Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-10-27
2002-03-12
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S016700, C530S322000, C530S329000, C530S344000, C530S345000
Reexamination Certificate
active
06355611
ABSTRACT:
BACKGROUND OF THE INVENTION
In 1999 new cases of cancer of the prostate gland were expected to be diagnosed in 179,300 men in the U.S. and 37,000 American males were expected to die from this disease (Landis, S. H. et al.
CA Cancer J. Clin.
49:8-31 (1999)). Prostate cancer is the most frequently diagnosed malignancy (other than that of the skin) in U.S. men and the second leading cause of cancer-related deaths (behind lung cancer) in that group.
Compositions useful in the treatment of prostatic cancer and related conditions are described in U.S. Pat. No. 5,948,750, issued Sep. 7, 1999 (corresponding to PCT Publ.No. WO 98/18493). Said compositions comprise chemical conjugates comprising known cytotoxic agents and oligopeptides having amino acid sequences that are selectively proteolytically cleaved by free prostate specific antigen and that include a cyclic amino acid having a hydrophilic substituent. The oligopeptide moieties are selected from oligomers that are selectively recognized by free prostate specific antigen (PSA) and are capable of being proteolytically cleaved by the enzymatic activity thereof.
Ideally, the cytotoxic activity of the cytotoxic agent is greatly reduced or absent when the intact oligopeptide containing the PSA proteolytic cleavage site is bonded directly, or through a chemical linker, to the cytotoxic agent. Also ideally, the cytotoxic activity of the cytotoxic agent increases significantly, or is restored completely, upon proteolytic cleavage of the attached oligopeptide at the cleavage site. Anthracycline antibiotics, in particular doxorubicin, are among the cytotoxic agents that were described in the published patent applications as preferably incorporated into such conjugates, which may be referred to as PSA conjugates. The PSA conjugates that incorporate doxorubicin that have been previously described incorporate the oligopeptide on the amine moiety of the sugar residue of doxorubicin. Those oligopeptides preferably incorporate a N-terminus protecting group to prevent or reduce proteolysis of the oligopeptide by non-PSA enzymes.
Among the preferred N-terminus protecting groups that are incorporated onto a PSA conjugate are the dicarboxylic acid alkanes, such as succinyl, glutaryl and the like. One of the preferred compounds described in U.S. Ser. No. 08/950,805, now U.S. Pat. No. 5,948,750 (PCT Publ.No. WO 98/18493) incorporating such an N-terminus protecting group is the compound of Formula 4:
It is the object of this invention to provide a salt form of Compound 4 which is characterized by properties that offer advantages in the preparation, handling, storage and delivery of the compound to a patient in need of anti-cancer treatment.
It is the further the object of this invention to provide a stable lyophilized formulation of Compound 4 which is characterized by properties that offer advantages in the storage of the compound and delivery of the compound to a patient in need of anti-cancer treatment.
SUMMARY OF THE INVENTION
A sodium salt of a PSA conjugate compound having the formula 5 is disclosed:
Such a salt is useful in the treatment of prostate cancer and benign prostatic hyperplasia (BPH).
Also described are formulations that comprise the salt of the invention and methods of preparing the salt.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to the sodium salt of the formula 5:
It has been surprisingly discovered that the sodium salt of a PSA conjugate compound, which is specifically described as the free acid in Example 4 of PCT Publ. No. WO 98/18493, is characterized by several advantageous physical properties when compared to the previously described free acid form (formula 4 hereinabove).
In particular, the sodium salt is crystalline and can be precipitated from an aqueous solution by the addition of a water miscible organic solvent. Such water miscible solvents include, but are not limited to tetrahydrofuran, methanol, ethanol, isopropanol and acetone. Preferably, acetone is utilized to precipitate the salt from solution. The crystalline nature of the sodium salt also allows for the purification of large quantities of the compound by recrystallization. Purification of the previously disclosed free acid requires the use of chromatographic techniques and freeze drying/lyophilization that are not amenable to large scale preparations which are often associated with commercial pharmaceutical agents.
It has also been surprisingly discovered that the sodium salt compound of the Formula 5 is more thermally stable than the corresponding free acid compound (Formula 4). An aqueous solution of the sodium salt of the instant invention has a pH of greater than 5.0. It has been discovered that the bond between the sugar moiety of doxorubicin and the tetracyclic doxorubicinone moiety is more readily cleaved at aqueous pH of less than 4.0. Therefore the sodium salt offers clear formulation advantages over the free acid, which has an unbuffered aqueous pH of less than 4.0.
It has further been discovered that the sodium salt of the Formula 5 offers advantages with respect to dissolution in water. The solubility of the sodium salt of the Formula 5 at room temperature is greater than 277 mg/mL of water. The solubility of the free acid (Compound 4) is 13.8 mg/mL of water at room temperature. It has also been surprisingly found that the sodium salt of the Formula 5 dissolves in water without forming aggregates, such as those that have been observed for the free acid. It has been found that the formation of aggregates hinders the filtration of an aqueous solution of the free acid compound through a 0.22&mgr; filter, which is used to sterilize the aqueous solution prior to administration.
The instant invention is also directed to the process for the preparation of the salt of the Formula 5 which comprises the step of treating the acid of the Formula 4 with a base. The bases that may be used in the preparation of the salt of the Formula 5 include, but are not limited to: NaOH, Na
2
CO
3
, sodium acetate, sodium citrate (citric acid, trisodium salt) and the like. The preferred base is NaOH.
The instant invention is further directed to an alternative process for the preparation of the salt of the Formula 5 which comprises the step of treating the piperidine salt of the acid of the Formula 4 with a base. The bases that may be used in this preparation of the salt of the Formula 5 include, but are not limited to: NaOH, Na
2
CO
3
, sodium acetate, sodium citrate and the like. The preferred base is sodium acetate.
The instant invention is also directed to an second alternative process for the preparation of the salt of the Formula 5 which comprises the steps of a) treating the intermediate of the Formula 3
with piperidine to provide a resulting mixture; b) treating the resulting mixture with an acid to provide a second resulting mixture; and c) treating the second resulting mixture with a base. The bases that may be used in this preparation of the salt of the Formula 5 include, but are not limited to: NaOH, Na
2
CO
3
, sodium acetate, sodium citrate and the like. The preferred base is sodium acetate. The acid that may be used in this preparation of the salt of the Formula 5 include, but are not limited to: hydrochloric acid and acetic acid. The preferred acid is acetic acid.
In an embodiment of the instant process, the process further comprises the step of precipitating the sodium salt of the Formula 5 from the resulting aqueous solution by adding a water miscible organic solvent to the solution. Such water miscible solvents include, but are not limited to, tetrahydrofuran, isopropanol and acetone. Preferably, acetone is utilized to precipitate the salt from solution.
In another embodiment of the instant process, the process further comprises the step of isolating the salt of the Formula 5 from the resulting aqueous solution by evaporating the solvent.
It has been surprisingly discovered that a lyophilized formulation of the PSA conjugate compound 4, which is specifically described in Example 4 of PCT Publ.No. WO 98/18493, is characteri
Almarsson Örn
Cameron Mark
Karki Shyam B.
Kaufman Michael J.
Lieberman David R.
Daniel Mark R.
Merck & Co. , Inc.
Muthard David A.
Russel Jeffrey E.
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