloses the preparation of lyophilized products of bendamustine obtained by using mixtures of water and organic solvents such as t-butanol, ethanol, n-propanol, n-butanol, isopropanol, methanol, acetone, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid and cyclohexane.

In the document there are reported data according to which the use of organic solvents and water significantly contributes to the stabilization of the active ingredient and to the obtainment of a lyophilized product with a low content of impurities, especially of HP1 impurity.

The document however does not report any data about the content of residual solvents remaining in the products after the lyophilization. Furthermore, the use of an organic solvent in the mixture to be lyophilized necessarily involves the use of suitable lyophilizers that are able to operate with organic solvents, with the consequent increase of the production costs.

The data reported in WO advice against the lyophilization of bendamustine hydrochloride from sole water. About this solution, it is reported that after 6 hours there is the formation of a precipitate, showing the low solubility of bendamustine hydrochloride in water.

Furthermore, samples of the same solution, analyzed by HPLC after 0, 3, 6, 24 hours page 30, lines and table 3; page 43, lines show that bendamustine quickly degrades in water, by predominantly forming the HP1 degradation product.

The possibility that a vial of a cytotoxic active ingredient could break during the lyophilization represents a particularly undesired feature from the safety point of view. CN discloses the lyophilization of bendamustine hydrochloride from solutions using water as sole solvent. The treatment of the active ingredient in warm conditions in the first steps of the process inevitably causes the degradation of said active, as shown by the data reported in the cited patent application where the lyophilized product prepared according to the disclosed method has an overall impurity content of 1.

Moreover, the examples reported in the cited patent application do not define the concentrations and the times needed to prepare the described lyophilized products. CN discloses a process for the preparation of lyophilized formulations of bendamustine hydrochloride in which no organic solvents are used. This document does not report information about the purity of the obtained lyophilized products, but only about their assay in active ingredient without providing details about the obtainment of said assay.

The data reported in this document show a complete lack of correlation between the assay of the obtained lyophilized products and the temperature at which they are prepared. This is in contrast with what it is known in the literature about the stability in water of bendamustine see the aforementioned Pharmazie WO discloses the lyophilization of bendamustine hydrochloride using mixtures of solvents, such as acetone and acetonitrile, and water; from these mixtures, lyophilized products with high purity wherein HP1 does not exceed 0.

However, also this document does not report the amount of the organic solvent that is present as residual solvent in the lyophilized product and also in this case the use of the organic solvent in the mixture to be lyophilized requires suitable equipments with higher production costs with respect to the use of lyophilizers from sole water. US describes the preparation of lyophilized bendamustine hydrochloride from solutions that do not contain organic solvents.

In all the examples described in this patent application it is used a ratio API: A high quantity of mannitol increases the possibility of having undesirable events, especially from the point of view of safety, such as breaking of the vials during lyophilization see references at pages and lowers the solubility of the active principle in the pre-lyophilization solution, increasing the possibility that this precipitates before freezing, giving a lyophilisate of poor quality.

Therefore, there is still the need to find a method, easily to be industrialized, to lyophilize bendamustine hydrochloride at low cost, that is able to produce a lyophilized product with a low content of impurities, that reconstitutes within a minute, that does not contain organic solvents, that is stable on time and that show a negligible risk of vial breakage during the lyophilization. This result is particularly unexpected in view of the prior art that clearly advices the person skilled in the art against any attempts to lyophilize bendamustine hydrochloride without using organic solvents, as the product easily degrades by dissolving it in sole water.

Such result is achieved by using special arrangements in the steps of pre-lyophilization and mixing of the active ingredient with the excipients and water and by using reduced amounts of mannitol in comparison to the prior art.

Particularly the temperature in the various steps for the preparation of the solution to be lyophilized and the concentrations of the active ingredient and of the excipients have to be strictly controlled.

In fact, even if from one side higher temperatures increase the solubility of the active ingredient, from the other side they cause its faster degradation with the consequent formation of considerable amounts of by-products. Generally, the complete dissolution is obtained after minutes at said temperature.

Alternatively, the process foresees the preliminary preparation of a solution of water and excipients at a concentration of between 8.

