Phosphaplatin liquid formulations

Abstract

To provide, in one embodiment, stable ready-to-use liquid formulations of these compounds in order to remedy possible degradation of monomeric phosphaplatin complexes in aqueous solutions, especially under acidic conditions.SOLUTION: Disclosed herein are: pharmaceutical compositions of phosphaplatin compounds, in particular, buffered stable liquid formulations of pyrodach-2 ready for use in treatment of various cancers; and methods of preparation.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 USC § 119(e) of U.S. Provisional Application No. 62 / 319,047, filed April 6, 2016, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE PRESENT APPLICATION The present invention relates to pharmaceutical compositions of phosphaplatin compounds useful as anti-cancer agents, in particular stable liquid formulations that can be used to treat a variety of cancers. [Background technology]

[0003] 2. Background of the Invention Monomeric phosphaplatin complexes have shown great potential for the treatment of a variety of diseases, including a wide range of cancers. See, for example, WO2009 / 021082, WO2011 / 153365, and WO2012 / 096722. Like many therapeutically useful platinum compounds, phosphaplatin complexes are typically administered parenterally, e.g., by intravenous ("iv" or "iv") injection. Drugs for parenteral administration are typically formulated as liquids or as lyophilized solids that require reconstitution in a sterile vehicle prior to administration. Liquid formulations are highly preferred over lyophilized formulations because a) they are more economical and simpler to manufacture, and b) they are much easier to administer since they do not require reconstitution in a sterile vehicle prior to use. The pH of liquid drug formulations for iv administration is typically formulated in a pH range that is close to the physiological range of blood pH (7.3-7.4) to avoid the clinical challenges associated with administering drug formulations whose pH differs significantly from that of blood. Liquid formulations that are stable and easily stored at ambient temperature are highly preferred over liquid or lyophilized formulations that must be stored under refrigerated or frozen conditions. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO2009 / 021082 [Patent Document 2] WO2011 / 153365 [Patent Document 3] WO2012 / 096722 Summary of the Invention [Problem to be solved by the invention]

[0005] Due to the potential decomposition of monomeric phosphaplatin complexes in aqueous solution, especially under acidic conditions, the preparation of stable, ready-to-use liquid formulations of these compounds remains a challenge. [Means for solving the problem]

[0006] In one aspect, the present invention provides a liquid pharmaceutical composition comprising a phosphaplatin compound and an aqueous buffer solution having a pH of 7 or greater, preferably in the pH range of 7 to 9. The buffer solution is an aqueous solution comprising a phosphate, a carbonate / bicarbonate, or a combination thereof.

[0007] In some embodiments, the phosphaplatin compound is a pyrophosphato-platinum(II) complex having the formula (I) or (II): [ka] or a salt thereof, wherein R 1 and R 2 are each independently selected from NH3, a substituted or unsubstituted aliphatic amine, and a substituted or unsubstituted aromatic amine; R 3 is selected from substituted or unsubstituted aliphatic or aromatic 1,2-diamines.

[0008] In more preferred embodiments, the phosphaplatin compound is selected from the group consisting of trans-1,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) ("trans-pyrodach-2"), either of the two enantiomers (R,R)-pyrodach-2 and (S,S)-pyrodach-2, and cis-1,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) ("cis-pyrodach-2").

[0009] [ka]

[0010] The most preferred embodiment of the formulation exhibits potential for multi-year stability at ambient temperature. The formulation provides a sterile concentrated solution of (R,R)-pyrodach-2 that is easily diluted in standard IV fluids used in IV administration of cancer drugs or sterile solutions at suitable concentrations in vials, ready for use with patients.

[0011] In another aspect, the invention provides a process for making liquid formulations, particularly ready-to-use formulations, of a phosphaplatin compound in a buffer solution as described herein, comprising the steps of: a) dissolving a phosphaplatin compound in an aqueous buffer containing a sufficient amount of hydroxide base such that the pH remains above 7; b) optionally adding hydroxide base to adjust the pH to a desired range; and c) filtering the solution to obtain the liquid formulation.

[0012] In another aspect, the present invention relates to the use of the stable liquid formulation according to any of the embodiments disclosed herein in the treatment of cancer.

[0013] These and other aspects of the present invention will be better understood with reference to the following drawings, detailed description, and claims. BRIEF DESCRIPTION OF THE DRAWINGS [Brief description of the drawings]

[0014] [Figure 1] Shown is the potency of capped 1 mg / mL (R,R)-pyrodach-2 solutions in various buffers stored in a controlled stability chamber at 25° C. / 60% RH as monitored by HPLC. [Diagram 2] Shown is the potency of capped 1 mg / mL (R,R)-pyrodach-2 solutions in various buffers stored in a controlled stability chamber at 40° C. / 75% RH as monitored by HPLC. [Diagram 3] Shown is the potency of capped 1 mg / mL (R,R)-pyrodach-2 solutions in 10 mM potassium phosphate buffers of various pH values ​​stored in a controlled stability chamber at 25° C. / 60% RH as monitored by HPLC. [Figure 4] Shown is the potency of capped 1 mg / mL (R,R)-pyrodach-2 solutions in 10 mM potassium phosphate buffers of various pH values ​​stored in a controlled stability chamber at 40 °C / 75% RH as monitored by HPLC. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Detailed Description of the Invention In one aspect, the invention provides a pharmaceutical composition comprising a phosphaplatin compound and an aqueous buffer solution having a pH of 7 or greater.

[0016] In one embodiment of this aspect, and sometimes preferred, the pharmaceutical composition is a ready-to-use liquid formulation suitable for parenteral administration.

