Appeal No. 2005-1535
Application No. 10/049,379
Recently, a pharmaceutically stable oxaliplatinum preparation,
ready to be administrated parenterally by perfusion, constituted by an
aqueous solution of oxaliplatinum at a concentration of about 2 mg/ml, and
not containing other adjuvants, has been described by lbrahim and [sic] al.
in WO 96104904. .... [T]his preparation was not satisfactory, in particular,
because of its oxaliplatinum concentration which was much lower than the
solubilities mentioned above. This low concentration is required to prevent
all risk of precipitates or crystals susceptible to appear, for example,
during conservation at low temperatures in a refrigerator or during
transport at winter conditions. When such precipitates appear in a
pharmaceutical preparation, the hospital staff is generally warned, if there
is a doubt, to keep this sample out. If however, a redissolution should be
attempted, a heating process at temperatures higher than 40°C,possibly
coupled with sonication should be done.
This is why a pharmaceutical preparation based on an
oxaliplatinum solution at a concentration of 2 mg/ml, ... needs
manipulation of big volumes. For example, the generally recommended
dosage during a short perfusion treatment of between 2 and 6 hours, is of
130 mg oxaliplatinum per m2 body surface. When taking an average body
surface of 1[.]7 m2, it is then advisable to use at least 110 ml of this 2
mg/ml preparation.
One of the aims of the present invention is to make available a
stable oxaliplatinum pharmaceutical preparation, for parenteral
administration intended to be perfused of [sic] injected, in which the
oxaliplatinum concentration would be clearly increased in a way to
significantly reduce the volumes to manipulate and/or to use.
Specification, pages 1-2.
[A]lcohols like ethanol and benzyl alcohol, dimethylformamid or
dimethylacetamid did not allow, mixed with water, to considerably enhance
the solubility of oxaliplatinum. Among the polyalkenes and in particular the
polyalkene glycols having a molecular weight between 150 and 6000, only
polyethylene glycol allows to enhance considerably the oxaliplatinum
solubility. This compound has nevertheless not been retained as possible
solvent component because the obtained solution was strongly colored.
The crown ethers as some cyclodextrines allowed to enhance very slightly
the oxaliplatinum concentration but not sufficiently for the desired
applications. Among the carbon hydrates solubilised in water, lactose,
sorbitol, solketal, mannitol, amongst others, have shown to be ineffective.
Other carbohydrates such as cellobiose, trehalose, melibiose, gentiobiose,
raffinose, stachyose or melozitose have shown that, solubilised in water,
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