Platinum derivative pharmaceutical formulations

Details Platinum derivative pharmaceutical formulations Platinum derivative pharmaceutical formulations

2002-08-22

2004-01-06

Reamer, James H (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S492000

Reexamination Certificate

active

06673805

ABSTRACT:

FIELD OF THE INVENTION
The present invention pertains to the field of pharmaceutical compositions for the treatment of neoplastic diseases and, particularly, it relates to pharmaceutical formulations comprising a platinum derivative.
SUMMARY OF THE INVENTION
The present invention is directed to novel stable formulations of oxaliplatin alone or combined in fixed ratios with irinotecan, wherein lactic acid and/or a pharmaceutically acceptable salt thereof serves as a novel mean for preparing a dosage unit with an improved stability. A method for manufacturing such formulations ready for administration and their use in the antitumor therapy are also within the scope of the invention.
BACKGROUND OF THE INVENTION
Oxaliplatin, also known as L-OHP, is a third generation platinum complex.
The term “oxaliplatin” as used herein, includes cis-oxalato(trans-l-1,2-diaminocyclohexane)platinum(II), its optic enatiomer cis-oxalato(trans-d-1,2-diaminocyclohexane)platinum(II) and any racemic mixture thereof. The term “oxaliplatin” also includes cis-oxalato (trans-l-1,2-diaminocyclohexane) platinum (II) having high optical purity, namely an optical purity equal to or higher than about 99.5%, for example a cis-oxalato (trans-l-1,2-diaminocyclohexane) platinum(II), wherein the melting point is between about 198° C. and about 292° C., obtained following the procedure described in Tanaka U.S. Pat. No. 5,338,874 and, especially, a cis-oxalato(trans-l-1,2-cyclohexanediamine)platinum(II), which possesses optical purity of about 99.94% or more and a melting point between about 198.3° C. and about 199.7° C., obtained following the procedure disclosed in Tanaka U.S. Pat. No. 5,420,319.
Oxaliplatin has entered clinical development and achieved approval for marketing. During its development, oxaliplatin has aroused lively interest due, firstly, to its in vitro and in vivo antitumoral activity, especially in cisplatin-resistant models and cell lines expressing resistance genes, and, secondly, to its good clinical tolerance, the absence of renal or auditory toxicity being combined with a low hematotoxicity. Combined with other antitumoral agent cytotoxic agents (5-FU, raltitrexed, irinotecan or cisplatin), oxaliplatin produces an additive and often synergistic cytotoxic effect. The oxaliplatin-5FU+FA combination is now well established in metastatic colorectal cancer. Regarding its particular cytotoxic characteristics and its activity in mismatch repair deficient cells (which are resistant to cisplatin and carboplatin), oxaliplatin is shown potential in a large variety of solid tumor types, notably in association with other cytotoxic agents, thus opening the path to a wider range of indications. Kidani et al,. U.S. Pat. No. 4,169,846, discloses cis-platinum(II) complexes of 1,2-diaminocyclohexane active as antitumor compounds. Cis-oxalato(trans-l-1,2-diaminocyclohexane)platinum(II) is specifically disclosed in Example 4(i).
SmithKline Beecham, U.S. Pat. No. 5,633,016, discloses a method for inhibiting tumour cell growth using synergistic combination of a camptothecin analogue and a platinum coordination compound, e.g. cisplatin and oxaliplatin.
Tanaka, U.S. Pat. No. 5,290,961, discloses a process for preparing various platinum compounds including oxaliplatin, which comprises adding silver ion solution to cis-platinum (II) di halogen compound, filtering of silver halide, adding iodide compound and active carbon then adding organic di basic acid.
Tanaka, U.S. Pat. Nos. 5,338,874, 5,298,642 and 5,420,319, disclose optically pure oxaliplatin and methods for preparing the same.
Debiopharm, International patent application WO94/12193, discloses a freeze-dried composition for jointly administering cisplatin and oxaliplatin.
Tanaka, U.S. Pat. No. 5,420,319, discloses oxaliplatin having high optical purity and a process for obtaining it.
