Solvent-free, ready-to-use formulation of bortezomib

Abstract

The present invention provides a composition comprising Bortezomib, a potent anti-cancer agent. More particularly, the present invention relates to a Bortezomib formulation, that is formulated into a stable ready-to-use liquid injectable formulation with refrigeration at 2-8ºC as storage condition. Further, the present invention provides a formulation that is free of a non- aqueous solvent and employs water as the solvent. Further, the present invention relates to a process for preparation of the stable Bortezomib formulation.

Description

[0001] SOLVENT-FREE, READY-TO-USE FORMULATION OF BORTEZOMIB

[0002] FIELD OF THE INVENTION

[0003]

[0001] The present invention relates to a composition comprising Bortezomib, a potent anticancer agent. More particularly, the present invention relates to a solvent-free stable liquid ready -to-use injectable formulation of Bortezomib and a process for its preparation.

[0004] BACKGROUND OF THE INVENTION

[0005]

[0002] Bortezomib [(lR)-3-methyl-l -[[(2S)-1 -oxo-3-phenyl-2[(pyrazinylcarbonyl) amino] propyl] amino] butyl] boronic acid is 26S proteasome inhibitor and used as antineoplastic agent for the treatment of relapsed multiple myeloma and mantle cell lymphoma. Bortezomib is structurally represented as:

[0006]

[0003] US Patent No. 5780454 describes Bortezomib, related compounds and synthetic process of preparation thereof.

[0007]

[0004] Butyl boronic acids (includes Bortezomib) are readily oxidized by air to generate 1- butanol and boric acid, which limit the pharmaceutical utility of boronic acid compounds, complicating the characterization of pharmaceutical agents that comprise the boronic acid compounds and limit their shelf-life.

[0008]

[0005] US Patent Nos. 6958319, 6713446, 6297217 and 7119080 disclose formation of diester of boronic acid functional group in Bortezomib and the like, with mannitol after lyophilization. To circumvent the issues with stability of bortezomib in water and well known non-aqueous solvents, Bortezomib is lyophilized and reconstituted prior to injection. Commercially, Bortezomib is sold as mannitol ester under the brand name VELCADE® marketed by Millennium Pharma, which is supplied as a sterile lyophilized powder for subcutaneous and intravenous infusion in single-dose vials. As per the label of VELCADE® approved by USFDA, each single dose vial contains 3.5 mg of Bortezomib and 35 mg mannitol and should be reconstituted with 0.9 % sodium chloride to a final concentration of 2.5 mg / mL or 1 mg / mL of Bortezomib before administration. VELCADE®, when reconstituted, forms a solution consisting of the mannitol ester of Bortezomib in equilibrium with free Bortezomib. As instructed in the USFDA approved label, the reconstituted material may be stored in the original vial and / or the syringe prior to administration. Such reconstituted product may be stored for up to 8 hours when exposed to normal indoor lighting.

[0009]

[0006] International application publication No. WO 2010 / 089768 discloses the approaches to stabilize Bortezomib that include lyophilized formulations of Bortezomib with tromethamine. However, all of these formulations failed to provide storage stable liquid formulations having sufficient stability for commercially relevant period of time, especially which are not obtained by reconstitution of a lyophilized product.

[0010]

[0007] Though lyophilization approach solves the issues associated with stability of Bortezomib, lyophilization involves complex manufacturing processes, which in turn results in increasing manufacturing costs. Before administration to patients in clinics or hospitals, such lyophilized powder formulation must be reconstituted with suitable fluids to achieve desired concentration for administration. Therefore, an additional step of reconstitution is mandatory for such lyophilized formulation which causes inconveniences raising safety issues and risks of contamination by microorganisms. In addition, improper reconstitution may lead to high or low dosing to the patient in need. Moreover, the reconstituted solutions of Bortezomib are suitable for administration for up to only 8 hours when stored at room temperature.

[0011]

[0008] On the other hand, development of stable liquid, ready -to-use injectable formulation of Bortezomib was also found challenging in light of the prior arts. Wu et al. in "Degradation pathways of a peptide boronic acid derivative, 2-Pyz- (CO)-Phe-Leu-B(OH)(2)" Journal of Pharmaceutical Sciences, 2000, 89(6): 758-65, discloses initial pre-formulation study results of Bortezomib and possible degradation products in various conditions. Wu reports that when in a polyethylene glycol (PEG) 300: Ethanol: Water (40: 10:50) solvent system, significant (as much as 20%) quantities of degradation were observed at 25°C in 24 hours. Further, in ethanol: normal saline solution (2:98, pH 2.8), Bortezomib (0.5 mg / mL) degraded 20% at 25°C in 1 month. In propylene glycol (PG): Ethanol: Water (50: 10:40), the stability of bortezomib was improved but still degraded 20% in 8 months when stored at 25°C. As a whole Wu article teaches that Bortezomib shows erratic stability behaviour while formulated as liquid solutions containing water and well known non-aqueous solvents frequently used in parenteral dosage forms.