The resultant pre-lyophilization solutions, containing a concentration of the active ingredient from 5. The process object of the present invention does not also require any pH adjustment in any of its phases and does not provide treatments with active charcoal.

The excipients that are used for the preparation of the aqueous solution to be added to the aqueous solution of bendamustine hydrochloride according to the lyophilization process, object of the present invention, are excipients conventionally used for the preparation of lyophilized products.

Particularly, bulking agents such as mannitol, lactose, sucrose and their mixtures are used. Mannitol is particularly preferred. The lyophilized product of bendamustine hydrochloride object of the present invention can contain also a stabilizing amount of NaCl. When present, NaCl is added to the aqueous solution of the excipients and stabilizes the pre-lyophilization solution that is obtained after the addition of the aqueous solution of bendamustine hydrochloride to the suitably cooled aqueous solution of the excipients.

For an effective stabilization, the concentration of NaCl in the pre-lyophilization solution is preferably from 0. In the present context the absence of residual organic solvents in the lyophilized product means that the content of residual organic solvents is from 0 ppm to 10 ppm.

It is evident to the person skilled in the art that the purity degree of an active ingredient in lyophilized products depends on the purity degree of the used raw material.

In the specific case of bendamustine, the purity degree particularly depends on the lyophilization process used, due to the inherent instability of the molecule in water. Preferably, the lyophilized product obtained from an aqueous solution according to the process of the present invention has a purity higher than Moreover, the lyophilized products obtained with the process object of the present invention can be reconstituted in less than a minute resulting in clear and colorless solutions suitable for injectable preparations.

Such lyophilized products are also stable under the standard conditions of the accelerated stability test. In order to better illustrate the present invention without limiting it, the following examples are now given. PXRD of the product obtained in the example 2. PXRD of the product obtained in the example 3.

PXRD of the product obtained in the example 6. PXRD of the product obtained in the example 7. PXRD of the product obtained in the example 9. PXRD of the product obtained in the example 10. PXRD of the product obtained in the example The mixture was stirred for a few seconds.

The mixture was stirred up to dissolution. In a 25 ml flask, After about 30 seconds the complete dissolution of the solid was observed. Cu Voltage of the X ray tube: Rotation Time of rotation of the sample s: X'Celerator Type of detector: RTMS detector Scan axis: Continue Counting time s: X'Pert Data Collector vs.

The HPLC purity was The lyophilized reconstituted with 40 ml of water for injectable solutions provided a clear and colorless solution in 1 minute. In a 50 ml flask, The lyophilized product reconstituted with 40 ml of water for injectable solutions provided a clear and colorless solution in 1 minute.

Table 2 reports the data of the variation of purity over the time of the mixtures obtained as reported in the previous examples, expressed in terms of formation of the HP1 impurity only, that is the only one to be formed in detectable amounts.

The other two main known impurities, bendamustine dimer trichloride and bendamustine ethyl ester, were not found to be present in detectable amounts even if the used HPLC method was also validated for their evaluation. All the preparations reported in table 2 were made by dissolving bendamustine hydrochloride having HPLC purity In a ml flask, After about 5 minutes a complete dissolution of the solid was observed.

A lyophilized product having a content of water of 2. A complete dissolution of the solid was obtained after about 30 seconds. At the end of the lyophilization cycle the vials were discharged and some of them were analyzed with respect to the water content and the HPLC purity of the lyophilized product.

The obtained data are summarized in the following table. Bendamustine Water content HP1 purity K. The amounts of dimer trichloride and ethyl ester impurity evaluated by the used HPLC method see example 1which has a Limit of Detection of 0. The analysis showed that the lyophilized product did not contain detectable residual solvents. The Limit of Detection of the used method was equal to 10 ppm. Some of the produced vials were reconstituted at room temperature with different amounts of water for injection observing a complete dissolution in the times reported in the following table.

Bendamustine HP1 purity Vial n. The complete dissolution of the solid was obtained after about 30 seconds. At the end of the lyophilization cycle the vials were discharged and some of them were analyzed with respect to the water content and the HPLC purity see example 1 of the lyophilized. The amounts of dimer trichloride and ethyl ester impurity evaluated with the used HPLC method which has a Limit of Detection of 0. The amounts of dimer trichloride and ethyl ester impurity evaluated with the used HPLC method see example 1 which has a Limit of Detection of 0.

