WO2015198257A1 - Stable carfilzomib injection - Google Patents

Stable carfilzomib injection Download PDF

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Publication number
WO2015198257A1
WO2015198257A1 PCT/IB2015/054772 IB2015054772W WO2015198257A1 WO 2015198257 A1 WO2015198257 A1 WO 2015198257A1 IB 2015054772 W IB2015054772 W IB 2015054772W WO 2015198257 A1 WO2015198257 A1 WO 2015198257A1
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WIPO (PCT)
Prior art keywords
injection
carfilzomib
stable
pharmaceutically acceptable
acid
Prior art date
Application number
PCT/IB2015/054772
Other languages
French (fr)
Inventor
Ashish Sehgal
Pankaj Patel
Piyush Patel
Original Assignee
Intas Pharmaceuticals Ltd.
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Publication date
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Publication of WO2015198257A1 publication Critical patent/WO2015198257A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to a stable Carfilzomib injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility, wherein the said injection is free from cyclodextrin derivatives. Further the present invention also relates to a process for the preparation of the stable Carfilzomib injection and methods of treatment thereof.
  • Proteasome inhibitor compounds such as Bortezomib and Carfilzomib have been available as FDA approved drugs for the treatment of multiple myeloma.
  • Carfilzomib Injection (KYPROLIS ® available as 60 mg/vial) marketed by Onyx Pharms, is approved for use in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy and have demonstrated disease progression on or within 60 days of completion of the last therapy.
  • Carfilzomib is a peptide epoxyketone compound, which is having very low solubility in water. Due to its chemical complexity and low aqueous solubility, it results into several challenges to formulate pharmaceutical compositions with desired bioavailability.
  • the chemical structure of Carfilzomib is shown as below:
  • Carfilzomib is disclosed in U.S. Patent Nos. 7,232,818; 7,417,042; 7491704 and 8129346, which describe the peptide epoxyketone compounds and its use for the treatment of cancer.
  • U.S. Patent No. 7,737,112 discloses the pharmaceutical composition comprising Carfilzomib and a substituted cyclodextrin selected from hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin (SBECD).
  • the present invention provides a stable Carfilzomib Injection as a pre- lyophilization solution that produces a stable lyophized powder.
  • the present invention also provides a ready-to-use or ready-to-dilute composition.
  • the primary object of the present invention is to provide a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility and wherein the said injection is free from cyclodextrin derivatives.
  • Another object of the invention is to provide a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives.
  • Another object of the invention is to provide a process for the preparation of a stable Carfilzomib Injection, wherein the said injection is free from cyclodextrin derivatives.
  • Another object of the invention is to provide a stable Carfilzomib Injection for administering Carfilzomib in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy, and wherein the said injection is free from cyclodextrin derivatives.
  • the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility and wherein the said injection is free from cyclodextrin derivatives.
  • the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives.
  • the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with citric acid, tertiary butyl alcohol and water for injection.
  • the invention in another embodiment, relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with tertiary butyl alcohol, acetic acid and water for injection.
  • the invention relates to a process for the preparation of a stable Carfilzomib Injection, wherein the said injection is free from cyclodextrin derivatives.
  • Another object of the invention is to provide a stable Carfilzomib Injection for administering Carfilzomib in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy, and wherein the said injection is free from cyclodextrin derivatives.
  • the present invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility and wherein the said injection is free from cyclodextrin derivatives.
  • the present invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives.
  • the stable Carfilzomib Injection of the present invention have sufficient stability to allow storage at a commercially relevant temperature, such as between about O.degree. C. and about 40.degree. C, for a commercially relevant period of time, such as at least one month, preferably at least one year, and most preferably at least two years.
  • the stability can be measured using any physiochemical characterization techniques known to those skilled in the art.
  • the stable Carfilzomib Injection of the present invention maintain their physical and chemical stability to allow storage at a commercially relevant temperature, such as 2-8.degree. C. and 25.degree. C.
  • injection shall mean a pharmaceutical composition that is made under conditions such that it is suitable for parenteral administration to humans, e.g., it is made under GMP conditions and contains pharmaceutically acceptable excipients.
  • stable Carfilzomib Injection means: (i) a pre-lyophilization solution that produces a stable lyophized powder; or (ii) a pharmaceutical composition in the form of ready-to-use injection.
