STABLE READY-TO-USE CARMUSTINE PHARMACEUTICAL COMPOSITION

Abstract

The present invention relates to a ready-to-use solution of carmustine that does not require dissolution or dilution of the carmustine prior to addition to saline and dextrose parenteral solutions. In particular, the invention relates to a stable liquid pharmaceutical composition containing carmustine in the form of ready-to-use solution and method for preparing the same.

Claims

1-7. (canceled)

8. A method of administering carmustine to a patient comprising the steps of: (i) adding a carmustine solution directly to 500 ml of a 0.9% sodium chloride injection solution or 500 ml of a 5% dextrose injection solution to form an administrable solution without any prior dissolution or prior dilution of the carmustine solution and (ii) parenterally administering the administrable solution to the patient wherein the carmustine solution consists of about 100 mg/mL to about 500 mg/mL of carmustine, a super refined polysorbate with a peroxide value below 10 meq O.sub.2/kg and optionally an antioxidant and the carmustine solution is provided in a sealed container that is free of polyvinyl chloride and free of di-2-ethylhexylphthalate prior to the addition to the 500 ml 0.9% sodium chloride injection solution or 500 ml of 5% dextrose injection solution.

9. The method according to claim 8, wherein the polysorbate is selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and mixtures thereof.

10. The method according to claim 8, wherein the polysorbate is super refined polysorbate 80.

11. The method according to claim 8, wherein the administrable solution has a concentration of about 0.2 mg/mL of carmustine.

12. The method according to claim 8, wherein the polysorbate is super refined polysorbate with a peroxide value about 0.2 meq O.sub.2/kg to about 0.5 meq O.sub.2/kg.

13. The method according to claim 12, wherein the polysorbate is super refined polysorbate with a peroxide value about 0.5 meq O.sub.2/kg.

14. The method according to claim 12, wherein the polysorbate is super refined polysorbate with a peroxide value about 0.2 meq O.sub.2/kg.

15. The method according to claim 8 wherein the carmustine solution is stored in the container with a head space within the container comprising not more than 6% oxygen.

16. The method according to claim 15 wherein after the carmustine solution is stored at 2° C. to 8° C. for 3 months in the sealed container the carmustine solution contains at least 90% by weight of the initial amount of carmustine and is free of visible particles.

17. The method according to claim 15 wherein after the carmustine solution is stored at 2° C. to 8° C. for 3 months in the sealed container the carmustine solution contains at least 95% by weight of the initial amount of carmustine and is free of visible particles.

18. A method of administering carmustine to a patient consisting of: (i) adding a carmustine solution directly to 500 ml of a 0.9% sodium chloride injection solution or 500 ml of a 5% dextrose injection solution to form an administrable solution without any prior dissolution or prior dilution of the carmustine solution and (ii) parenterally administering the administrable solution to the patient wherein the carmustine solution consists of about 100 mg/mL of carmustine, a super refined polysorbate 80 with a peroxide value about 0.2 meq O.sub.2/kg to about 0.5 meq O.sub.2/kg and optionally an antioxidant and the carmustine solution is provided in a sealed container that is free of polyvinyl chloride and free of di-2-ethylhexylphthalate and with a head space within the container comprising not more than 6% oxygen prior to the addition to the 500 ml 0.9% sodium chloride injection solution or 500 ml of 5% dextrose injection solution and wherein after the carmustine solution is stored at 2° C. to 8° C. for 3 months in the sealed container the carmustine solution contains at least 90% by weight of the initial amount of carmustine and is free of visible particles.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0038] The present invention relates to a stable, liquid pharmaceutical composition containing carmustine in the form of a ready-to-use solution and method for preparing the same.

[0039] As used herein, a “ready-to-use” or “RTU” composition is a sterile, liquid, injectable composition that is stable and has not been reconstituted from a lyophilizate.

[0040] Pharmaceutical Composition

[0041] One embodiment is a liquid, ready-to-use parenteral composition of carmustine dissolved in a suitable surfactant as the sole solvent.

