Stable pharmaceutical formulation

Abstract

The present invention relates to a stable formulation of cyclophosphamide comprising a therapeutically effective amount of cyclophosphamide, ethanol as solvent, polyethylene glycol as the solvent, and optionally, monothioglycerol as the anti-oxidant, wherein the composition is stable over its shelf life.

Claims

1. A stable ready-to-dilute composition comprising (i) cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount ranging from about 100 mg to about 1000 mg, (ii) about 40% to about 60% (w/v) of ethanol, (iii) about 0.005% to about 0.05% (w/v) of monothioglycerol as an antioxidant and (iv) more than 30% (w/v) of polyethylene glycol 400; wherein the ratio of ethanol to polyethylene glycol 400 is from 1:0.75 to 1:2, wherein the composition has no more than 4.0% of total impurities, no more than 0.2% of any unspecified impurity, no more than 0.50% of 3-(2-Chloroethyl)-2-oxo-2-hydroxy-1, 3, 6, 2-oxadiazaphosphonane (related compound B), no more than 0.50% of 3-[2-(2-Chloroethylamino) ethylamino] propyl dihydrogen phosphate (related compound D), no more than 1.5% of 2-((2-chloroethyl) (2-ethoxyethyl) amino)-1,3,2-oxazaphosphinane-2-oxide (related compound E) and no more than 1.5% of 3-aminopropyl hydrogen (2-chloroethyl)(2-ethoxyethyl) phosphoramidate (related compound F) when stored in a vial at about 2 degrees Celsius to about 8 degrees Celsius for at least 3 months.

2. The stable ready-to-dilute composition of claim 1, wherein the composition has a volume of 1 mL.

3. A stable ready-to-dilute composition consisting of (i) cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount ranging from about 100 mg to about 1000 mg, (ii) about 40% to about 60% (w/v) of ethanol, (iii) about 0.005% to about 0.05% (w/v) of monothioglycerol as an antioxidant and (iv) polyethylene glycol 400 qs to 100% volume, wherein the composition has no more than 4.0% of total impurities, no more than 0.2% of any unspecified impurity, no more than 0.50% of 3-(2-Chloroethyl)-2-oxo-2-hydroxy-1, 3, 6, 2-oxadiazaphosphonane (related compound B), no more than 0.50% of 3-[2-(2-Chloroethylamino) ethylamino] propyl dihydrogen phosphate (related compound D), no more than 1.5% of 2-((2-chloroethyl) (2-ethoxyethyl) amino)-1,3,2-oxazaphosphinane-2-oxide (related compound E) and no more than 1.5% of 3-aminopropyl hydrogen (2-chloroethyl)(2-ethoxyethyl) phosphoramidate (related compound F) when stored for 3 months in a vial at about 2 degrees Celsius to about 8 degrees Celsius.

4. The stable ready-to-dilute composition of claim 1, wherein the composition comprises cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount ranging from about 100 mg to about 500 mg.

5. The stable ready-to-dilute composition of claim 1, wherein the composition comprises cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount ranging from about 200 mg to about 400 mg.

6. The stable ready-to-dilute composition of claim 3, wherein the composition consists of cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount ranging from about 100 mg to about 500 mg.

7. The stable ready-to-dilute composition of claim 3, wherein the composition consists of cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount ranging from about 200 mg to about 400 mg.

8. The stable ready-to-dilute composition of claim 3, wherein the composition has a volume of 1 mL.

9. The stable ready-to-dilute composition of claim 1, wherein the composition is free of propylene glycol.

10. The stable ready-to-dilute composition of claim 3, wherein the composition is free of propylene glycol.

Description

DESCRIPTION

(1) The present invention provides stable formulations of cyclophosphamide that are ready-to-dilute, and do not require reconstitution. Further, it saves significant time as the composition can be directly administered (bolus) or injected into a bag containing a large volume parenteral, and the time taken to prepare the dose is reduced. It must be noted that drugs like cyclophosphamide are administered to the patient in an out-patient chemotherapy setting, wherein the patient comes in and waits while the healthcare professional prepares the dose. Thus, if the waiting time is reduced through use of the ready-to-dilute composition of the present invention, the exposure of the patient to other patients, and to hospital-derived infections, is also reduced.

(2) The present invention provides a ready-to-dilute composition of cyclophosphamide that is stable, and which provides the advantages of reduced dosing errors and ease of administration. The present invention provides a stable composition of cyclophosphamide comprising a therapeutically effective amount of cyclophosphamide, ethanol as solvent, polyethylene glycol as a solvent, and optionally, monothioglycerol as the anti-oxidant, wherein the composition is stable over its shelf-life.

