Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Reexamination Certificate
1999-02-22
2001-10-23
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
Reexamination Certificate
active
06306902
ABSTRACT:
The invention relates to pharmaceutically stable oxaliplatin solution formulations, to the method of use thereof in the treatment of cancer tumors, to processes for the preparation of such formulations and to a method for stabilizing solutions of oxaliplatin.
Kidani et al,. U.S. Pat. No. 4,169,846, issued Oct. 2, 1979, disclose cis-platinum(II) complexes of isomers (cis-, trans-d, and trans-1 isomers) of 1,2-diaminocyclohexane represented by the general formula
wherein the stereoisomerism of 1,2-diaminocyclohexane is cis, trans-d, or trans-1; and R′ and R
2
represent halogen atoms, or R′ and R
2
may, when taken together, form a group represented by the formula:
where R
3
represents a >CH
2
group, a >CHCH
3
or >CHCH
2
CH
3
group. Cis-oxalato(trans-1-1,2-diaminocyclohexane)platinum (II) is specifically disclosed as example 4(i). The compounds are stated to possess anti-tumor activity.
Okamoto et al., U.S. Pat. No. 5,290,961, issued Mar. 1, 1994, disclose a process for preparing various platinum compounds including cis-oxalato(trans-1-1,2-cyclohexane-diamine)platinum (II). A similar disclosure is found in EP 617043, published Sep. 28, 1994.
Tozawa et al., U.S. Pat. No. 5,298,642, issued Mar. 29, 1994, disclose a process for optically resolving optically active platinum compounds by the use of chiral high perfomance liquid chromatography. The resolution of cis-oxalato(trans-d and trans-1-1,2-cyclohexane-diamine)platinum (II) is specifically disclosed. Nakanishi et al., U.S. Pat. No. 5,338,874, issued Aug. 16, 1994, disclose optically pure cis-oxalato(trans-1-1,2-cyclohexanediamine)platinum (II) and methods of preparing the same. A similar disclosure is found in EP 567438, published Oct. 27, 1993.
Okamoto et al., U.S. Pat. No. 5,420,319, issued May 30, 1995, disclose cis-oxalato(trans-1-1,2-cyclohexanediamine)platinum(II) having high optical purity and a process for preparing the same. A similar disclosure is found in EP 625523, published Nov. 23, 1994.
Masao et al., EP. 715854, published Jun. 12, 1996, disclose a process of compatibly administering cis-oxalato(1R,2R-diaminocyclohexane)platinum(II), abbreviated as (“1-OHP”), with one or more existing carcinostatic substances and a carcinostatic substance comprising one or more compatible agents and 1-OHP.
Kaplan et al., Canadian patent application No. 2,128,641, published Feb. 12, 1995, disclose stable solutions of malonato platinum (II) antitumor agents, such as carboplatin, containing a stabilizing amount of 1,1-cyclobutanedicarboxylic acid or a salt thereof and a pharmaceutically acceptable carrier, said solution having a pH about 4 to about 8.
Ibrahim et al., WO94/12193, published Jun. 9, 1994, disclose a composition for jointly administering cisplatin and oxaliplatin, said composition being a freeze-dried composition containing cisplatin and oxaliplatin in a weight ratio of about 2:1 to 1:2 and a pharmaceutically acceptable chloride ion-free acidic buffer with a neutral substance being used as a ballast.
Tsurutani ET al., EP 486998, published May 27, 1992, disclose a slow-releasing composition comprising a platinum-containing anticancer agent bound to deacetylated chitin. A similar disclosure is found in U.S. Pat. No. 5,204,107, issued Apr. 20, 1993.
Ibrahim et al., Australian patent application No. 29896/95, published Mar. 7, 1996 (a patent family member of WO 96/04904, published Feb. 22, 1996), disclose a pharmaceutically stable preparation of oxaliplatin for parenteral administration consisting of a solution of oxaliplatin in water at a concentration in the range of 1 to 5 mg/mL and having a pH in the range of 4.5 to 6. A similar disclosure is found in U.S. Pat. No. 5,716,988, issued Feb. 10, 1998.