[0017] In some embodiments of this aspect, the concentration of the phosphaplatin compound is about 20 mg / mL or less.

[0018] In some embodiments of this aspect, the concentration of the phosphaplatin compound is from about 1 to about 10 mg / mL.

[0019] In some embodiments of this aspect, the concentration of the phosphaplatin compound is from about 1 to about 6 mg / mL.

[0020] In another embodiment of this aspect, the concentration of the phosphaplatin compound is about 5 mg / mL.

[0021] In another embodiment of this aspect, the buffer comprises a phosphate or bicarbonate / carbonate.

[0022] In some embodiments, the buffering agent is a phosphate group ion, i.e., phosphoric acid (PO 3- ), hydrogen phosphate (HPO4 2- ), and / or dihydrogen phosphate (H2PO4 - ).

[0023] In some embodiments, the buffering agent is a carbonate group ion, i.e., bicarbonate (HCO - ) and carbonate (CO3 2- ).

[0024] In some embodiments, the buffering agent is a phosphate group ion (PO 3- , HPO4 2- and / or H2PO4 - ions), as well as carbonate group ions (i.e., HCO3 - and CO3 2- ) is included.

[0025] In some embodiments of this aspect, the buffer salt concentration is from about 1 mM to about 100 mM.

[0026] In some embodiments of this aspect, the buffer salt concentration is from about 5 mM to about 50 mM.

[0027] In some embodiments of this aspect, the buffer salt concentration is about 10 mM.

[0028] In some embodiments of this aspect, the pH of the liquid pharmaceutical composition is within the range of about 7.0 to about 9.0.

[0029] In some embodiments of this aspect, the pH of the liquid pharmaceutical composition is within the range of about 7.0 to about 8.0.

[0030] In some embodiments of this aspect, the buffer comprises sodium phosphate or potassium phosphate, or a combination thereof.

[0031] In some embodiments of this aspect, the buffer contains potassium phosphate, the concentration of the phosphaplatin compound is 5 mg / mL, and the pH is within the range of about 7.0 to about 8.0.

[0032] In some embodiments of this aspect, the buffer concentration is about 10 mM.

[0033] In some embodiments of this aspect, the buffer comprises pyrophosphate.

[0034] In some embodiments of this aspect, the molar ratio of pyrophosphate anion to phosphaplatin compound is at least 0.1:1.

[0035] In some embodiments of this aspect, the molar ratio of pyrophosphate ion to phosphaplatin compound is about 0.2:1.

[0036] In some embodiments of this aspect, the molar ratio of pyrophosphate ion to phosphaplatin compound is about 0.4:1.

[0037] In some embodiments of this aspect, the concentration of the phosphaplatin compound is about 5 mg / mL, the pyrophosphate concentration is about 5.2 mM, and the pH is within the range of about 7.0 to about 8.0.

[0038] In some embodiments of this aspect, the phosphaplatin compound is a pyrophosphato-platinum(II) complex having the formula (I) or (II): [ka] or a salt thereof, wherein R 1 and R 2 are each independently selected from NH3, a substituted or unsubstituted aliphatic amine, and a substituted or unsubstituted aromatic amine; R 3 is selected from substituted or unsubstituted aliphatic or aromatic 1,2-diamines.

[0039] In some preferred embodiments, R of formula (I) 1 and R 2 are each independently selected from NH, methylamine, ethylamine, propylamine, isopropylamine, butylamine, cyclohexanamine, aniline, pyridine, and substituted pyridine; R 3 is selected from ethylenediamine and cyclohexanediamine.

[0040] In some more preferred embodiments of this aspect, the phosphaplatin compound is a 1,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) (“pyrodach-2”) complex selected from the group consisting of:

[0041] [ka]

[0042] In one preferred embodiment of this aspect, the phosphaplatin compound is trans-1,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) (“trans-pyrodach-2”) complex.

[0043] In another preferred embodiment of this aspect, the phosphaplatin compound is (R,R)-trans-1,2-cyclohexanediamine-(dihydrogenpyrophosphato)platinum(II) (“(R,R)-trans-pyrodach-2”).

[0044] In another preferred embodiment of this aspect, the phosphaplatin compound is (S,S)-trans-1,2-cyclohexanediamine-(dihydrogenpyrophosphato)platinum(II) ("(S,S)-trans-pyrodach-2)").

[0045] In another preferred embodiment of this aspect, the phosphaplatin compound is cis-1,2-cyclohexanediamine-(dihydrogen pyrophosphato)-platinum(II) (“cis-pyrodach-2”).

[0046] In some embodiments, the present invention provides liquid pharmaceutical compositions of phosphaplatin according to any rational combination of the embodiments described herein.

[0047] In another aspect, the present invention provides a liquid pharmaceutical composition according to any embodiment disclosed herein, or any combination thereof, for use in treating a disease or disorder.

[0048] In some embodiments, the disease or disorder is cancer.

[0049] In some embodiments, the cancer includes, but is not limited to, a cancer selected from the group consisting of gynecological cancer, genitourinary cancer, lung cancer, head and neck cancer, skin cancer, gastrointestinal cancer, breast cancer, bone and cartilage cancer, and blood cancer.

[0050] In some embodiments, the cancer is selected from the group consisting of ovarian cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, head and neck cancer, skin cancer, pancreatic cancer, breast cancer, liver cancer, gastric cancer, bone cancer, glioblastoma cancer, and colon cancer.

