Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1999-07-21
2001-09-11
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C514S492000, C264S004100, C264S004300
Reexamination Certificate
active
06287593
ABSTRACT:
The present invention relates to a lipid complex or liposome of highly insoluble platinum complexes, and more particularly to a phospholipid complex of a platinum dicarboxylate 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.
Several platinum complexes have shown excellent activity against cancer. The clinical use of such complexes has been severely limited by the insolubility of the complexes in pharmaceutically acceptable vehicles. For example, diaminocyclohexane (DACH) complexes with platinum compounds have been shown to be active against several types of cancer. However, the DACH-Pt complexes are quite insoluble in aqueous vehicles and many organic solvents. The insolubility of the DACH-Pt in organic solvents has precluded their encapsulation in liposomes or their use in lipid complexes by known methods.
Accordingly, there is a need for a solubilized, pharmaceutically stable form of the highly insoluble moieties such as DACH-Pt complexes.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a soluble, pharmaceutically acceptable dosage form of water-insoluble platinum complexes.
It is another object of the invention to provide phospholipid complexes or liposomes of diaminocyclohexane-platinum complexes.
It is still another object of the invention to provide a lyophilized pharmaceutically acceptable dosage form of diaminocyclohexane-platinum-phospholipid complexes or liposomes.
While the invention will hereafter be described with respect to the preparation of lipid complexes or liposomes of diaminocyclohexane-platinum malonate and lyophilizates of lipid complexes of diaminocyclohexane-platinum malonate, those skilled in the art will appreciate that the methods taught herein are also applicable to the preparation of lipid complexes or liposomes and lyophilizates of other platinum complexes which are considered water-insoluble and cannot be administered by injection or infusion.
In accordance with a specific embodiment of the present invention, phospholipid complexes or liposomes of a diaminocyclohexane-platinum dicarboxylate which can be reconstituted with a pharmaceutically acceptable aqueous diluent such as water for injection are provided.
The soluble phospholipid complex of the DACH-platinum dicarboxylate is prepared in situ by a method which comprises reacting DACH with potassium tetrachloroplatinate and potassium iodide to form DACH-platinum iodide followed by reacting the DACH-platinum iodide with silver nitrate to yield DACH-platinum nitrate. The DACH-platinum nitrate is then simultaneously reacted with a phospholipid in a chloroform/ethanol solution and a carboxylic acid to form the lipid complex of DACH-platinum dicarboxylate product. It has been found that carboxylation of the platinum complex greatly reduces its water solubility. In accordance with the invention, by postponing carboxylation until formation of the lipid complex or liposome, the solubility of the platinum entity is maintained so that a solution of the complex is available for formation of the lipid complex or liposome.
The DACH-Pt-dicarboxylates of the present invention can also be prepared as liposomes. Liposomes are widely described in the literature and their structure is well known. In the present invention, liposomes are made by forming a film of the active ingredient, in this case DACH-Pt nitrate and the phospholipid, adding a carboxylic acid, and evaporating the solvent for the phospholipid, e.g., chloroform/ethanol to form the film, adding water for injection, and finally homogenizing the formed liposome.
DETAILED DESCRIPTION OF THE INVENTION
The term “lipid complex” is an art recognized term in the preparation of pharmaceutical compounds. Lipid complexes are characterized by a non-covalent bond between the lipid and the pharmaceutical compound which is observed as a phase change in differential scanning calorimetry.
The term “pharmaceutically acceptable aqueous diluent” as used herein refers to water for injection, saline, and other known aqueous vehicles.
The term “lyophilization excipient” refers to a substance which is added to a solution prior to lyophilization to enhance characteristics such as the color, texture, strength, and volume of the cake. Examples of lyophilization excipients are provided below.
In accordance with one embodiment of the present invention, the lipid complexes of diaminocyclohexane platinum complexes are prepared according to the following reaction scheme:
As illustrated in the first step above, diaminocyclohexane (1), potassium tetrachlor-palatinate (2) and potassium iodide (3) in stoichiometric amounts are reacted together in water to yield diaminocyclohexane-platinum iodide (4) which is only slightly soluble in water. Silver nitrate solution (5) is added to the diaminocyclohexane-platinum iodide (3) to form diaminocyclohexane-platinum nitrate (6). The diaminocyclohexane-platinum nitrate (6) is water soluble but is not useful as an anti-neoplastic agent because of its nephrotoxic properties. The appropriate phospholipid (7), preferably, a mixture of dimyristoyl phosphatidyl choline and dimyristoyl phosphatidyl glycerol, in a chloroforn/ethanol solution is added to the daiminacyclohexane-platinum nitrate (6) simultaneously with an excess of a dicarboxylic acid (8) such as malonic acid (illustrated here). Upon removal of the chloroform/ethanol solvent by sparging with nitrogen, the diaminocyclohexane-platinum dicarboxylate (9) is formed which is, at the same time, complexed with the phospholipid (7). The diaminocyclohexane-platinum dicarboxylate product (9) is then centrifuged and resuspended in water for injection. While the above procedure is directed to preparing DACH complexes, those skilled in the art will recognize that other ligands or chelating agents can be used to provide other complexes.
The carboxylic acids useful in the present invention to prepare the diaminocyclohexane-platinum dicarboxylates include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, maleic acid, fumaric acid, azelaic acid, suberic acid, sebasic acid, tartaric acid, phthalic acid, and the like. The acid may be substituted or unsubstituted. In a preferred aspect of the invention, malonic acid is the acid of choice.
The diaminocyclohexane platinum-dicarboxylates useful in the present invention have the following structure:
where R
1
and R
2
are the same or different and represent, hydrogen, C
1
-C
10
alkyl C
6
-C
10
aryl, C
7
-C
18
alkaryl, C
7
-C
18
aralkyl, or R
1
and R
2
may form a substituted or unsubstituted, saturated or unsaturated, 4,5, or 6-member ring; or R
1
or R
2
may combine with R
1
or R
2
on an adjacent carbon atom to form a substituted or unsubstituted, saturated or unsaturated 4, 5, or 6-member ring; and n is 0-10.
Typically the diaminocyclohexane-platinum carboxylate is diaminocyclohexane-platinum oxalate, diaminocyclohexane-platinum malonate, diaminocyclohexane-platinum succinate, diaminocyclohexane-platinum glutarate, diaminocyclohexane-platinum adipate, diaminocyclohexane-platinum pimelate, diaminocyclohexane-platinum maleate, daiminocylclohexane-platinum fumerate, diaminocyclohexane-platinum phthalate, and diaminocyclohexane-platinum tartrate. Preferably, the diaminocyclohexane-platinum dicarboxylate is diaminocyclohexane-platinum malonate or a diaminocyclohexane-platinum malonate in which the malonate is substituted with, e.g., and alkyl group or the like such as a butyl group.
The organic solvent used to prepare the solution of the phospholipids must be compatible with the phospholipids and not destabilize them or the DACH-Pt nitrate complex. In addition, the lipids should be soluble enough in the solvent so as to be able to introduce enough of the lipid to form the complex yet minimize the amount of solvent that must be removed later. A volatile or low boiling solvent which can be readily removed from the dispersion of the lipid complex is most preferred. The sol
Kishore Gollamudi S.
McDonnell & Boehnen Hulbert & Berghoff
Pharmacia & Upjohn
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