Parenteral elsamitrucin formulations

• US 5,508,268 A
• Filed: 08/12/1993
• Issued: 04/16/1996
• Est. Priority Date: 08/12/1993
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Nassar, Munir N., Reff, Michael J., Agharkar, Sheeram N.
• Primary Examiner(s): Robinson, Douglas W.
• Assistant Examiner(s): Fonda, Kathleen Kahler
• Application Number:
  US08/105,541
• Time in Patent Office: 978 Days
• Field of Search: 514/28, 536/4.1, 536/17.2, 536/18.5, 536/18.7
• US Class Current: 514/28
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00

Abstract

Stable parenteral antitumor formulations contain elsamitrucin salt, a stabilizer and a buffer. The formations are optionally stored in sealed containers under air or nitrogen headspace.

Claims

1. An oxidatively stable composition consisting essentially of a solution of:

(a) an acid salt of elsamitrucin;

(b) a stabilizing amount of an antioxidant;

(c) sufficient buffer to maintain a solution pH of about 3.5 to about 4.5; and

(d) a pharmaceutically acceptable carrier.

2. The composition of claim 1 wherein the acid is at least one selected from the group consisting of:

hydrochloric, lactic, tartaric, glucuronic, methanesulfonic, adipic and succinic.

3. The composition of claim 2 wherein the molar ratio of drug base to acid is from about 1:

1 to about 1;

2.

4. The composition of claim 3 wherein the salt is an elsamitrucin:

succinic acid salt.

5. The composition of claim 1 wherein the antioxidant is at least one selected from the group consisting of:

sodium metabisulfite, acetone sodium bisulfite and sodium formaldehyde sulfoxylate.

6. The composition of claim 5 wherein the antioxidant is acetone sodium bisulfite.

7. The composition of claim 1 wherein the pH is about 4.

8. The composition of claim 7 wherein the salt is a 1:

1 elsamitrucin;

succinic acid salt.

9. The composition of claim 8 wherein the antioxidant is acetone sodium bisulfite.

10. A process for stabilizing elsamitrucin against oxidation comprising the steps:

(1) preparing an acid salt of elsamitrucin;

(2) dissolving the salt in a carrier;

(3) adjusting the pH of the resultant solution to about 3.5 to about 4.5 with a buffer; and

(4) admixing a stabilizing amount of an antioxidant with the buffered solution.

11. The process of claim 10 which includes the additional step of:

maintaining the buffered solution under nitrogen headspace.

12. The process of claim 10 which includes the additional steps of:

(5) purging the buffered solution with nitrogen gas; and

(6) maintaining the purged solution under nitrogen headspace.

13. A product useful for the parenteral treatment of tumors comprising a sealed container which contains:

(i) a pH 3.5 to 4.5 solution of an elsamitrucin salt in admixture with an antioxidant, and

(ii) nitrogen headspace gas.