[0012]

[0009] International application publication No. WO 2010 / 039762 discloses sugar free physical admixtures, lyophilized preparations or ready-to-use solutions, comprising Bortezomib. The specification of WO'762 publication does not disclose stability data for any liquid ready-to-use solutions of Bortezomib proven stability.

[0013]

[0010] US Patent No. 8,263,578 discloses a storage-stable liquid injectable composition that includes Bortezomib, wherein the composition comprises a single-phase liquid formulation comprising a 'substantially non-aqueous solvent system' suitable for injection wherein the solvent system comprises propylene glycol as a predominant component. As per the definition provided in the specification of US'578 patent, 'substantially non-aqueous solvent system' refers to a solvent system in which Bortezomib is completely soluble without water and that comprises water in a total amount of equal or less that 15% v / v. US'578 patent teaches that propylene glycol (PG) provides storage stable liquid injectable composition of Bortezomib, wherein in other non-aqueous solvents Bortezomib encountered stability or solubility issues. As reported in US'578, Bortezomib degraded to 76% in ethanol composition while stored at 40°C and 75% relative humidity for 1 month. Another non-aqueous solvent, polyethylene glycol (PEG) was not included in the study due to insolubility of Bortezomib in PEG. Further, only high amount of PG was found suitable for storage-stable liquid Bortezomib composition. Such liquid compositions with high amount of PG as non-aqueous solvent, was found to have unacceptable osmolality, which in turn can cause significant toxicity when administered directly without further dilution by subcutaneous and intravenous routes.

[0014] [OH] Therefore, there is a need in the art to provide a stable formulation of Bortezomib wherein Bortezomib is easily dissolved and thus provides a ready-to-use preparation that can be administered directly without further dilution. Also, there is a need in the art to address the toxicity issue that arise due to unacceptable osmolality when the formulations of Bortezomib are prepared in non-aqueous solvent, as well as to overcome the cost and / or complexity issues associated with the lyophilization process. OBJECTIVE OF THE INVENTION

[0015]

[0012] The main objective of the present invention is to provide a stable liquid formulation of Bortezomib.

[0016]

[0013] Another objective of the present invention is to provide solvent-free, stable liquid, ready -to-use injectable formulation of Bortezomib that offers improved efficacy and safety along with convenience of use.

[0017]

[0014] Yet another objective of the present invention is to provide a process for preparation of solvent-free, stable liquid, ready -to-use injectable formulation of Bortezomib.

[0018]

[0015] Yet another object of the present invention is to provide a Bortezomib formulation for the treatment or prophylaxis of a condition or disorder in a subject in need thereof by administering an effective amount of a ready-to-use formulation of Bortezomib.

[0019] SUMMARY OF THE INVENTION

[0020]

[0016] This summary is intended to introduce, in simplified form, a selection of concepts that are further described in the detailed description. This summary is merely presented as a brief overview of the subject matter described and claimed herein and does not aid in determining the scope of the claimed subject matter.

[0021]

[0017] In one aspect, the present invention provides a stable ready-to-use liquid formulation of Bortezomib or a pharmaceutically acceptable salt thereof.

[0022]

[0018] In an embodiment, the present invention provides a liquid injectable formulation comprising:

[0023] • a therapeutically effective amount of Bortezomib;

[0024] • water as solvent;

[0025] • mannitol; and

[0026] • alkali halide.

[0019] In another aspect, the present invention provides a process for preparation of a stable, ready -to-use, non-aqueous solvent free liquid injectable formulation of Bortezomib comprising: i) providing an aqueous mixture comprising Bortezomib, an alkali halide salt, and mannitol; ii) adding an alkaline pH adjusting agent to the mixture of step i); and iii) adjusting the pH of solution obtained in step ii) to 4.0 to 7.0 using an acidic pH adjusting agent.

[0027]

[0020] In yet another aspect, the present invention provides a Bortezomib formulation for the treatment or prophylaxis of a condition or disorder in a subject in need thereof by administering an effective amount of a ready -to-use liquid injectable formulation of Bortezomib.

[0028]

[0021] In still another aspect, the present invention provides a method of treatment or prophylaxis of a condition or disorder in a subject in need thereof by administering an effective amount of a ready-to-use formulation of Bortezomib or a pharmaceutically acceptable salt thereof. In another embodiment, the condition or disorder refers to a disease condition that is benefited by using Bortezomib. Examples of such a disorder include, but is not limited to multiple myeloma, mantle cell lymphoma etc.