[0051] In another aspect, the present invention provides the use of a liquid pharmaceutical composition according to any embodiment disclosed herein, or any combination thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder, including, but not limited to, any of gynecological cancer, genitourinary cancer, lung cancer, head and neck cancer, skin cancer, gastrointestinal cancer, breast cancer, bone and cartilage cancer, and hematological cancer. More specific non-limiting examples include ovarian cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, head and neck cancer, skin cancer, pancreatic cancer, breast cancer, liver cancer, gastric cancer, bone cancer, glioblastoma cancer, and colon cancer.

[0052] In another aspect, the present invention provides a process for preparing a liquid pharmaceutical composition of a phosphaplatin compound according to any embodiment disclosed herein, or any combination thereof, comprising: a) dissolving the phosphaplatin compound in an aqueous buffer containing a sufficient amount of a hydroxide base such that the pH remains above 7; b) optionally adding a hydroxide base to adjust the pH to a desired range; and c) filtering the solution to obtain the liquid formulation.

[0053] In one embodiment of this aspect, the aqueous buffer is a phosphate buffer, a carbonate / bicarbonate buffer, or a combination thereof.

[0054] In another embodiment of this aspect, the pH of the liquid formulation is within the range of about 7.0 to about 9.0.

[0055] In another embodiment of this aspect, the process further comprises adding a sufficient amount of pyrophosphate salt to stabilize the phosphaplatin compound in the liquid formulation.

[0056] In another embodiment of this aspect, said filtration is performed under sterile conditions.

[0057] In another embodiment of this aspect, the process further comprises the step of d) filling the solution into vials and stoppering and capping the vials in a sterile environment such that the formulation is ready for use.

[0058] In another embodiment of this aspect, the resulting liquid formulation is a formulation according to any one of the embodiments described herein, or any combination thereof.

[0059] When the term "about" is applied to a parameter such as pH, concentration, etc., it indicates that the parameter may vary within ±10%, preferably within ±5%, more preferably within ±5%. As will be appreciated by those of skill in the art, when a parameter is not critical, the number is often given for illustrative purposes only, rather than as a limitation.

[0060] As used herein, the terms "a," "an," or "the" refer to both the singular and the plural. In general, when either the singular or plural form of a noun is used, it refers to both the singular and the plural form of the noun.

[0061] Although the following detailed description illustrates certain aspects of the invention using only the (R,R)-pyrodach-2 isomer (or "PT-112") as a non-limiting example, as will be understood by those of skill in the art, the invention is equally applicable to all stereoisomers of pyrodach-2 complexes.

[0062] (R,R)-pyrodach-2 is a dibasic acid that exhibits low solubility in water. The pKa values ​​of the two acid groups of (R,R)-pyrodach-2 are approximately 2.6 and 4.4 (Inorg. Chem. 47, 7942 (2008)). Thus, simple dissolution of (R,R)-pyrodach-2 results in an acidic solution. Under acidic aqueous conditions, (R,R)-pyrodach-2 undergoes rapid hydrolysis. At higher pH, the acid groups of (R,R)-pyrodach-2 are ionized and the solubility of (R,R)-pyrodach-2 increases. In addition, deprotonation of the acid groups of (R,R)-pyrodach-2 dramatically reduces the rate of hydrolysis. The two pKa values ​​of (R,R)-pyrodach-2 indicate that aqueous solutions of (R,R)-pyrodach-2 within the physiological pH range of 7.0-7.5 have no buffering capacity. Thus, controlling the pH of an aqueous solution within the physiological pH range, much less the accurate and reproducible preparation of an aqueous solution of (R,R)-pyrodach-2 within this pH range by adjusting the pH of the aqueous solution with a hydroxide base, is extremely difficult. Thus, the development of aqueous formulations of (R,R)-pyrodach-2 with controlled pH stability within the physiological pH range of 7-7.5 preferably requires the use of a buffer. This presents a unique challenge as the pyrophosphate ligand in (R,R)-pyrodach-2 is kinetically unstable in solution and could potentially undergo reaction with anions present in many buffers. Table 1 summarizes the loss in potency as measured by HPLC of aqueous solutions of (R,R)-pyrodach-2 at 1 mg / mL in various buffers at ambient temperature. The HPLC system and conditions used to monitor stability are summarized in Table 2.

[0063] [Table 1]

[0064] [Table 2]

[0065] To develop a stable, ready-to-use aqueous formulation of (R,R)-pyrodach-2 with a controlled pH range of 7.0-8.0, the results of screening buffers for lack of reactivity towards (R,R)-pyrodach-2 in aqueous solution identified phosphate and bicarbonate / carbonate buffers as the most preferred. Temperature was observed to affect stability, with poorer stability observed at higher temperatures. Buffer concentration was also found to affect the stability of (R,R)-pyrodach-2 solutions, with poorer stability observed at higher buffer concentrations, but the effect of the cations associated with the buffer (e.g., potassium vs. sodium) was found to be minimal, if any. In the bicarbonate / carbonate buffer system, pH was found to have a significant effect on the stability of (R,R)-pyrodach-2, with reduced stability observed at higher pH and increasing carbonate to bicarbonate ion concentration ratios. In contrast, in phosphate buffer, pH was found to have minimal effect on the stability of (R,R)-pyrodach-2 above pH 7. Below pH 7, decomposition was found to result in the formation of a dimeric species ((R,R)-pyrodach-2 dimer), which is highly insoluble and precipitates from solution. Given the potential for decomposition in the presence of carbonate ions in bicarbonate / carbonate buffer systems, and the potential loss of buffering capacity due to equilibration with CO2 in the atmosphere or container headspace, phosphate provides an excellent buffer system for the production of buffered, aqueous, ready-to-use (R,R)-pyrodach-2 formulations with a controlled pH within the physiological range of 7-7.5, especially in large-scale manufacturing sites.