[0042] The concentration of carmustine in the liquid, ready-to-use parenteral composition may vary from about 2 mg/mL to about 500 mg/mL, preferably 100 mg/mL, 200 mg/mL or 300 mg/mL.

[0043] Suitable surfactants include, but are not limited to, sodium salts of fatty alcohol sulphates, partial fatty acid esters of polyhydroxyethylene sorbitan such as polyoxyethylene sorbitan monolaurate (e.g., polyoxyethylene (20) sorbitan monolaurate, which is referred to as polysorbate 20 or Tween® 20), polyoxyethylene sorbitan monopalmitate (e.g., polyoxyethylene (20) sorbitan monopalmitate, which is referred to as polysorbate 40 or Tween® 40), polyoxyethylene sorbitan monostearate (e.g., polyoxyethylene (20) sorbitan monosterate, which is referred to as polysorbate 60 or Tween® 60), and polyoxyethylene sorbitan monooleate (e.g., polyoxyethylene (20) sorbitan monooleate, which is referred to as polysorbate 80 or Tween® 80), polyoxyethylene sorbitan tristearate (e.g., polyoxyethylene (20) sorbitan tristearate, which is referred to as polysorbate 65 or Tween® 65), and polyoxyethylene sorbitan trioleate (e.g., polyoxyethylene (20) sorbitan trioleate, which is referred to as polysorbate 85 or Tween® 85), polyoxyethylene glycol esters, polyoxyethylene castor oil derivatives, Cremophor® EL (PEG-35 castor oil), Cremophor® RH40 (PEG-40 hydrogenated castor oil), polyoxyethylene 15 hydroxystearate, polyoxyethylene alkyl ethers (sold under the tradename Brij®); polyoxyethylene stearates (Myrj®), sorbitan derivatives, fatty acid esters of sorbitan, poloxamers (e.g., poloxamer 188, poloxamer 407, poloxamer 338, and poloxamer 184), poloxamine (e.g., poloxamine 304, poloxamine 904, and poloxamine 908), lecithin, an ethoxylated vegetable oil, vitamin E tocopherol propylene glycol succinate (vitamin E-TPGS), polyoxyethylene-polyoxypropylene block copolymers, incrocas 35, TPGS (D-α-tocopherol polyethylene glycol 1000 succinate), tyloxapol, sodium oleate, sodium deoxycholate and mixtures thereof.

[0044] In one preferred embodiment, the surfactant is selected from various grades of polysorbate, such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and mixtures thereof. More preferably, the surfactant is polysorbate (e.g., super refined polysorbate 80) with a peroxide value below 10 meq O.sub.2/kg. In one embodiment, the peroxide value is about 0.5 meq O.sub.2/kg. In yet another embodiment the peroxide value is about 0.2 meq O.sub.2/kg.

[0045] According to one preferred embodiment, 100 mg of carmustine is dissolved in a sufficient quantity of surfactant (up to 1 mL to make up the final volume). In one embodiment, the fill volumes of RTU liquid may be 1 mL or 3 mL.

[0046] The pharmaceutical composition may optionally include other optional pharmaceutical excipients such as antioxidants. Suitable antioxidants include, but are not limited to, acetone sodium bisulfite, argon, ascorbyl palmitate, ascorbic acid, sodium bisulfite, butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), citric acid, cystein/cysteinate HCl, acetylcystein, dithionite sodium (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acid, ethanolamine, glutamate monosodium, glutathione, formaldehyde sulfoxylate sodium, metabisulfite sodium, metabisulfite potassium, methionine, monothioglycerol (thioglycerol), sulfite sodium, tocopherols alpha, alpha tocopherol hydrogen succinate, thioglycolate sodium, sodium formaldehyde sulfoxylate, thiourea, and any combination of any of the foregoing.