[0029]

[0022] The present invention provides a solvent-free system, eliminating the need for nonaqueous solvents that often pose toxicity concerns in Bortezomib formulations. By relying solely on water as the solvent, the formulation achieves stability over commercially significant periods while ensuring safety and compatibility with the body's physiology.

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031]

[0023] At the very outset of the detailed description, it may be understood that the ensuing description only illustrates a particular form of this invention. However, such a particular form is only exemplary embodiment, and without intending to imply any limitation on the scope of this invention. Accordingly, the description is to be understood as an exemplary embodiment and teaching of invention and not intended to be taken restrictively.

[0032]

[0024] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the present disclosure.

[0025] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the methods. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the methods, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the methods.

[0033]

[0026] Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. In an embodiment, “about” can mean within one or more standard deviations, or within ± 30%, 25%, 20%, 15%, 10% or 5% of the stated value.

[0034]

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described.

[0035]

[0028] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0036]

[0029] As used herein, the term “comprises” or “comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

[0037]

[0030] The term “pharmaceutically acceptable carrier or excipient(s)” is used to describe an inert substance that is added to a pharmaceutical composition to make it easier to administer the active ingredient. This can include a range of substances, such as a surfactants, an tonicity agents, a pH adjusters, a buffers, a preservatives, vehicles, vegetable oils, and polyethylene glycols.

[0038]

[0031] The term “formulation” or “composition” refers to a pharmaceutical formulation of Bortezomib described herein with a pharmaceutically acceptable carrier and / or excipient. The terms “formulation” or “composition” can be used interchangeably.

[0039]

[0032] The term “Bortezomib” as used herein refers to “Bortezomib” or its pharmaceutically acceptable salt, or its pharmaceutically acceptable stereoisomer, or its pharmaceutically acceptable solvate, or its pharmaceutically acceptable hydrate, or its pharmaceutically acceptable anhydrate, or its pharmaceutically acceptable polymorph, or its pharmaceutically acceptable prodrug, and other similar form that is suitable for pharmaceutical use.

[0040]

[0033] The term “mg / mL”, or “mg per mL” refers to the mass of each component expressed in milligrams per milliliter of the total final volume of the formulation, with water for injection (WFI) added quantum satis (q.s.) to achieve the stated final volume.

[0041]

[0034] Other objects, feature, and aspects of the present invention are disclosed in or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not to be construed as limiting the broader aspects of the present invention.

[0042]

[0035] The phrase “Ready -to-use” refers to any form of Bortezomib that can be directly given to a patient without the need for additional processing or dilution.

[0043]

[0036] The primary focus of the present invention is to achieve a delicate balance between pH and solubility, while concurrently mitigating impurity formation and degradation of Bortezomib. This critical equilibrium enables the formulation to exhibit both enhanced solubility and prolonged stability, thus ensuring optimal therapeutic efficacy. Traditionally, it has been observed that higher pH levels correlate with increased solubility of Bortezomib. However, this advantageous characteristic often comes at the expense of heightened impurity formation and accelerated degradation rates. Accordingly, the present invention provides a multifaceted approach to overcome the challenge and provides a formulation which is a ready to use stable liquid formulation of Bortezomib.

[0044]

[0037] In an embodiment, the present invention provides a liquid injectable formulation comprising:

[0045] • a therapeutically effective amount of Bortezomib;

[0046] • water as solvent;

[0047] • mannitol; and

[0048] • alkali halide.

[0049]

[0038] The formulation of the present invention is free of a non-aqueous solvent and shows stability when stored in refrigerator at 2-8°C conditions.

[0050]

[0039] In an embodiment, the amount of water in the formulation ranges from about 0.1 mL to about 10 mL, preferably, from 1 mL to 5 mL, and more preferably about 1 mL.

[0051]

[0040] In an embodiment, the amount of Bortezomib in the formulation ranges from about 1 to about 10 mg per mL, preferably from 1 to 5 mg per mL, more preferably, 2.5 mg per mL.

[0052]

[0041] In an embodiment, the amount of mannitol in the formulation ranges from about 5 to about 50 mg per mL, preferably, from 10 to 30 mg per mL, and more preferably 25 mg per mL.

[0053]

[0042] In an embodiment, the alkali halide is selected from the group comprising of sodium chloride, potassium chloride, ammonium chloride, calcium chloride, or a combination thereof. In another embodiment, the amount of alkali halide ranges from about 5 to 20 mg per mL, or from 10 to 15 mg per mL.

[0054]

[0043] By carefully selecting pH conditions conducive to improved solubility without compromising stability, the composition of Bortezomib achieves a delicate equilibrium that optimizes the formulation's performance. This strategic choice allows for enhanced drug solubility, thereby facilitating efficient drug delivery and bioavailability.

