Bristol Metformin/Glyburide Patent Could Extend Glucophage Exclusivity

Bristol has a patent application pending that covers low-dose combinations of metformin ( Glucophage ) and glyburide.

The patent application describes "a method for treating type 2 diabetes in drug naive patients, employing a low-dose formulation which includes metformin and glyburide." The patent appears to cover separate administration of metformin and glyburide in addition to Bristol's fixed-dose combination Glucovance .

"The low-dose pharmaceutical formulation containing metformin in combination with glyburide may be administered orally in the same dosage form or in separate oral dosage forms or by injection," the international patent application published by the World Intellectual Property Organization states.

The pending patent raises the stakes for generic companies seeking approval of metformin.

Multiple ANDAs are "approvable" at FDA pending a decision on Bristol's arguments that pediatric labeling changes for metformin block generic approvals (¹ (Also see "Metformin Generics Are "Approvable"; Barr Says Delay Helps Other Generics" - Pink Sheet, 15 Oct, 2001.), p. 9).

The pediatric exclusivity reauthorization legislation would create a mechanism for approval of ANDAs that do not have the same pediatric information as innovator drugs. Bristol is understood to be urging legislators to take steps to ensure that the bill does not affect metformin or else face a constitutional challenge (see ² ).

The metformin/glyburide patent application has apparently been pending for two years. The international filing date was Oct. 13, 2000, and the application states that it "is a continuation in part of U.S. application serial no. 09/432,465, filed Nov. 3, 1999 (attorney file LA0046)."

Bristol presumably expects the patent to be issued ahead of the expiration of Waxman/Hatch exclusivity for Glucovance on July 31, 2003.

The combination application refers to another pending patent, apparently related to a novel salt of metformin. "The term 'metformin' as employed herein refers to metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, the metformin (2:1) fumarate salt, and the metformin (2:1) succinate salt as disclosed in U.S. application serial number 09/262,526 filed March 4, 1999," the application says.

The application also cites the basic metformin patent (3,174,901), which was issued March 23, 1965. That patent covers pharmaceutically acceptable salts of metformin, including hydrochloride. The marketed formulation of Glucophage is metformin HCl.

The combination patent application seeks to patent the discovery that "the low-dose formulation has at least substantially equivalent efficacy in treating type 2 diabetes as compared to formulations containing higher doses of metformin and/or glyburide, but with substantially reduced side effects."

Under the patent, "metformin will be employed in a weight ratio to the glyburide in the range from about 1,000:1 to about 10:1, preferably from about 400:1 to about 50:1, more preferably from about 200:1 to about 100:1."

Glucovance tablets are available in glyburide/
metformin dose combinations of 1.25 mg/250 mg, 2.5 mg/500 mg and 5 mg/500 mg. Labeling states that dosing "must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glyburide/2,000 mg metformin."

"The low-dose formulation employed in the method of the invention will include a starting 'low-dose' of the active anti-diabetes drug components, that is a starting dosage for such drug prescribed in generally accepted medical practice in the first-line therapy of treating diabetes," the application states.

The starting dose for Glucovance as initial therapy is 1.25 mg glyburide/250 mg metformin once or twice daily with meals. The recommended starting dose for Glucophage is 500 mg twice a day or 850 mg once a day with meals; the starting dose for the extended-release Glucophage XR is 500 mg once daily.

If the patents are issued and listed by Bristol in the "Orange Book" before the pending generics are approved, the ANDA applicants would have to file challenges to the new patents, triggering an automatic 30-month stay of approval.