[0066] [ka]

[0067] Freezing an aqueous formulation is one way to slow the rate of degradation and improve the stability of drug substances formulated in aqueous media. The effect of freeze-thaw cycles on the stability of (R,R)-pyrodach-2 in various buffers was evaluated. The data summarized in Table 3 show higher levels of degradation at higher buffer concentrations. In addition, consistent with the observation of selective precipitation of disodium phosphate during freezing, higher levels of degradation were observed with sodium salts compared to potassium salts in phosphate buffer systems, which results in a significant decrease in pH during freezing, a phenomenon not observed with potassium phosphate buffers (Archives of Biochemistry and Biophysics 384, 398, 2000). Thus, the use of potassium salts is preferred over the use of sodium salts in phosphate-buffered (R,R)-pyrodach-2 formulations.

[0068] [Table 3]

[0069] Solubility of (R,R)-pyrodach-2 in aqueous buffer solutions at pH 7-7.5 indicates that solutions of at least 20 mg / mL can be readily achieved. However, clinical use of platinum oncolytic agents such as (R,R)-pyrodach-2 indicates that a concentration of 5 mg / mL is highly desirable for a ready-to-use aqueous formulation. Buffer capacity modeling indicates that 10 mM concentrations of phosphate or bicarbonate provide sufficient buffer capacity and acceptable pH control for a 5 mg / mL aqueous solution of (R,R)-pyrodach-2.

[0070] The rapid hydrolysis of (R,R)-pyrodach-2, particularly the formation of highly insoluble dimeric impurities upon dissolution of (R,R)-pyrodach-2 in water or in a buffer such as phosphate buffer when the pH is neutral or below, precludes large-scale production of aqueous, ready-to-use formulations of (R,R)-pyrodach-2 adjusted to the physiological pH range of 7-7.5 by simply adding base to a slurry of (R,R)-pyrodach-2 in water or by adding a buffer solution to effect dissolution and subsequently adjusting the pH to the desired range. Rather, effective control of degradation and impurity formation requires dissolution of (R,R)-pyrodach-2 under near neutral or basic pH conditions. We have found that this can be accomplished by adding (R,R)-pyrodach-2 to a solution of buffer and adding sufficient hydroxide base to neutralize all of the added (R,R)-pyrodach-2. Once all the solids have dissolved, the pH of the solution is adjusted to the final desired range by the addition of small amounts of hydroxide. In this way, dissolution of the drug substance is carried out under approximately neutral or basic pH conditions.

[0071] A scalable and cost-effective process for the manufacture of a ready-to-use formulation of (R,R)-pyrodach-2 in 10 mM buffer adjusted to a pH of 7.0-7.5 includes the steps of a) preparing an aqueous solution of 10 mM buffer, b) adding sufficient hydroxide base to neutralize the added (R,R)-pyrodach-2 to reach a pH of about 7, c) adding (R,R)-pyrodach-2 and dissolving it, d) adding additional hydroxide, if necessary, to adjust the pH to a range of about 7.0-7.5, and e) filtering the solution under sterile conditions and filling the solution into glass vials which are then capped with stoppers and / or caps. Stability data was generated for two large batches of (R,R)-pyrodach-2 at 5 mg / mL in 10 mM potassium phosphate buffer. One such batch at pH=7.2 was evaluated at both 25°C / 60%RH and refrigerated (2-8°C) conditions and the data are summarized in Tables 4 and 5, respectively. While slow degradation is observed over 24 months at 25°C / 60%RH, under refrigerated conditions the formulation exhibits excellent stability over the same or even longer (36 months) period (see Table 5). Similar observations are made for the ready-to-use liquid formulation at pH 7.4, as shown in Tables 6 and 7.

[0072] [Table 4A] [Table 4B]

[0073] [Table 5A] [Table 5B]

[0074] [Table 6A] [Table 6B]

[0075] [Table 7A] [Table 7B]

[0076] Stability data for batches of (R,R)-pyrodach-2 at 5 mg / mL in 10 mM bicarbonate buffer (pH 8.6) at 25° C. / 60% RH, 2-8° C. and −20° C. are summarized in Tables 8, 9, and 10, respectively.

[0077] Surprisingly, it has been found that the addition of small amounts of pyrophosphate ions dramatically improves the thermal stability of ready-to-use aqueous formulations of (R,R)-pyrodach-2. This addition not only slows down the rate of decomposition as a function of temperature, but also serves to reduce the concentration of several impurities, including (DACH)Pt-Cl2, which is a possible impurity present in (R,R)-pyrodach-2 based on the method of preparation (WO2013176764 A1), (R,R)-pyrodach-2 dimer, and an impurity formed in (R,R)-pyrodach-2 formulated in phosphate buffer and eluting at an RRT of about 3.1-3.2 in the HPLC system described in Example 3.

[0078] The ability of added pyrophosphate to reduce the concentration of (R,R)-pyrodach-2 dimer is particularly advantageous since this impurity forms readily in aqueous solutions of (R,R)-pyrodach-2 at less than 7, is highly insoluble, and can precipitate from aqueous (R,R)-pyrodach-2 solutions at very low concentrations. For example, in a 5 mg / mL ready-to-use formulation of (R,R)-pyrodach-2 prepared according to Example 6, in which the initial concentration of (R,R)-pyrodach-2 dimer was approximately 0.6 area %, the dimer was observed to begin to precipitate as a crystalline solid between 6 and 9 months of storage at 2-8°C, and crystallization was observed in all sample vials by 12 months of storage.