[0044] In a specific embodiment, the present invention provides a liquid injectable formulation comprising:

[0055] • 1 to 10 mg / mL of Bortezomib;

[0056] • 0.1 to 10 mL water as solvent;

[0057] • 5 to 50 mg / mL mannitol; and

[0058] • 5 to 20 mg / mL alkali halide.

[0059]

[0045] The present invention ensures the solubilization of Bortezomib by modulating pH. When Bortezomib is in solubilized form, it interacts with mannitol to form mannitol boronic ester which has high aqueous solubility and is in solution state even in the pH range of 4.0 to 7.0. The solubility of Bortezomib is thus optimized. By carefully modulating the pH of the formulation, the present invention has overcome the solubility challenges associated with Bortezomib, ensuring its efficacy and therapeutic potential.

[0060]

[0046] In another aspect, the invention provides a process of preparation of a Bortezomib formulation, wherein the formulation is a stable, ready-to-use, non-aqueous solvent free formulation. The said process for the preparation of Bortezomib formulation comprises following steps: i) mixing Bortezomib, an alkali halide, and mannitol in water to obtain an aqueous mixture; ii) adding an alkaline pH adjusting agent to the aqueous mixture of step i) to obtain a solution; and iii) adjusting the pH of the solution obtained in step ii) to about 4.0 to 7.0 using an acidic pH adjusting agent to obtain the ready-to-use liquid formulation of Bortezomib.

[0061]

[0047] In an embodiment, step i) to obtain the aqueous mixture of Bortezomib comprises the steps of: a) purging water with nitrogen gas; b) adding mannitol to the water of step a) to obtain a solution I; c) adding alkali halide to the solution I obtained in step b) to obtain a solution II; and d) adding Bortezomib to the solution II obtained in step c) to obtain the aqueous mixture of Bortezomib.

[0048] In an embodiment, the nitrogen purging in step a) is conducted till the dissolved oxygen is less than about 3 ppm.

[0062]

[0049] In an embodiment, the amount of water employed in step a) ranges from about O.lmL to about 10 mL, preferably, from 1 mL to 5 mL, and more preferably about ImL.

[0063]

[0050] In an embodiment, the amount of mannitol employed in step b) ranges from about 5 to about 50 mg per mL, preferably, from 10 to 30 mg per mL, and more preferably 25 mg per mL.

[0064]

[0051] In an embodiment, the amount of alkali halide added in step c) ranges from about 5 to 20 mg per mL or from 10 to 15 mg per mL. In an embodiment, the alkali halide is selected from the group consisting of sodium chloride, potassium chloride, ammonium chloride, calcium chloride and the like, or a combination thereof.

[0065]

[0052] In an embodiment, the amount of Bortezomib added in step d) ranges from about 1 to about 10 mg per mL, preferably from 1 to 5 mg per mL, more preferably, 2.5 mg per mL.

[0066]

[0053] In an embodiment, the alkaline pH adjusting agent employed in step ii) is selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), ammonium hydroxide (NH4OH), calcium hydroxide (Ca(OH)2), magnesium hydroxide (Mg(OH)2), aluminum hydroxide (A1(OH)3), sodium bicarbonate (NaHCOs) or a combination thereof.

[0067]

[0054] In an embodiment, the acidic pH adjusting agent employed in step iii) is selected from the group consisting of hydrochloric acid (HC1), sulfuric acid (H2SO4), phosphoric acid (H3PO4), acetic acid (CH3COOH), citric acid (CeHsO?), tartaric acid (CdHsOe), lactic acid (C3H5O3) or a combination thereof.

[0068]

[0055] In an embodiment, the alkaline and acidic pH adjusting agents are employed in the form of their respective aqueous solutions, concentrations ranging from about 0.01 N to 10 N, preferably 0.1 N to 5 N, and more preferably, 0.5 N to 1 N. The amount of the alkaline pH adjusting agent added vary depending on the concentration and quantity sufficient to modify the pH in the range of about pH 8.0 to about 14.0, preferably pH 9.0 to 13.0 and more preferably 10.0 - 12.0. The acidic pH adjusting agent quantity vary in such a to bring the pH of the bulk solution in the range of about 3.0 to about 8.0, preferably pH 4.0 to 7.0.

[0056] In a preferred embodiment, the alkaline pH adjusting agent in step ii) is sodium hydroxide, the acidic pH adjusting agent in step iii) is hydrochloric acid, and the alkali halide is sodium chloride.