[0047] The concentration of antioxidant may range between 0.001 mg/mL to 5 mg/mL

[0048] In one embodiment, the pharmaceutical composition, after storage at 2-8° C. for 3, 6, 9, or 12 months, contains at least 90, 92, 94, 95, 96, 97, or 98% by weight of the initial amount of carmustine. In another embodiment, the pharmaceutical composition, after storage at 2-8° C. for 3, 6, 9, or 12 months, contains at least 90% by weight of the initial amount of carmustine.

[0049] Process of Preparation for the RTU Composition

[0050] The liquid, ready-to-use parenteral composition of carmustine may be prepared by: [0051] a) dissolving carmustine in a sufficient quantity of a suitable surfactant (e.g., to achieve 100 mg/mL concentration), [0052] b) aseptic filtration (e.g., with a sterile 0.22 micron filter) of the carmustine solution obtained in step (a) to obtain a sterile product, and [0053] c) filling the solution obtained in step (b) into a suitable container/closure system

[0054] Optionally, purging inert gas (nitrogen) during any of the aforementioned steps.

[0055] The liquid, ready-to-use parenteral formulation of carmustine may be a clear, pale yellow and free from visible particles.

[0056] In one embodiment, the stable liquid, ready-to-use parenteral formulation of carmustine of present invention has a concentration of about 100 mg/mL of carmustine.

[0057] This liquid, ready-to-use parenteral formulation of carmustine can be filled in a suitable container/closure system, e.g., ampoules, vials, and prefilled syringe system. The ready-to-use solution may be stored in an amber type-I glass vial or polypropylene container (such as a polypropylene container which is polyvinyl chloride (PVC) free and di-2-ethylhexy phthalate (DEHP) free). These solutions are preferably not stored in a polyvinyl chloride container. In one embodiment, the head space of each vial contains no more than 6.0% by volume oxygen.

[0058] The liquid, ready-to-use parenteral formulation of carmustine may have a pH in the range of 4-7.

[0059] Prior to administration, the liquid, ready-to-use parenteral composition of carmustine may be further admixed with 0.9% sodium chloride injection (e.g., Sodium Chloride Injection, USP) or 5% dextrose injection (e.g., 5% Dextrose Injection, USP) to form an administrable solution. For instance, in one embodiment, the ready-to-use composition is further admixed with 500 mL of 0.9% sodium chloride injection or 5% dextrose injection.

[0060] The U.S. Pharmacopeia, USP 42-NF 37 (2019) is hereby incorporated by reference, including the entries for Sodium Chloride Injection, USP and 5% Dextrose Injection, USP.

[0061] The administrable solution may be a faint yellow colour with a pH in the range of 4 to 7 and osmolality in the range of 330-390 mOsmol/L.

[0062] The administrable solution may be stored in a glass or polypropylene container (such as a polypropylene container which is polyvinyl chloride (PVC) free and di-2-ethylhexy phthalate (DEHP) free). These solutions are preferably not stored in a polyvinyl chloride container.

[0063] The administrable carmustine solution can have a concentration of about 0.2 mg/mL of carmustine

[0064] As used herein, a “stable” composition means no aggregation observed when stored at conventional storage conditions like 2° C. to 8° C. (long term) for appropriate time and wherein the assay of carmustine is not less than 90% (based on 100% initial carmustine).

[0065] The carmustine content may be determined by methods known in the art, such as high performance liquid chromatography (HPLC method), and spectrophotometry (UV spectrophotometry). HPLC was used for performing the carmustine assay studies described herein.

[0066] Based on the results of table 2, it was concluded that the liquid, ready-to-use parenteral formulation of carmustine of the present invention, was stable for up to 3 months when stored at 2° C.-8° C.

[0067] Administration

[0068] The carmustine administrable solution may be administered by slow intravenous infusion over at least two hours. In one embodiment, the injected area is monitored during the administration. In another embodiment, the rate of administration of the intravenous infusion is no more than 1.66 mg/m.sup.2/min.