  • the stable lyophized powder of the present invention appears as white to off white lyophilized powder that can be reconstituted in less than 300 seconds and wherein the pH of the reconstituted solution is less than 6.
  • the stable lyophized powder of the present invention can be prepared using standard equipment as used for lyophilization or freeze-drying method.
  • the organic solvents and water for injection are subject to evaporation during lyophilization process.
  • the lengthy exposure time during reconstitution process of lyophilized powder shall increase the potential for loss of potency and impurity formation due to hydrolysis.
  • the stable Carfilzomib Injection as a pre-lyophilization solution that produces a stable lyophized powder can be reconstituted in a time period of less than 5 minutes (i.e. 300 seconds).
  • the reconstitution time of the stable lyophized powder is less than 90 seconds.
  • the water content of the said lyophilized powder is less than 5%.
  • the water content is less than about 2%.
  • the stable Carfilzomib Injection of the present invention can be provided as a ready-to-use injection.
  • the ready-to-use injection of the present invention comprises Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives. Further, the said ready-to-use injection provides the advantage of elimination of the need for lyophilization step and thereby the need for subsequent reconstitution step.
  • the stable Carfilzomib Injection of the present invention as a ready-to-use injection appears as clear yellowish solution without the presence of any particulate matter, thereby the said injection maintains physical and chemical stability to allow storage at a commercially relevant temperature, such as 2-8.degree. C. and 25.degree. C.
  • the ready-to-use Injection can be diluted with a suitable diluent before administration.
  • suitable diluents include, but are not limited to, water, saline, dextrose, and water for injection.
  • the stable lyophized powder of Carfilzomib can also be reconstituted directly with a suitable diluent before administration.
  • suitable diluents include, but are not limited to, water, saline, dextrose, and water for injection.
  • the stable Carfilzomib Injection of the present invention can be provided as a kit comprising: (i) a product vial composition comprising a stable lyophilized powder of Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component; and (ii) a diluent vial composition comprising suitable solvents, preferably Dimethylacetamide, Polysorbates or mixtures thereof. More preferably, the diluent vial comprises a mixture of Dimethylacetamide and Polysorbate 80.
  • the diluent vial composition further optionally comprises the pharmaceutically acceptable excipients in an amount that can be determined by any person with ordinary skill in the art.
  • the “acid component” of the present invention includes any pharmaceutically acceptable organic or inorganic acids.
  • the acid component includes, non-limiting examples, such as citric acid, tartaric acid, succinic acid, acetic acid, glacial acetic acid, maleic acid, phosphoric acid or combinations thereof.
  • the acid component is citric acid. More preferably, the acid is citric acid anhydrous.
  • the "organic solvent” of the present invention includes, non-limiting examples, such as dehydrated alcohol, Tertiary butyl alcohol (TBA), propylene glycol, polyethylene glycol, glycerol, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and mixtures thereof.
  • the organic solvent is tertiary butyl alcohol and/or dehydrated alcohol.
  • the amount of organic solvent in the composition can be decided by any skilled person known in the art.
  • the amount of organic solvent in the said composition is about 10-70% V/V, more preferably is about 30- 40% V/V.
  • the term "pharmaceutically acceptable excipients” includes any suitable excipients such as buffers, bulking agents, diluents, sugars, cellulose and its derivatives, pH-adjusting agents, solubilizers, antioxidants, preservatives, surfactants, isotonicity agents, and/or lyoprotectants.
  • Carfilzomib or pharmaceutically acceptable salts thereof shall comprise of any pharmaceutically acceptable forms of Carfilzomib, including its free form (zwitter ion), and its pharmaceutically acceptable complexes, acid addition salts, base addition salts solvates, hydrates, and polymorphs.
  • the present invention relates to a process for the preparation of a stable Carfilzomib Injection, which can be prepared either by lyophilization method and reconstituted prior to use, or as a ready-to-use injection. Lyophilization methods are well-known to a person skilled in the art.
  • Lyophilization methods are well-known to a person skilled in the art.
  • following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of the invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made without departing from the scope of the invention.
  • the stable Carfilzomib Injection of the present invention as described in following examples (1 to 5) are prepared by lyophilization method.