(3) The ready-to-dilute compositions of the present invention include cyclophosphamide in the form of its pharmaceutically acceptable salt or solvate. In preferred embodiments the cyclophosphamide is present in the form of cyclophosphamide monohydrate.

(4) The compositions of the present inventions contain the cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount of about 100 mg to about 1000 mg by weight of anhydrous cyclophosphamide. In embodiments, the compositions comprise the cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount of about 200 mg to about 500 mg by weight of anhydrous cyclophosphamide. In embodiments, the compositions comprise the cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount of about 200 mg to about 400 mg by weight of anhydrous cyclophosphamide. In embodiments, the compositions comprise the cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount of about 200 mg to about 300 mg by weight of anhydrous cyclophosphamide. In embodiments, the compositions comprise the cyclophosphamide or its pharmaceutically acceptable salt or solvate in an amount of about 200 mg by weight of anhydrous cyclophosphamide.

(5) The ready-to-dilute compositions of the present invention include a solvent that is critical to providing solubility and long term stability of the cyclophosphamide contained therein. The solvent used may be a single solvent or a mixture of one or more solvents. The pharmaceutically acceptable solvents that may be used in the ready-to-dilute compositions of the present invention may be selected from the group consisting of ethanol, polyethylene glycol or a mixture thereof. The solvents used in the compositions of the present invention do not include propylene glycol. Although the prior art, such as U.S. Pat. No. 9,662,342 (Aurobindo) and WO2020178725, taught use of propylene glycol as a solvent for cyclophosphamide, and although US20170143744 (DRL) taught polyol free compositions of cyclophosphamide, the inventors have found that stable ready-to-dilute compositions of cyclophosphamide can be obtained by (a) using polyethylene glycol (a glycol) and (b) by avoiding propylene glycol, and further wherein the amount of ethanol is kept below 60% of the total composition.

(6) The ready-to-dilute compositions of the present invention use ethanol, preferably absolute ethanol, as a solvent for solubilizing cyclophosphamide or its pharmaceutically acceptable salt or solvate as the sole solvent, or it may use a combination of ethanol with polyethylene glycol. In preferred embodiments of the invention, the ready-to-dilute compositions of the present invention use ethanol and polyethylene glycol 400 as the solvent. The amount of ethanol that may be used ranges from about 40% to about 60% of the total compositions. The amount of polyethylene glycol 400 (PEG 400) that may be used is more than 30% of the total composition. Typically, the ratio of ethanol to PEG 400 ranges from 1:0.75 to 1:2.

(7) The ready-to-dilute compositions of the present invention include monothioglycerol as an antioxidant. It may be present in an amount ranging from about 0.005% to about 0.05% of the total composition.

(8) The term “shelf life” refers to the amount of time the pharmaceutical composition may be stored without loss of potency and/or performance profile. In some embodiments of the present invention, shelf life refers to the amount of time the pharmaceutical composition may be stored without loss of about 4%, about 3%, about 2% or about 1% of the potency and/or performance of the active, when stored at refrigerated conditions, i.e. about 2° C. to about 8° C. The stable compositions provided herein are designed to have shelf life of at least 24 months.

(9) As discussed above, the cyclophosphamide ready-to-dilute composition of the present invention is stable over its shelf life. The specification for impurities in the ready-to-use composition, at shelf-life, when stored at about 2° C. to about 8° C., is as seen in Table 1 below

(10) TABLE-US-00001 TABLE 1 Impurity specification at shelf-life for ready-to use compositions of the present invention Impurity Specification Related Compound B Not more than 0.50% Related Compound D Not more than 0.50% Related Compound E Not more than 1.5% Related Compound F Not more than 1.5% Any unspecified Impurity Not more than 0.2% Total Impurities Not more than 4.0%

(11) The impurities are described in Table 2 below.