Debiopharm, U.S. Pat. No. 5,716,988, discloses a stable oxaliplatin preparation for parenteral administration comprising an aqueous solution of oxaliplatin, in a concentration of 1 to 5 mg/ml, and with a pH in the range of 4.5 to 6.
Tanaka, European patent application No. 715,854, discloses a combination of: (a) at least one of cisplatin, carboplatin, 5-fluorouracil (5-FU), tegaful, carmoful, doxifluridine, uracil, irinotecan, adriamycin, etoposide, mitomycin, mitoxantrone and bleomycin; and (b) oxaliplatin, which produces an additive or synergistic effect on killing cells during cancer therapy.
Tanaka, U.S. Pat. No. 5,959,133, discloses high-yielding process for obtaining chelating platinum complexes including oxaliplatin, which does not contain dihydroxoplatinum complex impurity.
Pharmacia & Upjohn Co., U.S. Pat. No. 6,287,593, discloses a phospholipid complex of a platinum dicarboxylate including oxaliplatin, which can be reconstituted in a pharmaceutically acceptable vehicle with or without lyophilization and administered to a patient in the treatment of cancer and other diseases.
Debiopharm, European patent application No. 1121117 discloses a liquid pharmaceutical preparation of oxaliplatin packaged in a container, preferably in a sealed soft bag for medical use. The liquid preparation of oxaliplatin can advantageously be presented in the form of a bag with several compartments containing doses of a ready-to-use solution.
Sanofi-Synthelabo, U.S. Pat. No. 6,063,780, discloses a treatment of mammalian solid tumors with the co-administration of 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) paclitaxel and oxaliplatin.
Debiopharm, International patent application No. WO 01/15691, discloses stable solutions of oxaliplatin, ready for parenteral administration, containing 1,2-propane diol, glycerol, maltitol, sucrose,and/or inositol.
BioNumerik, U.S. Pat. No. 6,066,666, discloses pharmaceutical formulations comprising a platinum analogue compound, e.g. oxaliplatin and a protective agent having either a sulfhydryl moiety or being reducible disulfide.
Bristol-Myers Squibb, International patent application WO 01/66102 discloses oral dosage forms for administration of the combination of tegafur+uracil (UFT), folinic acid, and oxaliplatin and methods of using the same.
Sanofi-Synthelabo, U.S. Pat. No. 6,306,902, discloses a stable oxaliplatin solution formulation comprising a therapeutically effective amount of oxaliplatin, an effective stabilizing amount of a buffering agent and a pharmaceutically acceptable carrier wherein the buffering agent is oxalic acid or an alkali metal salt thereof.
Bissery M. C., U.S. patent application Ser. No. 20010041712 discloses anticancer treatments with associations of camptothecin derivatives such as irinotecan (CPT-11, CAMPTOSAR®), topotecan, 9-aminocamptothecin, 9-nitrocamptothecin, and platinum derivatives including cisplatin (cis-platinum, cis-diaminedichloroplatinum, or CDDP), carboplatin, and oxaliplatin.
At present, oxaliplatin is solely marketed in the form of lyophilized preparations, which need to be reconstituted before administration. The currently marketed formulation is a lyophilized powder (50, 100 mg) to be reconstituted just before administration to a patient with water for injection or a 5% glucose solution and finally diluted with a 5% glucose solution (0.2 mg/ml final concentration).
The lyophilized oxaliplatin can present some disadvantages, which do not render particularly attractive the use of this product in such a pharmaceutical form.
Both the manufacturing and the reconstitution of such preparations expose the involved personnel (workers, pharmacists, medical personnel, nurses) to risks of contamination, which are particularly serious due to the toxicity of the antitumor substances. To administer a lyophilized preparation, double handling of the drug is required, the lyophilized cake having to be first reconstituted and then administered and, moreover, in some cases, the complete dissolution of the powder can require shaking.
The disadvantages connected with the manufacturing and the reconstitution of a lyophilized preparation would be highly reduced if a ready-to-use (RTU) solution of oxaliplatin, whose preparat

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