WO1985004552A1

WO1985004552A1 - Solutions of mitomycin

Info

Publication number: WO1985004552A1
Application number: PCT/US1985/000575
Authority: WO
Inventors: Norman E. Hoffman
Original assignee: Baxter Travenol Laboratories, Inc.
Priority date: 1984-04-10
Filing date: 1985-04-05
Publication date: 1985-10-24
Also published as: JPS61501848A; EP0179092A4; EP0179092A1

Abstract

A buffered aqueous solution of mitomycin is made having a pH of between 7.5 and 8.0. This solution can be stored, without freezing, for at least 15 days without substantial reduction in mitomycin activity.

Description

SOLUTIONS OF MITOMYCIN

TECHNICAL FIELD

Mitomycin is sold as a cancer chemotherapy agent which has antibiotic activity by Bristol Meyers under the trademark 5 MUTAMYCIN®. See the 38th edition of the Physician Desk Refer¬ ence®, page 750 (1984).

Typically, mitomycin is provided to patients intermit¬ tently at six to eight week intervals.

Recently, there is a growing interest in the use of con- 10 tinuous therapy as a new mode of administration of antitumor agents. The patient may be ambulatory, making use of an adminis¬ tration pump of known design, for example, the pump as shown in Cromie U. S. Patent No. 4,416,595. The patient may receive chemotherapy on a 24-hour a day basis, often with the highest ^•-^•5 concentration of chemotherapy agent being administered to the exact tumor site by means of a catheter. Thus, by this con¬ tinuous administrat on process, cancer can often be controlled in a manner better than a therapeutic regime using a general ad¬ ministration of mitomycin or other antitumor agent. 20 However, for use in continuous therapy, solutions of mitomycin must be provided having better stability than currently available reconstituted mitomycin solutions. For example, the official package circular for Bristol Meyers MUTAMYCIN states that MUTAMYCIN, reconstituted with Sterile Water for Injection to _s*. 25 a concentration of 0.5 mg. per ml, is stable for seven days at room temperature. The same product is stated to be stable at * room temperature for three hours when diluted to a concentration of 20 or 40 micrograms per ml with 5% dextrose injection, twelve hours with 0.9% sodium chloride injection, and 24 hours with sodium lactate injection.

There is a need, particularly when mitomycin is to be used in continuous therapy, for stable solutions of mitomycin having a shelf life at room temperature (i.e., 22°C) of pre- ferably at least 15 days and more, so that mitomycin solutions can be stored without the need for reconstituting them in a phar¬ macy prior to distribution to a patient, for 24-hour therapy or any other desired form of administration.

By this present invention, mitomycin solutions are dis- closed which have long shelf life in solution form, to facilitate packaging and storage of mitomycin solution. This provides a great improvement in the flexibility and convenience of mitomycin therapy. Description of the Invention In accordance with this invention, one may store, with¬ out freezing, a buffered aquόous solution of mitomycin having a pH of 7.5 to 8.0 for a period of at least 15 days. The solution can retain a mitomycin activity on the 15th day which is at least 90 percent of such activ y on the first day. Typically, the solution may contain from 10 micrograms to one mg. of mitomycin per ml. of solution.

The buffer mentioned above must be pharmacologically ac¬ ceptable so as to be suitable for administration, and should be present in its dosage form in a concentration to provide no more than a minor osmotic gradient with blood. One highly suitable buffer for this purpose is a mixture of moπosodium phosphate and disodium phosphate, which is a basically conventional and well-known pharmaceutical buffer. Other suitable buffers may be used as well.

It has been found that with the maintenance of mitomycin solutions at a pH of 7.5 to 8.0, and preferably pH 7.6 to 7.9, great improvements in the stability of the solution can be achieved. Particularly, mitomycin solutions can be provided which are stable for at least 15 days storage at room temperature, and much longer if refrigerated. By the term "stable" the intended meaning is that the amount of active mitomycin present in the solution at the end of a given period is at least 90 percent of the amount of active mitomycin present at the beginning of the period over which stability is measured.

EXAMPLE

A solution was prepared by adding to 5 weight percent dextrose injection solution the following amounts of solutes per 100 ml. of solution: 0.134 gram of disodium phosphate; 0.0105 gram of monosodium phosphate; and 5 milligrams of lyophilized mitomycin. The resulting solution has a pH between 7.7 and 7.8. Storage of the solution at room temperature (about 22°C) for 19 days resulted in less than a 10% loss of mitomycin concentration from the solution.

The above solution was clear and free from particulate matter. A solution suitable for IV administration may be prepared from the above formulation following appropriate sterilization if necessary, for example, by filtration through a 0.22 micron filter.

The above has been offered for illustrative purposes only, and is not intended to limit the scope of the invention of this application, which is as defined in the claims below.

Claims

WHAT IS CLAIMED IS:

1. An aqueous solution of mitomycin having a pH of 7.5 to 8.0, said mitomycin solution containing a buffe suitable for I.V. admin stration, to maintain said pH.

2. The solution of claim 1 in which said solution con¬ tains from 10 ug to 1 mg. of mitomycin per ml. of solution.

3. The method of storing without freezing a buffered, aqueous solution of mitomycin having a pH of 7.5 to 8.0 for period of at least 15 days, whereby said solution retains a mitomycin activity on the 15th day of at least ninety percent of said activity on the first day.

5. The method of claim 4 in which said solution con¬ tains on at least the first day, from 10 ug to 1 mg of mitomycin per ml . of solution.

5. The method of claim 4 in which said pH is 7.6 to 7.9.