(12) TABLE-US-00002 TABLE 2 Name of Chemical name of the Impurity impurity Structure Related Compound B 3-(2-Chloroethyl)-2-oxo-2- hydroxy-1,3,6,2- oxadiazaphosphonane Related Compound D 3-[2-(2-Chloroethyl- amino)ethylamino]propyl dihydrogen phosphate Related Compound E 2-((2-chloroethyl)(2- ethoxyethyl)amino)-1,3,2- oxazaphosphinane-2-oxide Related Compound F 3-aminopropyl hydrogen (2- chloroethyl)(2-ethoxyethyl) phosphoramidate

(13) In preferred embodiments, the ready-to-dilute compositions of the present invention have no more than 4.0% of total impurities when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(14) In another embodiment, the ready-to-dilute composition of the present invention has no more than 0.50% of related compound B in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(15) In yet another embodiment, the ready-to-dilute composition of the present invention has no more than 0.50% of related compound D in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(16) In another embodiment, the ready-to-dilute composition of the present invention has no more than 1.5% of related compound E in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(17) In one embodiment, the ready-to-dilute composition of the present invention has no more than 1.5% of related compound F in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(18) In yet another embodiment, the ready-to-dilute composition of the present invention has no more than 0.2% of any unspecified impurity in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(19) In one embodiment, the ready-to-dilute composition of the present invention has no more than 4.0% of total impurities and no more than 0.50% of related compound B in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(20) In one embodiment, the ready-to-dilute composition of the present invention has no more than 4.0% of total impurities and no more than 0.50% of related compound D in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(21) In one embodiment, the ready-to-dilute composition of the present invention has no more than 4.0% of total impurities and no more than 1.5% of related compound E in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(22) In one embodiment, the ready-to-dilute composition of the present invention has no more than 4.0% of total impurities and no more than 1.5% of related compound F in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(23) In one embodiment, the ready-to-dilute composition of the present invention has no more than 4.0% of total impurities and no more than 0.2% of any unspecified impurity in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(24) In some embodiments, the ready-to-dilute compositions of the present invention have no more than 4.0% of total impurities, no more than 0.2% of any unspecified impurity and no more than 0.50% of related compound B in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(25) In some embodiments, the ready-to-dilute compositions of the present invention have no more than 4.0% of total impurities, no more than 0.2% of any unspecified impurity and no more than 0.50% of related compound D in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(26) In other embodiments, the ready-to-dilute compositions of the present invention have no more than 4.0% of total impurities, no more than 0.2% of any unspecified impurity and no more than 1.5% of related compound E in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(27) In yet other embodiments, the ready-to-dilute compositions of the present invention have no more than 4.0% of total impurities, no more than 0.2% of any unspecified impurity and no more than 1.5% of related compound F in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(28) In some embodiments, the ready-to-dilute compositions of the present invention have no more than 4.0% of total impurities, no more than 0.2% of any unspecified impurity, no more than 0.50% of related compound B and no more than 0.50% of related compound D in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(29) In some embodiments, the ready-to-dilute compositions of the present invention have no more than 4.0% of total impurities, no more than 0.2% of any unspecified impurity, no more than 0.50% of related compound B, no more than 0.50% of related compound D and no more than 1.5% of related compound E in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(30) In some embodiments, the ready-to-dilute compositions of the present invention have no more than 4.0% of total impurities, no more than 0.2% of any unspecified impurity, no more than 0.50% of related compound B, no more than 0.50% of related compound D and no more than 1.5% of related compound F in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(31) In highly preferred embodiments, the ready-to-dilute compositions of the present invention have no more than 4.0% of total impurities, no more than 0.2% of any unspecified impurity, no more than 0.50% of related compound B, no more than 0.50% of related compound D, no more than 1.5% of related compound E and no more than 1.5% of related compound F in the composition at the end of 24 months, when stored at about 2 degrees Celsius to about 8 degrees Celsius.

(32) The ready-to-dilute compositions of the present invention are prepared by aseptic process, wherein the dispensing and admixture of the excipients and cyclophosphamide is carried out under aseptic conditions under laminar flow conditions. Once the solution of the composition is obtained, it is sterilized by passing through 0.2μ polytetrafluoroethylene (PTFE) membrane filter and filled into vials. The vials used typically may be clear USP Type I glass vials that are pharmaceutically acceptable. The vials are stoppered with coated bromobutyl rubbers, followed by flip top aluminium seals.

(33) The ready-to-dilute to compositions of the present invention are stored at about 2 degrees Celsius to about 8 degrees Celsius. When stored under these conditions, the compositions were found to remain stable, as defined herein, for at least 24 months.

(34) Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

(35) Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination.

(36) Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted.

(37) All publications, patent applications, patents, and other references mentioned are incorporated by reference herein in their entirety for all purposes.

(38) As used herein, “a,” “an,” or “the” can mean one or more than one. For example, “a” solvent can mean a single solvent or a multiplicity of solvents.

(39) Also as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

(40) Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound, related compound, impurity or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ±10% of the specified amount.