[0079] [Table 8]

[0080] [Table 9]

[0081] [Table 10]

[0082] Comparison of the stability data for (R,R)-pyrodach-2 solutions at a concentration of 5 mg / mL in 10 mM potassium phosphate buffer adjusted to pH 7.0-7.5 at 25° C. / 60% RH in Table 4 with the stability data for formulations at the same concentration containing approximately 0.5 molar equivalents of added pyrophosphate in Table 11 shows that the addition of pyrophosphate ions dramatically slows the rate of degradation of (R,R)-pyrodach-2, making the stability of the pyrophosphate formulation at 25° C. comparable / superior to that of the formulation without added pyrophosphate stored under refrigerated conditions. The stability data for the formulation with added pyrophosphate at 40° C. / 75% RH in Table 12 is even more dramatic. A kinetic / design of experimental study was utilized to demonstrate the effect of pyrophosphate on a buffered aqueous ready-to-use formulation of (R,R)-pyrodach-2 (Example 9).

[0083] The data further demonstrate that the addition of buffer salts such as phosphate or carbonate / bicarbonate is unnecessary to achieve pH control; rather, the buffering capacity of pyrophosphate within the physiological pH range is sufficient to control pH in aqueous formulations of (R,R)-pyrodach-2. From a clinical perspective, it is desirable to keep the amount of pyrophosphate ion to a minimum in aqueous formulations of (R,R)-pyrodach-2. A ratio of 1 molar equivalent of pyrophosphate ion to (R,R)-pyrodach-2 was found to provide sufficient stability for aqueous solutions of (R,R)-pyrodach-2 at physiological pH, such that the formulated ready-to-use formulation has a commercial shelf life of several years when stored at standard International Committee on Harmonization (ICH) storage conditions of 25°C / 60% RH (i.e., ambient temperature). More optimally, a molar ratio of about 0.5 moles of pyrophosphate ion to (R,R)-pyrodach-2 has been found to provide acceptable stability for ready-to-use aqueous formulations of (R,R)-pyrodach-2. Most preferably, the formulation consists of a 5 mg / mL aqueous solution of (R,R)-pyrodach-2 in pyrophosphate salt adjusted to pH 7-7.5. Furthermore, including pyrophosphate ion in the formulation, or as the only buffering agent, eliminates the possibility of precipitation of impurities, particularly the highly insoluble (R,R)-pyrodach-2 dimer impurity, from ready-to-use aqueous formulations of (R,R)-pyrodach-2.

[0084] [Table 11]

[0085] [Table 12]

[0086] Evidence that the addition of pyrophosphate reverses the formation of PT-112 dimers in aqueous formulations of PT-112 was provided in the following experiment. A 5 mg / mL aqueous solution of PT-112 was prepared by dissolving PT-112 in 10 mM potassium phosphate buffer containing potassium hydroxide added such that the pH of the final solution was approximately 6.5. The solution was allowed to stir at ambient temperature for approximately 24 hours, during which time the PT-112 dimer level increased from approximately 0.33% in the API to approximately 1.02% in the formulated solution. The pH of a portion of the solution was subsequently adjusted to approximately pH 7.5 with potassium hydroxide, and the concentration of the dimer was observed to gradually decrease over a period of 7 days at ambient temperature, accompanied by a corresponding increase in the RRT3.1-3.2 impurity. However, by adjusting the pH of a portion of the solution with potassium hydroxide to approximately pH 7.5 and adding 0.5 equivalents of pyrophosphate, the dimer level was observed to gradually decrease to essentially undetectable levels after 9 days at ambient temperature. This decrease was not accompanied by the formation of the RRT3.1-3.2 impurity, nor any new impurities; rather, an increase in the concentration of PT-112 was observed. EXAMPLES

[0087] Example 1 Effect of buffer strength Preparation of buffer solutions 10 mM sodium phosphate, pH 7 - 200 mL of 10 mM sodium phosphate, dibasic adjusted with approximately 177 mL of 10 mM sodium phosphate, monobasic -Final pH7.02 100 mM sodium phosphate, pH 7 - 200 mL of 100 mM sodium phosphate, dibasic and monobasic, approximately 138 mL of 100 mM sodium phosphate -Final pH6.98 10 mM potassium phosphate, pH 7 - 200 mL of 10 mM potassium phosphate, dibasic adjusted with approximately 126 mL of 10 mM potassium phosphate, monobasic -Final pH7.01 100 mM potassium phosphate, pH 7 - 200mL of 100mM potassium phosphate, dibasic adjusted with approximately 125mL of 10mM potassium phosphate, monobasic -Final pH7.02 10mM sodium carbonate -pH adjustment not performed -Final pH 10.84 100mM Sodium Carbonate -pH adjustment not performed -Final pH 11.39 10mM Sodium Bicarbonate -pH adjustment not performed -Final pH8.18 100mM Sodium Bicarbonate -pH adjustment not performed -Final pH8.06

[0088] (R,R)-Pyrodach-2 was dissolved in each of these buffers to prepare 1 mg / mL solutions. Potency of stoppered solutions stored in controlled stability chambers at 25° C. / 60% RH and 40° C. / 75% RH was monitored by HPLC. See Figures 1 and 2.