  • the finished product obtained by lyophilization method contains Carfilzomib as 60 mg/vial or 45 mg/vial.
  • Example 1 Carfilzomib Injection as a Lyophilized powder.
  • TSA Tertiary butyl alcohol
  • the bulk solution is prepared according to the above example to obtain 2mg/ml and 6mg/ml solution. Further, in order to obtain 60mg/vial or 45mg/vial of the lyophilized product, the equivalent amount of solution is filled in vial and subjected to lyophilization process.
  • Diluent vial composition is prepared by admixing Dimethylacetamide and Polysorbate 80.
  • the stable Carfilzomib Injection of the present invention comprises a kit comprising a product vial composition (i.e. stable lyophilized powder) and a diluent vial composition, as illustrated above.
  • a product vial composition i.e. stable lyophilized powder
  • a diluent vial composition as illustrated above.
  • Example 2 Carfilzomib Injection as a Lyophilized powder.
  • Example 3 Carfilzomib Injection as a Lyophilized powder.
  • TSA Tertiary butyl alcohol
  • Example 4 Carfilzomib Injection as a Lyophilized powder.
  • Example 5 Carfilzomib Injection as a Lyophilized powder.
  • TSA Tertiary butyl alcohol
  • water for injection to be evaporated during lyophilization process.
  • the lyophilized compositions as described in Examples 2 to 5 can also be provided as a kit as illustrated in the Example 1.
  • the stable Carfilzomib Injection of the present invention can be provided as a ready-to-use injection.
  • Example 6 provides stable Carfilzomib Injection as Ready- to-use injection.
  • Example 6 Carfilzomib Ready-to-use (RTU) Injection.
  • the stable Cafilzomib Injection as Ready-to-use injection is prepared by admixing Carfilzomib and citric acid anhydrous in mixture of dimethylacetamide and Polysorbate 80.
  • the above data confirms the stability of the present invention as a ready-to-use injection, wherein the said injection maintains physical and chemical stability to allow storage at a commercially relevant temperature, such as 2-8.degree. C. and 25.degree. C.
  • the present invention of stable Carfilzomib Injection provides cost effective and commercially feasible solution over problems associated with the existing Carfilzomib compositions.

Abstract

The present invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility and wherein the injection is free from cyclodextrin derivatives.

Description

STABLE CARFILZOMIB INJECTION.
RELATED APPLICATIONS
This application is related to Indian Provisional Application 2079/MUM/2014 filed 26th June, 2014 and is incorporated herein in its entirety.
FIELD OF THE INVENTION
The present invention relates to a stable Carfilzomib injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility, wherein the said injection is free from cyclodextrin derivatives. Further the present invention also relates to a process for the preparation of the stable Carfilzomib injection and methods of treatment thereof.
BACKGROUND OF THE INVENTION
Proteasome inhibitor compounds such as Bortezomib and Carfilzomib have been available as FDA approved drugs for the treatment of multiple myeloma. Carfilzomib Injection (KYPROLIS® available as 60 mg/vial) marketed by Onyx Pharms, is approved for use in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy and have demonstrated disease progression on or within 60 days of completion of the last therapy.
Chemically, Carfilzomib is a peptide epoxyketone compound, which is having very low solubility in water. Due to its chemical complexity and low aqueous solubility, it results into several challenges to formulate pharmaceutical compositions with desired bioavailability. The chemical structure of Carfilzomib is shown as below:
Figure imgf000003_0001
Carfilzomib is disclosed in U.S. Patent Nos. 7,232,818; 7,417,042; 7491704 and 8129346, which describe the peptide epoxyketone compounds and its use for the treatment of cancer. U.S. Patent No. 7,737,112 discloses the pharmaceutical composition comprising Carfilzomib and a substituted cyclodextrin selected from hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin (SBECD).
Since Carfilzomib has low aqueous solubility, the development of a stable Carfilzomib Injection is very challenging. Further, the cost-effective accessibility and feasibility of substituted cyclodextrins limits their extensive use. Hence there exists a need to make available simple methods of formulating stable lyophilized Carfilzomib Injections with pharmaceutically acceptable excipients.
The U.S. Patent Application No. US2014/073583 describes a liquid formulation comprising (i) Carfilzomib, (ii) a water-miscible organic solvent and (iii) a nonvolatile sugar acid.