[0069]

[0057] The present invention ensures solubilization of Bortezomib by modulating pH to basic by adding alkaline pH adjusting agents. When the Bortezomib is in solubilized form, it interacts with mannitol to form mannitol boronic ester which has high aqueous solubility and will be in solution state even in the pH range of 4.0 to 7.0. After complete solubilization, pH is readjusted to pH range of 4.0 to 7.0 by using equivalent moles of acidic pH adjusting agents. The solubility of Bortezomib is thus optimized based on suitable selection of pH adjusting agents. By carefully modulating the pH of the formulation, the present invention has overcome the solubility challenges associated with Bortezomib, ensuring its efficacy and therapeutic potential.

[0070]

[0058] In an embodiment, the process of preparation of the ready-to-use liquid formulation of Bortezomib comprises the steps of: i) mixing Bortezomib, sodium chloride, and mannitol in water to obtain an aqueous mixture; ii) adding sodium hydroxide to the aqueous mixture of step i) to obtain a solution having a pH ranging from about 8.0 to about 14.0; and iii) adjusting the pH of the solution obtained in step ii) to 4.0 to 7.0 using hydrochloric acid to obtain the ready-to-use liquid formulation of Bortezomib.

[0071]

[0059] In an embodiment, Bortezomib is employed in an amount ranging from about 1 to about 10 mg / mL, mannitol is employed in an amount ranging from about 5 to about 50 mg / mL, and sodium chloride is employed in an amount ranging from 5 to 20 mg / mL.

[0072]

[0060] In a preferred embodiment, the step i) to obtain the aqueous mixture of Bortezomib comprises the steps of: a) purging water with nitrogen gas; b) adding mannitol to the water obtained in step a) to obtain a solution I; c) adding sodium chloride to the solution I obtained in step b) to obtain a solution II; and d) adding Bortezomib to the solution II obtained in step c) to obtain the aqueous mixture of Bortezomib.

[0073]

[0061] When sodium hydroxide and hydrochloric acid are used for pH adjustment, at the end of the process of preparation of the Bortezomib formulation, sodium chloride salt is formed which is a widely used pharmaceutical tonicity agent for injectable formulation. Sodium chloride is also used as a tonicity agent in the Reference Listed Product VELCADE® (bortezomib) for Injection.

[0074]

[0062] In an embodiment, the formulation is an injection formulation, and the solution obtained in step d) is made up to the required dilution with water. The solution is then filtered, preferably through 0.2 micron membrane filter.

[0075]

[0063] In yet another aspect, the present invention provides a Bortezomib formulation for the treatment or prophylaxis of a condition or disorder in a subject in need thereof by administering an effective amount of a ready-to-use formulation of Bortezomib or a pharmaceutically acceptable salt thereof.

[0076]

[0064] In certain embodiments, the condition or disorder refers to a disease condition that is benefited by using Bortezomib. Examples of such a disorder include, but is not limited to multiple myeloma, mantle cell lymphoma etc.

[0077]

[0065] In yet another aspect, the present invention provides a method of treatment or prophylaxis of a condition or disorder in a subject in need thereof by administering an effective amount of a ready-to-use formulation of Bortezomib or a pharmaceutically acceptable salt thereof. In another embodiment, the condition or disorder refers to a disease condition that is benefited by using Bortezomib. Examples of such a disorder include, but is not limited to multiple myeloma, mantle cell lymphoma etc.

[0078]

[0066] The present invention thus not only simplifies the formulation process but also enhances patient safety and convenience. With a focus on eliminating any non-aqueous solvent and pH-related solubility, the invention represents a significant advancement in Bortezomib formulation technology, promising improved therapeutic outcomes for patients particularly with relapsed multiple myeloma and mantle cell lymphoma.

[0067] Advantages of the present invention include:

[0079] • The formulation of the present invention is a ready-to-use solution for injection,

[0080] • The formulation of the present invention is available directly as a solution, • The present invention employs a controlled two-step pH adjustment to achieve solubility, generating sodium chloride in situ,

[0081] • The liquid formulation remains stable for extended periods under refrigerated storage, and

[0082] • The ready-to-use format eliminates the reconstitution step, reducing the risk of dosing errors, contamination, and patient inconvenience

[0083]

[0068] The present disclosure now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure and are not intended to limit the present disclosure in any way.

[0084] EXAMPLES

[0085]

[0069] Preparation of a ready-to-use liquid injectable formulation of Bortezomib:

[0086] Examples: 1, 2, 3 & 4 q.s.: quantity sufficient; mg: milli gram; mL: milli litre

[0087]

[0070] Manufacturing Process:

[0088] Step-1: Collected 70% of batch size Water for Injection, purged with N2 gas to get DO level less than 3 ppm. Step-2: Dispensed quantity of Mannitol was added to the step-1 Water for Injection.