Some of the produced vials were reconstituted at room temperature with different amounts of water for injection, observing the complete dissolution in the times reported in the following table. Volume of added water Time for complete Appearance of the for injectable solutions ml solubilization sec reconstructed solution 40 60 Clear and colorless 20 Clear and colorless 15 Clear and colorless 10 Clear and colorless.

In a pre-dissolutor, equipped with cooling jacket, 21 kg of water for injection were charged. The content of the pre-dissolutor was transferred into a dissolutor with a peristaltic pump, washing the pre-dissolutor with 3 liters of water for injection.

The final weight of the mixture contained in the dissolutor was brought to The appearance of the solution was checked, then the solution was filtered on a sterilization filter Millipak porosity 0. Part of the solution was collected in order to verify the absence of bacterial contamination and pyrogens.

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This application is a continuation of U. The present invention pertains to the field of pharmaceutical compositions for the treatment of various disease states, especially neoplastic diseases and autoimmune diseases. Particularly, it relates to pharmaceutical formulations comprising nitrogen mustards, particularly the nitrogen mustard bendamustine, e. The present invention claims the benefit of and priority to U. The following description includes information that may be useful in understanding the present invention.

It is not an admission that any such information is prior art, or relevant, to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art. Because of their high reactivity in aqueous solutions, nitrogen mustards are difficult to formulate as pharmaceuticals and are often supplied for administration in a lyophilized form that requires reconstitution, usually in water, by skilled hospital personal prior to administration.

Once in aqueous solution, nitrogen mustards are subject to degradation by hydrolysis, thus, the reconstituted product should be administered to a patient as soon as possible after its reconstitution. It has been widely used in Germany to treat chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer. Due to its degradation in aqueous solutions like other nitrogen mustards , bendamustine is supplied as a lyophilized product.

The finished lyophilisate is unstable when exposed to light. Therefore, the product is stored in brown or amber-colored glass bottles. Currently bendamustine is formulated as a lyophilized powder for injection with mg of drug per 50 mL vial or 25 mg of drug per 20 mL vial. The vials are opened and reconstituted as close to the time of patient administration as possible.

The product is reconstituted with 40 mL for the mg presentation or 10 mL for the 25 mg presentation of Sterile Water for Injection. The reconstituted product is further diluted into mL, q. The route of administration is by intravenous infusion over 30 to 60 minutes. The mL admixture solution must be administered to the patient within 7 hours of vial reconstitution assuming room temperature storage of the admixture. The reconstitution of the present bendamustine lyophilized powder is difficult.

Reports from the clinic indicate that reconstitution can require at least fifteen minutes and may require as long as thirty minutes. Besides being burdensome and time-consuming for the healthcare professional responsible for reconstituting the product, the lengthy exposure of bendamustine to water during the reconstitution process increases the potential for loss of potency and impurity formation due to the hydrolysis of the product by water.

Thus, a need exists for lyophilized formulations of bendamustine that are easier to reconstitute and which have a better impurity profile than the current lyophilate lyophilized powder formulations of bendamustine.

Lyophilized cyclophoshamide is known in the art see e. The lyophilized nitrogen mustard Ifosfamide is disclosed in International Publication No. The present invention is directed to stable pharmaceutical compositions of nitrogen mustards, in particular lyophilized bendamustine and its use in treatment of various disease states, especially neoplastic diseases and autoimmune diseases. An embodiment of the invention is a pharmaceutical composition of bendamustine containing not more than about 0.

In a preferred embodiment is a pharmaceutical composition of bendamustine containing not more than about 0. Another embodiment of the invention is a lyophilized preparation of bendamustine containing not more than about 0. Yet another embodiment of the invention is a lyophilized preparation of bendamustine containing not more than about 0.

Yet another embodiment of the invention is a lyophilized preparation of bendamustine wherein the concentration of bendamustine ethylester Formula IV is no more than 0.