(41) The term “cyclophosphamide” may be used interchangeably with “cyclophosphamide and its pharmaceutically acceptable salt or solvate”.

(42) The present invention is further illustrated by reference to the following examples which are for illustrative purpose only and do not limit the scope of the invention in any manner.

EXAMPLES

Example 1

(43) TABLE-US-00003 Ingredients Quantity/mL % w/v Cyclophosphamide   200 mg 20 Monothioglycerol 0.138 mg 0.01 Polyethylene glycol-400 Qs to 1 mL  QS to 100

Example 2

(44) TABLE-US-00004 Ingredients Quantity/mL % w/v Cyclophosphamide    200 mg 20 Ethanol (99% USP) 0.03-0.06 mL 2-5 or 20 mg-50 mg Monothioglycerol   0.138 mg 0.01 Polyethylene glycol-400  Qs to 1 mL QS to 100

Example 3

(45) TABLE-US-00005 Ingredients Quantity/mL % w/v Cyclophosphamide    200 mg 20 Ethanol (99% USP) 0.44-0.51 mL 45-50 or  350-400 mg Monothioglycerol   0.138 mg 0.01 Polyethylene glycol 400  Qs to 1 mL QS to 100

(46) For each of Examples 1, 2 and 3—All ingredients were dispensed as per the manufacturing formula and the required quantity of ethanol was transferred into a compounding vessel. The required quantity of Cyclophosphamide was added into the compounding vessel under stirring at about 400 to about 500 rpm to get a clear solution. Monothioglycerol was added into the above compounding vessel under stirring to get a clear solution. This was followed by addition of polyethylene glycol 400 and the volume was made up. The solution was stirred well to get a clear homogenous solution. The bulk solution was filtered through 0.2μ PTFE membrane filter and filled into vials (Fill vol: 2.5 mL and 5 mL), stoppered, and sealed.

(47) The compositions of Examples 1, 2 and 3 were packaged in clear USP Type-1 glass vials, closed with coated bromobutyl rubber stoppers and flip top aluminium seals.

Example 4

(48) The above exemplified formulations of cyclophosphamide were subjected to the stress stability test wherein the temperature was set at 40° C. for a time period of 5 days. The control used in the test is similar to the commercialized product of Ingenus Pharmaceuticals (disclosed and claimed in US 20180055861, and approved as NDA #212501 by the USFDA), which was prepared inhouse for the comparative testing. The Ingenus/control product includes 500 mg cyclophosphamide, 1.55 g Ethanol, 0.085 g Propylene Glycol, 0.085 g Polyethylene glycol 400 and 0.345 mg Monothioglycerol. The results of the stability testing are summarized in Table 3 below.

(49) TABLE-US-00006 TABLE 3 Stress stability results of Cyclophosphamide injection (Stress at 40° C./5 days) Ingenus product Product (control) Example-1 Example-2 Example-3 Total Impurities 4.95 3.98 3.6 3.64 (% w/w)

(50) It was observed that the total impurity percentage was less than that for the control.

Example 5

(51) The composition of Example 3 was charged for stability under two separate conditions of temperature and humidity and tested. The results are tabulated in Table 4 below.

(52) TABLE-US-00007 TABLE 4 Stability Data of Cyclophosphamide Injection, 200 mg/mL Fill volume: 2.5 mL 2-8°C 25 ± 2° C./60 ± 5% RH Test Initial 1M 2M 3M 6M 1M 2M 3M 6M Description CCS CCS CCS CCS CCS CCS CCS CCS Pale yellow pH 3.98 3.91 4.45 4.25 4.45 4.44 4.44 4.15 3.70 Assay (%) 102.3 101.8 101.0 100.1 99.04 98.4 95.9 91.5 82.87 Related Substances by HPLC (% w/w) Related compound-B 0.05 0.09 0.09 0.11 0.12 0.22 0.28 0.21 0.15 Related compound-D 0.01 0.05 0.04 0.03 ND 0.12 0.14 0.12 0.12 Related Compound-E ND 0.11 0.16 0.20 0.26 0.56 1.10 1.52 2.51 Related Compound-F 0.02 0.30 0.32 0.37 0.6 1.36 2.75 3.00 6.67 Any unspecified impurity 0.01 0.04 0.02 0.04 0.07 0.08 0.26 0.30 0.87 Total Impurities 0.46 0.71 0.67 0.80 1.14 2.67 5.29 6.41 14.11 ND: Not Detected; CCS: Clear colorless solution