[0089] Example 2 Effect of pH on phosphate buffer solution stability Preparation of buffer solutions 10 mM potassium phosphate, pH 6.5 -50mL of 10mM potassium phosphate, dibasic adjusted with approximately 145mL of 10mM potassium phosphate, monobasic -Final pH6.50 10 mM potassium phosphate, pH 7 - 200 mL of 10 mM potassium phosphate, dibasic adjusted with approximately 126 mL of 10 mM potassium phosphate, monobasic -Final pH7.01 10 mM potassium phosphate, pH 7.5 -50mL of 10mM potassium phosphate, dibasic adjusted with approximately 14mL of 10mM potassium phosphate, monobasic -Final pH7.50 10 mM potassium phosphate, pH 8.0 -50mL of 10mM potassium phosphate, dibasic adjusted with approximately 4mL of 10mM potassium phosphate, monobasic -Final pH8.00 10 mM potassium phosphate, pH 8.5 -50mL of 10mM potassium phosphate, dibasic adjusted with approximately 1mL of 10mM potassium phosphate, monobasic -Final pH8.49 10 mM potassium phosphate, pH 9.0 -90mL of 10mM potassium phosphate, dibasic adjusted with less than 1mL of 10mM potassium phosphate, monobasic -Final pH 9.02

[0090] (R,R)-pyrodach-2 was dissolved in each of these buffers to prepare a 1 mg / mL solution. The potency of the stoppered solutions stored in controlled stability chambers at 25° C. / 60% RH and 40° C. / 75% RH was monitored by HPLC, from which the reported data at T=3 days for the pH 7.0 buffered solutions are shown in Figures 3 and 4, respectively.

[0091] Example 3 [Table 13]

[0092] [Table 14]

[0093] Example 4 Ready-to-use (R,R)-pyrodach-2 formulation at 5 mg / mL in 10 mM sodium bicarbonate pH 9.0-9.5 (Pharmatek (R,R)-pyrodach-2 prototype stability protocol)

[0094] • Transfer 1680.0 mg ± 0.5 mg of sodium bicarbonate to a 2 L volumetric flask. • Fill the flask to approximately 75% by volume with water, swirling as necessary to dissolve all solids. • 32.0 mL of 1 N NaOH is volumetrically transferred to the flask. Dilute to volume with water and mix thoroughly. Record the pH of the final solution. This is the diluent. ●Transfer 7653.1 mg ± 0.5 mg of (R,R)-pyrodach-2 to a compounding vessel. ● Transfer the 1500 mM diluted solution into a container and stir to dissolve the solids. • Record the pH of the final solution. • Transfer the entire solution through a 0.22 μm sterile filter membrane into a sterile collection container. ●Calculate the concentration of the (R,R)-pyrodach-2 solution.

[0095]

number

[0096] In a laminar flow hood: Fill 10 mL sterile Type 1 borosilicate glass vials to a fill volume of 10 mL, stopper the vials with 20 mm sterile rubber stoppers and crimp seal with 20 mm crimp tops. • Place vials in stability chambers at 25°C / 60% RH, 2-8°C, and -20°C. HPLC method of Example 3 for monitoring purity and impurities.

[0097] Example 5 A 15mg / mL ready-to-use formulation of (R,R)-pyrodach-2 V is the required final volume of the solution to be made Dissolve V x 11.4 mg sodium phosphate, tribasic (dodecahydrate) + V x 4.26 mg sodium, dibasic (anhydrous) in V mL distilled water. Stir until the buffer salts are dissolved. Add (R,R)-pyrodach-2 in an amount of V × 15 mg to the stirred buffer solution. Stir on a magnetic stirrer until the solid (R,R)-pyrodach-2 is completely dissolved (10-30 min). • Record the pH of the solution. • If necessary, adjust the pH to 7.0-7.4 by adding and dissolving V x 1.8 mg of sodium phosphate, tribasic (dodecahydrate) with stirring and record the final pH. To prepare a low concentration (R,R)-pyrodach-2 solution, dilute the above 15 mg / mL (R,R)-pyrodach-2 solution with an appropriate amount of vehicle.

[0098] Example 6 Ready-to-use preparation of (R,R)-pyrodach-2 5 mg / mL in 10 mM potassium phosphate, pH 7.2-7.5

[0099] • Transfer 4564.6 mg ± 0.5 mg of potassium phosphate, dibasic, trihydrate to a 2 L volumetric flask. • Fill the flask to approximately 75% by volume with water, swirling as necessary to dissolve all solids. • 32.0 mL of 1 N KOH is volumetrically transferred to the flask. • Dilute the flask to volume with water and mix thoroughly. Record the pH of the final solution. This is the diluent. ●Transfer 7653.1 mg ± 0.5 mg of (R,R)-pyrodach-2 to a compounding vessel. ●Transfer 1500mL of the diluted solution to a container and stir to dissolve the solids. • Record the pH of the final solution. • Transfer the entire solution through a 0.22 μm sterile filter membrane into a sterile collection container. ●Calculate the concentration of the (R,R)-pyrodach-2 solution.