[0089] Step-3: Required quantity of Sodium Chloride was added to the step-2 solution.

[0090] Step-4: Dispensed quantity of Bortezomib was added to the step-3 solution.

[0091] Step-5: Required quantity of Sodium Hydroxide was added to the step-4 solution.

[0092] Step-6: pH of step-5 solution was adjusted in between the pH 4.0 to 7.0 with diluted Hydrochloric Acid solution.

[0093] Step-7: Volume make up was done up to 100% batch with Water for Injection for step-6 bulk solution.

[0094] Step-8: The step-7 bulk solution was filtered through 0.2 micron membrane filter and filled into Type-I USP glass vials with Headspace Oxygen level control below 2% optionally target Headspace Oxygen level can also achieved by applying vacuum cycles in lyophilizer and stoppered with stoppers and sealed with aluminum flip-off seals.

[0095]

[0071] Examples: 5, 6, 7, 8, 9 & 10 q.s.: quantity sufficient; mg: milli gram, mL: milli litre

[0096]

[0072] Manufacturing Process:

[0097] Step-1: Collected 70% of batch size Water for Injection, purged with N2 gas to get DO level less than 3 ppm. Step-2: Dispensed quantity of Mannitol was added to the step-1 Water for Injection.

[0098] Step-3: Dispensed quantity of Sodium Chloride was added to the step-2 solution.

[0099] Step-4: Dispensed quantity of Bortezomib was added to the step-3 solution.

[0100] Step-5: Measured quantity of IN Sodium Hydroxide solution was added to step-4 solution.

[0101] Step-6: Measured quantity of IN Hydrochloric Acid solution was added to step-5 solution and checked the pH of solution. The pH of the solution laid between 4.0 and 7.0.

[0102] Step-7: Volume make up was done up to 100% batch with Water for Injection for step-6 bulk solution.

[0103] Step-8: The step-7 bulk solution was filtered through 0.2 micron membrane filter and filled into Type-I USP glass vials with Headspace Oxygen level control below 2% optionally target Headspace Oxygen level can also achieved by applying vacuum cycles in lyophilizer and stoppered with stoppers and sealed with aluminum flip-off seals.

[0104]

[0073] Examples: 11, 12, 13, 14, 15 & 16 q.s.: quantity sufficient; mg: milli gram; mL: milli litre

[0105]

[0074] Manufacturing Process:

[0106] Step-1: Collected 70% of batch size Water for Injection, purged with N2 gas to get DO level less than 3 ppm.

[0107] Step-2: Dispensed quantity of Mannitol was added to the step-1 Water for Injection.

[0108] Step-3: Dispensed quantity of Sodium Chloride was added to the step-2 solution.

[0109] Step-4: Dispensed quantity of Bortezomib was added to the step-3 solution.

[0110] Step-5: Dispensed quantity of Sodium Hydroxide was added to step-4 solution. Step-6: Dispensed quantity of Hydrochloric Acid solution was added to step-5 solution and checked the pH of solution. The pH of the solution laid between 4.0 and 7.0.

[0111] Step-7: Volume make up was done up to 100% batch with Water for Injection for step-6 bulk solution.

[0112] Step-8: The step-7 bulk solution was filtered through 0.2 micron membrane filter and filled into Type-I USP glass vials with Headspace Oxygen level control below 2% optionally target Headspace Oxygen level can also achieved by applying vacuum cycles in lyophilizer and stoppered with stoppers and sealed with aluminum flip-off seals.

[0113]

[0075] Examples: 17, 18, 19 & 20 q.s.: quantity sufficient; mg: milli gram; mL: milli litre

[0114]

[0076] Manufacturing Process:

[0115] Step-1: Collected 70% of batch size Water for Injection, purged with N2 gas to get DO level less than 3 ppm.

[0116] Step-2: Dispensed quantity of Mannitol was added to the step-1 Water for Injection.

[0117] Step-3: Dispensed quantity of Sodium Chloride was added to the step-2 solution.

[0118] Step-4: Dispensed quantity of Bortezomib was added to the step-3 solution.

[0119] Step-5: pH of step-4 solution was adjusted in between the pH 4.0 to 7.0 with diluted Sodium Hydroxide solution and diluted Hydrochloric Acid solution.

[0120] Step-6: Volume make up was done up to 100% batch with Water for Injection for step-5 bulk solution.

[0121] Step-7: The step-7 bulk solution was filtered through 0.2 micron membrane filter and filled into Type-I USP glass vials with Headspace Oxygen level control below 2% optionally target Headspace Oxygen level can also achieved by applying vacuum cycles in lyophilizer and stoppered with stoppers and sealed with aluminum flip-off seals.