Therefore, there exists the need for the development of a stable Carfilzomib Injection that substantially increases the solubility and provides the desired bioavailability. In particular, the present invention provides a stable Carfilzomib Injection as a pre- lyophilization solution that produces a stable lyophized powder. Alternatively, the present invention also provides a ready-to-use or ready-to-dilute composition. OBJECTS OF THE INVENTION
The primary object of the present invention is to provide a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility and wherein the said injection is free from cyclodextrin derivatives.
Another object of the invention is to provide a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives. Another object of the invention is to provide a process for the preparation of a stable Carfilzomib Injection, wherein the said injection is free from cyclodextrin derivatives.
Another object of the invention is to provide a stable Carfilzomib Injection for administering Carfilzomib in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy, and wherein the said injection is free from cyclodextrin derivatives.
SUMMARY OF THE INVENTION
In a first embodiment, the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility and wherein the said injection is free from cyclodextrin derivatives.
In another embodiment, the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives. In another embodiment, the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with citric acid, tertiary butyl alcohol and water for injection.
In another embodiment, the invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with tertiary butyl alcohol, acetic acid and water for injection.
In another embodiment, the invention relates to a process for the preparation of a stable Carfilzomib Injection, wherein the said injection is free from cyclodextrin derivatives.
Another object of the invention is to provide a stable Carfilzomib Injection for administering Carfilzomib in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy, and wherein the said injection is free from cyclodextrin derivatives. DETAILED DESCRIPTION
The present invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility and wherein the said injection is free from cyclodextrin derivatives.
The present invention relates to a stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives.
The stable Carfilzomib Injection of the present invention have sufficient stability to allow storage at a commercially relevant temperature, such as between about O.degree. C. and about 40.degree. C, for a commercially relevant period of time, such as at least one month, preferably at least one year, and most preferably at least two years. The stability can be measured using any physiochemical characterization techniques known to those skilled in the art. The stable Carfilzomib Injection of the present invention maintain their physical and chemical stability to allow storage at a commercially relevant temperature, such as 2-8.degree. C. and 25.degree. C.
The term "Injection" as used herein shall mean a pharmaceutical composition that is made under conditions such that it is suitable for parenteral administration to humans, e.g., it is made under GMP conditions and contains pharmaceutically acceptable excipients. For the sake of the present invention, as used herein the term "stable Carfilzomib Injection" means: (i) a pre-lyophilization solution that produces a stable lyophized powder; or (ii) a pharmaceutical composition in the form of ready-to-use injection. The stable lyophized powder of the present invention appears as white to off white lyophilized powder that can be reconstituted in less than 300 seconds and wherein the pH of the reconstituted solution is less than 6.
The stable lyophized powder of the present invention can be prepared using standard equipment as used for lyophilization or freeze-drying method. The organic solvents and water for injection are subject to evaporation during lyophilization process.
The lengthy exposure time during reconstitution process of lyophilized powder shall increase the potential for loss of potency and impurity formation due to hydrolysis. The stable Carfilzomib Injection as a pre-lyophilization solution that produces a stable lyophized powder, can be reconstituted in a time period of less than 5 minutes (i.e. 300 seconds). Preferably, the reconstitution time of the stable lyophized powder is less than 90 seconds. Further, the water content of the said lyophilized powder is less than 5%. Preferably, the water content is less than about 2%.
In another embodiment, the stable Carfilzomib Injection of the present invention can be provided as a ready-to-use injection.
The ready-to-use injection of the present invention comprises Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives. Further, the said ready-to-use injection provides the advantage of elimination of the need for lyophilization step and thereby the need for subsequent reconstitution step.
The stable Carfilzomib Injection of the present invention as a ready-to-use injection appears as clear yellowish solution without the presence of any particulate matter, thereby the said injection maintains physical and chemical stability to allow storage at a commercially relevant temperature, such as 2-8.degree. C. and 25.degree. C.
The ready-to-use Injection can be diluted with a suitable diluent before administration. Suitable diluents include, but are not limited to, water, saline, dextrose, and water for injection.
The stable lyophized powder of Carfilzomib can also be reconstituted directly with a suitable diluent before administration. Suitable diluents include, but are not limited to, water, saline, dextrose, and water for injection.