[0069] The carmustine administrable solution may be administered to a patient to treat brain tumors glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, metastatic brain tumors, multiple myeloma, relapsed or refractory Hodgkin's lymphoma, or relapsed or refractory Non-Hodgkin's lymphomas.

[0070] In one embodiment, the carmustine administrable solution is administered to a patient as a single agent or in a combination therapy (such as with other chemotherapeutic agents) to treat (i) brain tumors glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, or metastatic brain tumors, (ii) multiple myeloma in combination with prednisone, (iii) relapsed or refractory Hodgkin's lymphoma in combination with other approved drugs (such as chemotherapeutic agents), or (iv) relapsed or refractory Non-Hodgkin's lymphomas in combination with other approved drugs (such as chemotherapeutic agents).

[0071] The carmustine administrable solution may be administered as a single agent in previously untreated patients at a dose of 150 to 200 mg/m.sup.2 carmustine intravenously every 6 weeks. The carmustine administrable solution may be administered as a single dose or divided into daily injections such as 75 to 100 mg/m.sup.2 on two successive days. The dose may be lowered when the carmustine administrable solution is used with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted. The carmustine administrable solution may be administered for the duration according to the established regimen. In one embodiment, the patient is premedicated before each dose with antiemetics.

[0072] The dosing (after the initial dose) may be adjusted according to the hematologic response of the patient to the preceding dose. In one embodiment, the patient is dosed as follows:

TABLE-US-00001 Nadir After Prior Dose Percentage of Prior Dose to Leukocytes/mm.sup.3 Platelets/mm.sup.3 be Given >4000 >100,000 100% 3000-3999 75,000-99,999 100% 2000-2999 25,000-74,999  70% <2000  <25,000  50%

[0073] The hematologic toxicity can be delayed and cumulative. In one embodiment, the patient's blood counts are monitored weekly. In another embodiment, a repeat course of the carmustine administrable solution is not administered until circulating blood elements have returned to acceptable levels (platelets above 100 Gi/L, leukocytes above 4 Gi/L and absolute neutrophil count above 1 Gi/L). In yet another embodiment, the interval between courses is 6 weeks.

[0074] In yet another embodiment, renal function is evaluated prior to administration and/or periodically during treatment. In one embodiment, carmustine treatment is discontinued if the creatinine clearance is less than 10 mL/min. In another embodiment, carmustine is not administered to patients with compromised renal function. In yet another embodiment, transaminases and bilirubin are monitored periodically during treatment.

[0075] The following examples further illustrate the invention but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be varied by one of ordinary skill in the art.

[0076] All patents and other references cited herein are hereby incorporated by reference in their entireties

EXAMPLES

Example 1

[0077]

TABLE-US-00002 TABLE 1 Composition of liquid, ready-to-use parenteral formulations of carmustine Composition Formulation 1 Carmustine 100 mg Polysorbate 80 NF q.s to 1 mL [0078] (a) 100 mg of carmustine was dissolved in sufficient quantity (q.s. to 1 mL) of polysorbate 80 NF surfactant, under inert (nitrogen) gas purging. [0079] (b) The solution obtained in step (a) was aseptically filtered (sterile 0.22 micron filter) under inert (nitrogen) gas purging to obtain a sterile product. [0080] (c) The solution obtained in step (b) was filled into a sterile amber coloured type-I glass vial.

[0081] The stability of the formulation was tested after 3 months of storage at 2-8° C. The results are provided in Table 2 below.

TABLE-US-00003 TABLE 2 Evaluation of liquid ready-to-use parenteral formulations of carmustine Stability data 3 months Test Initial (2° C.-8° C.) Description Clear pale yellow Clear pale yellow color solution color solution Assay 101.50%  97.21%  Related substances Impurity A* 0.20% 1.80% Any unspecified impurity BLD** BLD** Total impurities 0.20% 1.80% *Impurity A refers to 1,3-bis(2-chloroethyl)urea *BLD: below limit of detection