[0122]

[0077] Examples: 21, 22, 23 & 24: q.s.: quantity sufficient; mg: milli gram; mL: milli litre; not in the composition

[0123]

[0078] Manufacturing Process:

[0124] Step-1: Collected 70% of batch size Water for Injection, purged with N2 gas to get DO level less than 3 ppm.

[0125] Step-2: Dispensed quantity of Mannitol was added to the step-1 Water for Injection.

[0126] Step-3: Dispensed quantity of Sodium Chloride was added to the step-2 solution.

[0127] Step-4: Dispensed quantity of Bortezomib was added to the step-3 solution.

[0128] Step-5: Measured quantity of 0.1N / 0.5N / IN / 2N Sodium Hydroxide solution was added to step-4 solution.

[0129] Step-6: Measured quantity of 0.1N / 0.5N / IN / 2N Hydrochloric Acid solution was added to step-5 solution and checked the pH of solution. The pH of the solution laid between 4.0 and 7.0.

[0130] Step-7: Volume make up was done up to 100% batch with Water for Injection for step-6 bulk solution.

[0131] Step-8: The step-7 bulk solution was filtered through 0.2 micron membrane filter and filled into Type-I USP glass vials with Headspace Oxygen level control below 2% optionally target Headspace Oxygen level can also achieved by applying vacuum cycles in lyophilizer and stoppered with stoppers and sealed with aluminum flip-off seals.

[0132]

[0079] Example: 25 q.s.: quantity sufficient

[0133] # 0.28 mg of Sodium was contributed from 0.024 mL of 0.5 N Sodium Hydroxide and 0.42 mg of Chlorine was contributed from 0.024 mL of 0.5 N Hydrochloric acid forming 0.7 mg of Sodium chloride in situ.

[0134] * 8.3 mg of Sodium chloride was obtained from direct addition and 0.7 mg of Sodium chloride was contributed from in situ formation thereby providing 9 mg / mL of total Sodium chloride in the final drug product.

[0135]

[0080] Manufacturing process:

[0136] Step-1: Collected Water for Injection, purged with Nitrogen gas.

[0137] Step-2: Dispensed quantity of Mannitol was added and dissolved in the step-1 Water for Injection.

[0138] Step-3: Dispensed quantity of Sodium Chloride was added and dissolved in the step-2 solution and the solution was cooled to 15 ± 3 °C temperature.

[0139] Step-4: Dispensed quantity of Bortezomib added to the step-3 solution.

[0140] Step-5: Required quantity of 0.5N Sodium hydroxide solution was added to the step-4 solution.

[0141] Step-6: The pH of step-5 solution was adjusted between pH 4.0 to 7.0 with required quantity of 0.5N Hydrochloric Acid solution.

[0142] Step-7: Volume make up was done up to 100% batch with Water for Injection for step-6 bulk solution. Step-8: Aseptically the step-7 bulk solution was filtered through 0.2 pm membrane filter and filled into Type-I USP glass vials with Headspace Oxygen level control below 2%, optionally target Headspace Oxygen level can also be achieved by applying vacuum cycles in lyophilizer and stopper with stoppers and seal with aluminum flip-off seals.

[0143] Step-9: Visually the sealed vials were inspected and labelled.

[0081] Composition of RLD Velcade ® vs Liquid Bortezomib Injection:

[0144] * Removed during lyophilization process; q.s.: Quantity sufficient

[0082] Composition of RLD Velcade® and Liquid Bortezomib Injection at the Time of

[0145] Administration q.s.: Quantity sufficient

[0146]

[0083] The important Physico-chemical parameters of drug product were analyzed for Liquid Bortezomib Injection and RLD Velcade® in order to demonstrate the similarity between both the products. The analytical results are presented in table below.

[0147]

[0084] Comparison of Physical and Chemical Parameters of RLD Velcade® and Liquid Bortezomib Injection 3.5 mg / 1.4 mL (2.5 mg / mL)

[0148] ND: Not detected

[0085] @ RLD data on reconstituted product made with 1.4 mL of 0.9% Sodium chloride Solution giving 2.5 mg / mL of Bortezomib

[0149]

[0086] Stability Data of Liquid Bortezomib Injection 3.5 mg / 1.4 mL (2.5 mg / mL) of the present invention:

[0150]

[0087] Stability studies at long term storage condition (5° ± 3°C) and accelerated storage condition (25±2°C / 60±5%RH) were performed for the proposed solution formulation packed in single dose vials. The stability results are provided in the below table.