In another embodiment, the stable Carfilzomib Injection of the present invention can be provided as a kit comprising: (i) a product vial composition comprising a stable lyophilized powder of Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component; and (ii) a diluent vial composition comprising suitable solvents, preferably Dimethylacetamide, Polysorbates or mixtures thereof. More preferably, the diluent vial comprises a mixture of Dimethylacetamide and Polysorbate 80. The diluent vial composition further optionally comprises the pharmaceutically acceptable excipients in an amount that can be determined by any person with ordinary skill in the art.
The "acid component" of the present invention includes any pharmaceutically acceptable organic or inorganic acids. The acid component includes, non-limiting examples, such as citric acid, tartaric acid, succinic acid, acetic acid, glacial acetic acid, maleic acid, phosphoric acid or combinations thereof. Preferably, the acid component is citric acid. More preferably, the acid is citric acid anhydrous. The "organic solvent" of the present invention includes, non-limiting examples, such as dehydrated alcohol, Tertiary butyl alcohol (TBA), propylene glycol, polyethylene glycol, glycerol, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and mixtures thereof. Preferably, the organic solvent is tertiary butyl alcohol and/or dehydrated alcohol. The amount of organic solvent in the composition can be decided by any skilled person known in the art. Preferably, the amount of organic solvent in the said composition is about 10-70% V/V, more preferably is about 30- 40% V/V.
For the sake of the present invention, the term "pharmaceutically acceptable excipients" includes any suitable excipients such as buffers, bulking agents, diluents, sugars, cellulose and its derivatives, pH-adjusting agents, solubilizers, antioxidants, preservatives, surfactants, isotonicity agents, and/or lyoprotectants.
For the sake of the present invention, the term "Carfilzomib or pharmaceutically acceptable salts thereof shall comprise of any pharmaceutically acceptable forms of Carfilzomib, including its free form (zwitter ion), and its pharmaceutically acceptable complexes, acid addition salts, base addition salts solvates, hydrates, and polymorphs. In another embodiment, the present invention relates to a process for the preparation of a stable Carfilzomib Injection, which can be prepared either by lyophilization method and reconstituted prior to use, or as a ready-to-use injection. Lyophilization methods are well-known to a person skilled in the art. In order to further illustrate the present invention, following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of the invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made without departing from the scope of the invention.
The stable Carfilzomib Injection of the present invention as described in following examples (1 to 5) are prepared by lyophilization method. The finished product obtained by lyophilization method contains Carfilzomib as 60 mg/vial or 45 mg/vial.
Example 1: Carfilzomib Injection as a Lyophilized powder.
Product Vial Composition:
Figure imgf000010_0001
* Tertiary butyl alcohol (TBA) and water for injection to be evaporated during lyophilization process.
The bulk solution is prepared according to the above example to obtain 2mg/ml and 6mg/ml solution. Further, in order to obtain 60mg/vial or 45mg/vial of the lyophilized product, the equivalent amount of solution is filled in vial and subjected to lyophilization process.
To obtain 60mg/vial product, the volume of 10ml of 6mg/ml solution is filled in the vial and lyophilized. Similarly, to obtain 45mg/vial product, the volume of 7.5 ml of 6mg/ml solution is filled in vial and lyophilized. Diluent vial composition:
Figure imgf000011_0001
Diluent vial composition is prepared by admixing Dimethylacetamide and Polysorbate 80.
The stable Carfilzomib Injection of the present invention comprises a kit comprising a product vial composition (i.e. stable lyophilized powder) and a diluent vial composition, as illustrated above.
Stability data of Carfilzomib In jection (60 mg/vial):
Figure imgf000011_0002
The above data confirms the stability of the present invention in the form of a stable lyophilized powder as white to off white lyophilized powder that can be reconstituted in less than 300 seconds, and wherein the pH of the reconstituted solution is less than 6. Other examples of stable Carfilzomib Injection in the form of stable lyophilized powder are as follows:
Example 2: Carfilzomib Injection as a Lyophilized powder.
Figure imgf000012_0001
* Dehydrated alcohol and water for injection to be evaporated during lyophilization process.
Example 3: Carfilzomib Injection as a Lyophilized powder.