In another embodiment of the invention is a lyophilized preparation of bendamustine containing not more than about 0. In a preferred embodiment is a lyophilized preparation of bendamustine containing not more than about 0. An aspect of this embodiment is lyophilized preparations of bendamustine containing not more than about 0.

Another embodiment of the invention is a pharmaceutical dosage form that includes a pharmaceutical composition of bendamustine containing not more than about 0. In preferred aspects of the invention, the dosage form can be about 5 to about mg of bendamustine, about 10 to about mg of bendamustine, about 25 mg of bendamustine, about mg of bendamustine, and about mg of bendamustine. Yet another embodiment of the invention is a pharmaceutical dosage form that includes a lyophilized preparation of bendamustine containing not more than about 0.

Preferred dosage forms can be about 5 to about mg of bendamustine, about 10 to about mg of bendamustine, about 25 mg of bendamustine, about mg of bendamustine, and about mg of bendamustine. In still another embodiment, the invention includes a pharmaceutical composition of bendamustine including bendamustine containing not more than about 0. In different aspects of this embodiment, the organic solvent is selected from one or more of tertiary butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, and cyclohexane.

Preferred organic solvents include one or more of ethanol, methanol, propanol, butanol, isopropanol, and tertiary butanol. A more preferred organic solvent is tertiary butanol, also known as TBA, t-butanol, tert-butyl alcohol or tertiary butyl alcohol. The present invention involves a method for obtaining agency approval for a bendamustine product, the improvement which includes setting a release specification for bendamustine degradants at less than about 4. An aspect of this embodiment is a method for obtaining agency approval for a bendamustine product which includes setting a release specification for HP1 to be less than or equal to 1.

The bendamustine product herein contains not more than about 0. Another embodiment is a method for obtaining agency approval for a bendamustine product, the improvement which includes setting a shelf-life specification for bendamustine degradants at less than about 7. Another embodiment of the invention is a process for manufacturing a lyophilized preparation of bendamustine which includes controlling for the concentration of bendamustine degradants in the final product, such that the concentration of bendamustine degradants is less than about 4.

The present invention discloses a process for manufacturing a lyophilized preparation of bendamustine which comprises controlling for the concentration of bendamustine degradants in the final product, such that, at release, the concentration of HP1 is less than 0. Another embodiment of the invention is a bendamustine pre-lyophilization solution or dispersion comprising one or more organic solvents where the solution or dispersions include at least one stabilizing concentration of an organic solvent which reduces the level of degradation of bendamustine so that the amount of HP1 produced during lyophilization from about 0 to 24 hours does not exceed about 0.

An aspect of this embodiment is the lyophilized powder produced from the pre-lyophilization solution or dispersion. Still another embodiment of the invention is a bendamustine pre-lyophilization solution or dispersion comprising one or more organic solvents where the solution or dispersions include at least one stabilizing concentration of an organic solvent which reduces the level of degradation of bendamustine so that the amount of bendamustine ethylester produced during lyophilization from about 0 to 24 hours does not exceed about 0.

Still another embodiment of the invention is a bendamustine pre-lyophilization solution or dispersion comprising one or more organic solvents where the solution or dispersions include at least one stabilizing concentration of an organic solvent which reduces the level of degradation of bendamustine so that the amount of bendamustine ethylester as shown in Formula IV produced during lyophilization from about 0 to 24 hours is no more than 0.

A preferred organic solvent is tertiary butanol. Preferred alcohols include one or more of methanol, ethanol, propanol, iso-propanol, butanol, and tertiary-butanol. A more preferred alcohol is tertiary-butanol. An aspect of this embodiment is the addition of an excipient before lyophilization. A preferred excipient is mannitol.

A preferred alcohol is tertiary-butanol. Another embodiment of the invention is the lyophilized powder or preparation obtained from the methods of preparing a bendamustine lyophilized preparation disclosed herein. The invention also involves bendamustine formulations for lyophilization that include an excipient and a stabilizing concentration of an organic solvent.

Included in this embodiment of the invention are the lyophilized preparations made from such bendamustine formulations. Included in the inventions are methods of treating a medical condition in a patient that involve administering a therapeutically effective amount of a pharmaceutical composition of the invention where the condition is amenable to treatment with said pharmaceutical composition.