[0088] Accelerated Stability Data of the Liquid Bortezomib Injection 3.5 mg / 1.4 mL (2.5 mg / mL) of the Present Invention:

[0089] Long-Term Stability Data of the Liquid Bortezomib Injection 3.5 mg / 1.4 mL (2.5 mg / mL) of the Present Invention:

Claims

We claim:

1. A ready -to-use liquid injectable formulation of Bortezomib comprising:• a therapeutically effective amount of Bortezomib;• water as solvent;• mannitol; and• alkali halide.

2. The liquid injectable formulation as claimed in claim 1, wherein the formulation comprises water in an amount ranging from about 0.1 mL to about 10 mL.

3. The liquid injectable formulation as claimed in claim 1, wherein the Bortezomib is present in an amount ranging from about 1 to about 10 mg / mL.

4. The liquid injectable formulation as claimed in claim 1, wherein the mannitol is present in an amount ranging from about 5 to about 50 mg / mL.

5. The liquid injectable formulation as claimed in claim 1, wherein the alkali halide is selected from the group comprising of sodium chloride, potassium chloride, ammonium chloride, calcium chloride or a combination thereof.

6. The liquid injectable formulation as claimed in claim 1, wherein the alkali halide is present in an amount ranging from 5 to 20 mg / mL.

7. The liquid injectable formulation as claimed in claim 1, wherein the formulation comprises:• 1 to 10 mg / mL of Bortezomib;• 0.1 to 10 mL water as solvent;• 5 to 50 mg / mL mannitol; and• 5 to 20 mg / mL alkali halide.

8. A process of preparation of a ready-to-use liquid injectable formulation of Bortezomib comprising:i) mixing Bortezomib, an alkali halide and mannitol in water to obtain an aqueous mixture; ii) adding an alkaline pH adjusting agent to the aqueous mixture of step i) to obtain a solution; and iii) adjusting the pH of the solution obtained in step ii) to about 4.0 to 7.0 using an acidic pH adjusting agent to obtain the ready-to-use liquid formulation of Bortezomib.

9. The process as claimed in claim 8, wherein the step i) to obtain the aqueous mixture of Bortezomib comprises: a) purging water with nitrogen gas; b) adding mannitol to the water obtained in step a) to obtain a solution I; c) adding alkali halide to the solution obtained in step b) to obtain a solution II; and d) adding Bortezomib to the solution obtained in step c) to obtain the aqueous mixture of Bortezomib.

10. The process as claimed in claim 8, wherein in step ii) the alkaline pH adjusting agent is selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), ammonium hydroxide (NH4OH), calcium hydroxide (Ca(OH)2), magnesium hydroxide (Mg(0H)2), aluminum hydroxide (Al(0H)3), sodium bicarbonate (NaHCOs) or a combination thereof.

11. The process as claimed in claim 8, wherein in step iii) the acidic pH adjusting agent is selected from the group consisting of hydrochloric acid (HC1), sulfuric acid (H2SO4), phosphoric acid (H3PO4), acetic acid (CH3COOH), citric acid (CeHsO?), tartaric acid (C4H5O6), lactic acid (C3H5O3) or a combination thereof.

12. The process as claimed in claim 8, wherein the alkaline and acidic pH adjusting agents are present in their respective aqueous solutions each at a concentration ranging from about 0.01 N to 10 N.

13. The process as claimed in claim 8, wherein in step ii) the alkaline pH adjusting agent is added to attain a pH ranging from about 8.0 to about 14.0.

14. The process as claimed in claim 8, wherein the process of preparation of the ready-to- use liquid formulation of Bortezomib comprises: i) mixing Bortezomib, sodium chloride, and mannitol in water to obtain an aqueous mixture; ii) adding sodium hydroxide to the aqueous mixture of step i) to obtain a solution having a pH ranging from about 8.0 to about 14.0; and iii) adjusting the pH of the solution obtained in step ii) to 4.0 to 7.0 using hydrochloric acid to obtain the ready -to-use liquid formulation of Bortezomib.

15. The process as claimed in claim 14, wherein Bortezomib is employed in an amount ranging from about 1 to about 10 mg / mL, mannitol is employed in an amount ranging from about 5 to about 50 mg / mL, and sodium chloride is employed in an amount ranging from 5 to 20 mg / mL.

16. The liquid injectable formulation as claimed in claim 1, wherein the formulation is used for treatment or prophylaxis of a condition or disorder that is benefited by using Bortezomib, wherein the condition or disorder is selected from multiple myeloma and mantle cell lymphoma.

17. A method of treatment or prophylaxis of a condition or disorder in a subject in need thereof by administering an effective amount of a ready-to-use formulation of Bortezomib or a pharmaceutically acceptable salt thereof.

18. The method as claimed in claim 16, wherein the condition or disorder is benefited by using Bortezomib, wherein the condition or disorder is selected from multiple myeloma and mantle cell lymphoma.

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