[0100]

number

[0101] Example 7 Ready-to-use preparation of (R,R)-pyrodach-2 5mg / mL in 10mM sodium phosphate, 5.2mM sodium pyrophosphate, pH 7.5

[0102] • Transfer 1419.6 mg ± 14.0 mg of anhydrous disodium hydrogen phosphate to a 1 L volumetric flask. • Transfer 2298.5 mg ± 23.0 mg of tetrasodium pyrophosphate decahydrate to the same 1 L volumetric flask. • Fill the flask to approximately 75% by volume with sterile water for injection, swirling as necessary to dissolve all solids. • 8.0 mL of 1 N NaOH is volumetrically transferred to the flask. • Dilute the flask to volume with water and mix thoroughly. Record the pH of the final solution - this is the vehicle. Determine the tare weight of a 500 mL compounding vessel equipped with a stirring bar. ●Transfer 2500.1 mg ± 25.0 mg of (R,R)-pyrodach-2 to a container. • Transfer 450.0 g ± 0.1 g of vehicle to the container and stir to dissolve the solids. • Determine the initial pH of the solution. • Slowly adjust the pH of the solution to 7.5 ± 0.1 by adding additional 1N NaOH. Determine the total weight of the solution and dilute the solution weight to 500.0 g ± 0.1 g by adding additional vehicle to the compounding vessel. Density = 1.00 g / mL. ●Stir the final solution for an additional 5 minutes. • Determine the pH of the final solution. • Pass the entire solution through a 0.22 μm PVDF Stericup filter into a sterile collection container. In a laminar flow hood: Fill 10 mL sterile tubing vials with 10 mL of solution, stopper with sterile Flurotec stoppers and crimp seal with flip-off seals. • Place vials in stability chambers at 40°C / 75% RH and 25°C / 60% RH. HPLC method of Example 3 for monitoring purity and impurities.

[0103] Example 8 Ready-to-use preparation of (R,R)-pyrodach-2 5mg / mL in 5.2mM sodium pyrophosphate, pH 7.5

[0104] • Transfer 2298.5 mg ± 23.0 mg of tetrasodium pyrophosphate decahydrate to a 1 L volumetric flask. • Fill the flask to approximately 75% by volume with sterile water for injection, swirling as necessary to dissolve all solids. • 14.5 mL of 1N NaOH is volumetrically transferred to the flask. • Dilute the flask to volume with water and mix thoroughly. Record the pH of the final solution - this is the vehicle. Determine the tare weight of a 500 mL compounding vessel equipped with a stirring bar. ●Transfer 2500.1 mg ± 25.0 mg of (R,R)-pyrodach-2 to a container. • Transfer 450.0 g ± 0.1 g of vehicle to the container and stir to dissolve the solids. • Determine the initial pH of the solution. • Slowly adjust the pH of the solution to 7.5 ± 0.1 by adding additional 0.1 N NaOH. Determine the total weight of the solution and dilute the solution weight to 500.0 g ± 0.1 g by adding additional vehicle to the compounding vessel. Density = 1.00 g / mL. ●Stir the final solution for an additional 5 minutes. • Determine the pH of the final solution. • Pass the entire solution through a 0.22 μm PVDF Stericup filter into a sterile collection container. In a laminar flow hood: Fill 10 mL sterile tubing vials with 10 mL of solution, stopper with sterile Flurotec stoppers and crimp seal with flip-off seals. • Place vials in stability chambers at 40°C / 75% RH and 25°C / 60% RH. HPLC method of Example 3 for monitoring purity and impurities.

[0105] Example 9 Design of Experimental Study on Pyrophosphate Ion Stabilization The formulations used for the design of the experimental studies are listed in Table 11. Stability evaluation at a highly stressful temperature of 60°C demonstrates that the addition of trace amounts of pyrophosphate ions, including only about 0.25 molar equivalents relative to the (R,R)-pyrodach-2 present, results in a dramatic reduction in the overall rate of decomposition of (R,R)-pyrodach-2 and appearance of impurities. In particular, the data show that pyrophosphate ions result in the gradual disappearance of several impurities that were initially present in the aqueous solution or formed during solution preparation due to impurities in (R,R)-pyrodach-2. Specifically, the presence of pyrophosphate salt results in the rapid disappearance of the (R,R)-pyrodach-2 dimer impurity and the RRT approx. 3.1-3.2 impurity.

[0106] [Table 15]

[0107] Example 10 Ready-to-use aqueous formulation of (R,R)-pyrodach-2 in 10 mL vials (5 mg / mL (R,R)-pyrodach-2 in 10 mM phosphate buffer, pH 7) To a 36 mL glass beaker equipped with a mechanical mixer was added 24645.5 g of sterile water for injection. With stirring, 47.03 g of potassium phosphate dibasic USP was added to dissolve the solids. To the stirred solution, 253.8 gm of 1.00 N potassium hydroxide was added. Sterile water for injection USP (900.0 gm) was used as a rinse to facilitate both additions. With vigorous stirring, (R,R)-pyrodach-2 (201.87 gm) was slowly added and stirring continued until all solids were dissolved. Sterile water for injection USP (900.0 gm) was used as a rinse to facilitate the addition. The pH was determined to be 6.7. A total of 85 mL of 1.00 N potassium hydroxide was added in 5.0 mL aliquots to adjust the pH to 7.3. The solution was sterile filtered through a 0.22μ Millipore Millipack filter and aseptically filled at 10 mL into 10 cc Wheaton clear molded vials, stoppered with 20 mm stoppers and capped with a crimp seal.

[0108] The foregoing examples and descriptions of certain preferred embodiments should be construed as illustrative rather than limiting of the present invention. As will be readily appreciated by those skilled in the art, many variations and combinations of the features described above can be utilized without departing from the present invention.

Claims

1. A liquid pharmaceutical composition comprising a phosphaplatin compound and an aqueous buffer solution having a pH of about 7 or greater.

2. 10. The liquid pharmaceutical composition of claim 1, wherein the liquid pharmaceutical composition is a ready-to-use liquid formulation suitable for parenteral administration.

3. 3. The liquid pharmaceutical composition of claim 1 or 2, wherein the concentration of the phosphaplatin compound is about 20 mg / mL or less.