Johnson, U.S. Pat. No. 5,633,016, issued May 27, 1997, discloses pharmaceutical compositions comprising a compound of the camptothecin analog class and a platinum coordination compound and a pharmaceutically acceptable carrier or diluent. A similar disclosure is found in WO93/09782, published May 27, 1993.
Bach et al., EP 393575, published Oct. 24, 1990, disclose a combination therapy of therapeutically-effective amounts of a cytoprotective copolymer and one or more directly acting antineoplastic agents for the treatment of neoplastic disease.
Nakanishi et al., EP 801070, published Oct. 15, 1997, disclose a process for preparing various platinum complexes including cis-oxalato(trans-1-1,2-cyclohexane-diamine)Pt(II).
Oxaliplatin is currently available for both preclinical and clinical trials as a lyophilized powder which is reconstituted just before administration to a patient with water for injection or a 5% glucose solution, followed by dilution with a 5% glucose solution. Such a lyophilized product can, however, have several disadvantages. First of all, the lyophilization process can be relatively complicated and expensive to perform. In addition, the use of a lyophilized product requires that the product be reconstituted at the time of use, which provides an opportunity for there to be an error in choosing the appropriate solution for the reconstitution. For instance, the mistaken use of a 0.9% NaCl solution, which is a very common solution for the reconstitution of lyophilized products or for the dilution of liquid preparations, in the reconstitution of a lyophilized oxaliplatin product would be detrimental to the active ingredient in that a rapid reaction would occur, resulting not only in the loss of oxaliplatin, but in the precipitation of the species produced. Other disadvantages of a lyophilized product are:
(a) reconstitution of a lyophilized product increases the risk of microbial contamination over a sterile product which does not require reconstitution;
(b) there is a greater risk of sterility failure with a lyophilized product as compared to a solution product sterilized by filtration or by heat (terminal) sterilization; and
(c) a lyophilized product has a potential for incomplete dissolution upon reconstitution resulting in particles which are undersirable for an injectable product.
It has been shown that in aqueous solutions oxaliplatin can, over time, degrade to produce as impurities varying amounts of diaquo DACH platin (formula I), diaquo
DACH platin dimer (formula II) and a platinum (IV) species (formula III). As the level of impurities present in any pharmaceutical formulation can, and in many cases does, affect the toxicological profile of the formulation, it would be desirable to develop a more stable solution formulation of oxaliplatin which either does not produce the above-described impurities at all or which produces such impurities in significantly smaller quantities than has heretofore been known.
Accordingly, a need exists for solution formulations of oxaliplatin in a ready-to-use (RTU) form, which overcome the above-described disadvantages and which are pharmaceutically stable over prolonged periods of storage, i.e., 2 years or more. It is accordingly an object of the present invention to overcome these disadvantages by providing a pharmaceutically stable oxaliplatin solution formulation in ready-to-use form.
More specifically, the present invention relates to a stable oxaliplatin solution formulation comprising oxaliplatin, an effective stabilizing amount of a buffering agent and a pharmaceutically acceptable carrier.
Oxaliplatin, which is known chemically as cis-oxalato(trans-1-1,2-cyclohexane-diamine)platinum (II) (can also be named as [SP-4-2]-(1R,2R)-(cyclohexane-1,2-diamine-k
2
N,N′ (oxalato(2-)-k
2
O
1
,O
2
]platinum (II), (1,2-cyclohexanediamine-N,N′)[ethanedioato(2-)-O,O′]-[SP-4-2-(1R-trans)]-platinum, cis-[oxalato(1R,2R-cyclohexanediamine)platinum (II)], [(1R,2R)-1,2-cyclohexanediamine-N,N′][oxalato(2-)-O,O′]platinum, [SP-4-2-(
1
R-trans)]-(1,2-cyclohexane-diamine-N,N′)[ethanedioato(2-)-O,O′]platinum, 1-OHP, and cis-oxalato(trans-1-1,2-diaminocyclo-hexane(platinum (II)), and has the chemical stricture shown below,
is a cytostatic ant
Anderson Nicholas H.
Blundell Ross
Brown Stephen
England David A.
Gray Martin R.
Alexander Michael D.
Goldberg Jerome D.
Sanofi-Synthelabo
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