Some conditions amenable to treatment with the compositions of the invention include chronic lymphocytic leukemia CLL , Hodgkin's disease, non-Hodgkin's lymphoma NHL , multiple myeloma MM , breast cancer, small cell lung cancer, hyperproliferative disorders, and an autoimmune disease. Preferred autoimmune diseases include rheumatoid arthritis, multiple sclerosis or lupus.

Included in the inventions are the use of the pharmaceutical compositions or pharmaceutical preparations of the invention in the manufacture of a medicament for the treatment of a medical condition, as defined herein, in a patient that involve administering a therapeutically effective amount of a pharmaceutical composition of the invention where the condition is amenable to treatment with said pharmaceutical composition.

Also included in the invention are methods of treating in which the pharmaceutical compositions of the invention are in combination with one or more anti-neoplastic agents where the antineoplastic agent is given prior, concurrently, or subsequent to the administration of the pharmaceutical composition of the invention.

Preferred antineoplastic agents are antibodies specific for CD Another embodiment of the invention is a lyophilization cycle for producing lyophilized bendamustine preparations of the invention.

Another aspect of this embodiment is the lyophilized powered prepared from such lyophilization cycles. The invention also encompasses a pharmaceutical dosage form of bendamustine containing not more than about 0. The present invention also includes pre-lyophilized pharmaceutical compositions of bendamustine. These and other embodiments of the invention are described hereinbelow or are evident to persons of ordinary skill in the art based on the following disclosures.

Results are presented as the area percent of the bendamustine peak. The aqueous solution may contain a non-aqueous solvent, i. Preferably, a lyophilized preparation is one in which the solid material is obtained by freeze-drying a solution composed of aqueous and one or more non-aqueous solvents, more preferably the non-aqueous solvent is an alcohol.

For purposes of the present invention stable pharmaceutical composition includes reference to pharmaceutical compositions with specific ranges of impurities as described herein.

Preferably, a stable pharmaceutical composition is one which has minimal degradation of the active ingredient, e. Therapeutically effective amount can also mean preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease prophylactic treatment. Further, therapeutically effective amount can be that amount that increases the life expectancy of a patient afflicted with a terminal disorder.

The cycle can be repeated about every three to four weeks. The cycle can be repeated after about 4 weeks. Controlling for degradants by setting release specifications for the amount of degradants can be used to facilitate regulatory approval of a pharmaceutical product by a regulatory agency, such as the U.

Food and Drug Administration both are hereby incorporated by reference herein, including any drawings. As used herein pharmaceutical composition includes but is not limited to a pre-lyophilization solution or dispersion as well as a liquid form ready for injection or infusion after reconstitution of a lyophilized preparation. The pharmaceutical dosage form can comprise a vial or syringe or other suitable pharmaceutically acceptable container.

The pharmaceutical dosage form suitable for injection or infusion use can include sterile aqueous solutions or dispersions or sterile powders comprising an active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol such as glycerol, propylene glycol, or liquid polyethylene glycols and the like, vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The prevention of the growth of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Preferably, an excipient is therapeutically inert. Excipients can also be those substances present in a pharmaceutical formulation as an indirect or unintended result of the manufacturing process.

Preferably, excipients are approved for or considered to be safe for human and animal administration, i. Preferred excipients include, but are not limited to, hexitols, including mannitol and the like.

For example, with respect to the degradant HP1, a stabilizing concentration of an organic solvent is that amount which results in an HP1 concentration area percent of bendamustine of less than about 0. The lower limit is the lowest amount that can be detected. The invention provides stable, pharmaceutically acceptable compositions prepared from bendamustine. In particular, the invention provides formulations for the lyophilization of bendamustine HCl.

The lyophilized powder obtained from such formulations is more easily reconstituted than the presently available lyophilized powder of bendamustine. The present invention further provides formulations of bendamustine useful for treating neoplastic diseases.

An aspect of the invention is conditions and means for enhancing the stability of bendamustine prior to and during the lyophilization process, upon shelf storage or upon reconstitution.

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