Figure imgf000012_0002
* Tertiary butyl alcohol (TBA) and water for injection to be evaporated during lyophilization process. Example 4: Carfilzomib Injection as a Lyophilized powder.
Figure imgf000012_0003
Dehydrated alcohol and water for injection to be evaporated during lyophilization process.
Example 5: Carfilzomib Injection as a Lyophilized powder.
Figure imgf000012_0004
Tertiary butyl alcohol (TBA) and water for injection to be evaporated during lyophilization process. The lyophilized compositions as described in Examples 2 to 5 can also be provided as a kit as illustrated in the Example 1. Further, the stable Carfilzomib Injection of the present invention can be provided as a ready-to-use injection. Example 6 provides stable Carfilzomib Injection as Ready- to-use injection.
Example 6: Carfilzomib Ready-to-use (RTU) Injection.
Figure imgf000013_0001
The stable Cafilzomib Injection as Ready-to-use injection is prepared by admixing Carfilzomib and citric acid anhydrous in mixture of dimethylacetamide and Polysorbate 80.
Stability Data of Ready-to-use Injection:
Figure imgf000013_0002
The above data confirms the stability of the present invention as a ready-to-use injection, wherein the said injection maintains physical and chemical stability to allow storage at a commercially relevant temperature, such as 2-8.degree. C. and 25.degree. C.
In summary, the present invention of stable Carfilzomib Injection provides cost effective and commercially feasible solution over problems associated with the existing Carfilzomib compositions.

Claims

We claim:
1. A stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with pharmaceutically acceptable excipients that substantially increase the solubility of Carfilzomib or pharmaceutically acceptable salts thereof, wherein the said injection is free from cyclodextrin derivatives.
2. A stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with at least one acid component, at least one organic solvent, optionally with other pharmaceutically acceptable excipients, and wherein the said injection is free from cyclodextrin derivatives.
3. The stable Carfilzomib Injection according to claim 2, wherein the acid component is selected from citric acid, tartaric acid, succinic acid, acetic acid, glacial acetic acid, maleic acid, phosphoric acid or combinations thereof.
4. The stable Carfilzomib Injection according to claim 2, wherein the organic solvent is selected from dehydrated alcohol, Tertiary butyl alcohol, propylene glycol, polyethylene glycol, glycerol, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and mixtures thereof.
5. A stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with citric acid, tertiary butyl alcohol and water for injection, wherein the said injection is free from cyclodextrin derivatives and wherein the said injection produces a stable lyophized powder that can be reconstituted in less than 300 seconds.
6. A stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with acetic acid, tertiary butyl alcohol and water for injection, wherein the said injection is free from cyclodextrin derivatives and wherein the said injection produces a stable lyophized powder that can be reconstituted in less than 300 seconds.
7. A kit comprising:
(i) a product vial composition comprising a stable lyophilized powder of Carfilzomib or pharmaceutically acceptable salts thereof with citric acid; and
(ii) a diluent vial composition comprising Dimethylacetamide and Polysorbate80.
8. A stable Carfilzomib Injection comprising Carfilzomib or pharmaceutically acceptable salts thereof with citric acid, Dimethyl acetamide and Polysorbate 80, wherein the said injection is free from cyclodextrin derivatives and wherein the said injection is a ready-to-use injection.
9. A process for the preparation of a stable Carfilzomib Injection, wherein the said injection is obtained as a lyophilized powder or as a ready-to-use injection.
10. A stable Carfilzomib Injection for administering Carfilzomib in patients in need thereof for the treatment of multiple myeloma, wherein the said injection is free from cyclodextrin derivatives.
PCT/IB2015/054772 2014-06-26 2015-06-25 Stable carfilzomib injection WO2015198257A1 (en)

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Publication number Priority date Publication date Assignee Title
WO2016116882A3 (en) * 2015-01-23 2016-11-03 Leiutis Pharmaceuticals Pvt Ltd Novel compositions of carfilzomib
US10098890B2 (en) 2016-10-29 2018-10-16 Cipla Limited Stable carfilzomib formulations
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WO2023220655A1 (en) 2022-05-11 2023-11-16 Celgene Corporation Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy
WO2023220641A2 (en) 2022-05-11 2023-11-16 Juno Therapeutics, Inc. Methods and uses related to t cell therapy and production of same

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