4. The liquid pharmaceutical composition of claim 3, wherein said concentration of said phosphaplatin compound is from about 1 to about 10 mg / mL.

5. The liquid pharmaceutical composition of claim 3, wherein said concentration of said phosphaplatin compound is from about 1 to about 6 mg / mL.

6. 4. The liquid pharmaceutical composition of claim 3, wherein the concentration of the phosphaplatin compound is about 5 mg / mL.

7. The liquid pharmaceutical composition according to any one of claims 1 to 6, wherein said buffer comprises a phosphate or a bicarbonate / carbonate.

8. The liquid pharmaceutical composition of claim 7, wherein the buffer salt concentration is from about 1 mM to about 100 mM.

9. The liquid pharmaceutical composition of claim 7, wherein the buffer salt concentration is from about 5 mM to about 50 mM.

10. 8. The liquid pharmaceutical composition of claim 7, wherein the buffer salt concentration is about 10 mM.

11. The liquid pharmaceutical composition according to any one of claims 1 to 10, wherein the pH is within the range of about 7.0 to about 9.

0.

12. The liquid pharmaceutical composition according to claim 11, wherein the pH is in the range of 7.0 to 8.

0.

13. 12. The liquid pharmaceutical composition of claim 11, wherein the buffer is a sodium salt or a potassium salt.

14. 12. The liquid pharmaceutical composition of claim 11, wherein the buffer is potassium phosphate, the concentration of the phosphaplatin compound is about 5 mg / mL, and the pH is from about 7.0 to about 8.

0.

15. 15. The liquid pharmaceutical composition of claim 14, wherein the buffer concentration is about 10 mM.

16. The liquid pharmaceutical composition according to any one of claims 1 to 15, wherein the buffer comprises pyrophosphate.

17. 17. The liquid pharmaceutical composition of claim 16, wherein the molar ratio of pyrophosphate anion to said phosphaplatin compound is at least about 0.1 to about 1.

18. 18. The liquid pharmaceutical composition of claim 17, wherein said molar ratio of pyrophosphate ions to said phosphaplatin compound is from about 0.2 to about 1.

19. 18. The liquid pharmaceutical composition of claim 17, wherein said molar ratio of pyrophosphate ions to said phosphaplatin compound is from about 0.4 to about 1.

20. 2. The liquid pharmaceutical composition of claim 1, wherein the concentration of said phosphaplatin compound is about 5 mg / mL, the concentration of said pyrophosphate is about 5.2 mM, and the pH is within the range of about 7.0 to about 8.

0.

21. The phosphaplatin compound is a pyrophosphato-platinum(II) complex having the formula (I) or (II): 【Chemistry 1】 or a salt thereof, wherein R １ and R ２ are each independently ３ , a substituted or unsubstituted aliphatic amine, and a substituted or unsubstituted aromatic amine; R ３ The liquid pharmaceutical composition according to any one of claims 1 to 20, wherein is selected from substituted or unsubstituted aliphatic or aromatic 1,2-diamines.

22. The liquid pharmaceutical composition of any one of claims 1 to 21, wherein said phosphaplatin compound is trans-1,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) ("trans-pyrodach-2") complex.

23. 23. The liquid pharmaceutical composition of any one of claims 1 to 22, wherein the phosphaplatin compound is (R,R)-trans-1,2-cyclohexanediamine-(dihydrogenpyrophosphato)platinum(II) ("(R,R)-trans-pyrodach-2").

24. 23. The liquid pharmaceutical composition of any one of claims 1 to 22, wherein the phosphaplatin compound is (S,S)-trans-1,2-cyclohexanediamine-(dihydrogenpyrophosphato)platinum(II) ("(S,S)-trans-pyrodach-2").

25. The liquid pharmaceutical composition of any one of claims 1 to 21, wherein said phosphaplatin compound is cis-1,2-cyclohexanediamine-(dihydrogen pyrophosphato)platinum(II) ("cis-pyrodach-2").

26. A liquid pharmaceutical composition according to any one of claims 1 to 25 for use in the treatment of a disease or disorder.

27. 26. The liquid pharmaceutical composition of any one of claims 1 to 25 for use in the treatment of cancer selected from the group consisting of gynecological cancer, genitourinary cancer, lung cancer, head and neck cancer, skin cancer, gastrointestinal cancer, breast cancer, bone and cartilage cancer, and blood cancer.

28. 1. A method for preparing a liquid pharmaceutical composition of a phosphaplatin compound, comprising: a) dissolving the phosphaplatin compound in an aqueous buffer containing a sufficient amount of a hydroxide base such that the pH remains above 7; b) optionally adding a hydroxide base to adjust the pH to a desired range; and c) filtering the solution to obtain a liquid formulation.

29. 29. The method of claim 28, wherein the aqueous buffer is a phosphate buffer, a carbonate / bicarbonate buffer, or a combination thereof.

30. 30. The method of claim 28 or 29, wherein the pH of the liquid formulation is within the range of about 7.0 to about 9.

0.

31. The method of any one of claims 28 to 30, further comprising adding a sufficient amount of pyrophosphate salt to stabilize the phosphaplatin compound in the liquid formulation.

32. The method of any one of claims 28 to 31, wherein the filtration is carried out under sterile conditions.

33. 33. The method of any one of claims 28 to 32, further comprising the step of: d) filling the solution into vials, stoppering and capping the vials in a sterile environment, and rendering the formulation ready for use.

34. The method according to any one of claims 28 to 33, wherein the liquid formulation obtained is a formulation according to any one of claims 1 to 27.

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