A pharmaceutical composition for boron neutron capture therapy (BNCT), and in particular for BNCT on hepatoma is disclosed. The pharmaceutical composition contains a therapeutically effective amount of triphenylboroxin (phenylboronic anhydride) as a boron source and a pharmaceutically acceptable carrier, such as lipiodol.

FIELD OF THE INVENTION

The present invention is related to a pharmaceutical composition for boron neutron capture therapy (herein after abbreviated as BNCT), and in particular to a pharmaceutical composition for BNCT containing triphenylboroxin as a boron source.

BACKGROUND OF THE INVENTION

In U.S. Pat. No. 6,117,852, the inventor of the present invention discloses a boron-containing lipiodol pharmaceutical composition comprising lipiodol, submicron boron powder, lecithin and C.sub.12 C.sub.22 fatty acid, wherein said submicron boron powder is suspended in said lipiodol in the presence of said lecithin and said C.sub.12 C.sub.22 fatty acid such as linoleic acid. This B-lipiodol pharmaceutical composition is at least useful in boron neutron capture therapy (BNCT) of hepatoma, wherein the lipiodol has a property of a high retention in hepatoma, the lecithin has a boron carrying capacity, and the C.sub.12 C.sub.22 fatty acid has a function of rendering lecithin soluble in lipiodol. In this B-lipiodol pharmaceutical composition the submicron boron powder must have an appropriate distribution of particle sizes in order to be uniformly dispersed therein. Details of U.S. Pat. No. 6,117,852 are incorporated herein by reference.

Using BSH (borocaptate sodium) and BPA (boronophenylalanine) in clinical trails for treatment of malignant melanoma and brain tumor has been reported [Mishima, Y., et al. Lancet, 12, 388 389 (1989); Hatanaka, H. and Nakagawa, Y. Int. J. Radiat. Oncol. Biol. Phys., 28, 1061 1066 (1994); Barth, R. F., et al. Int. J. Radiation Oncology Biol. Phys. Vol. 47, No. 1, 209 218 (2000)]. Further, Minoru Suzuki et al. have studied the effects of boron neutron capture therapy on liver tumors and normal hepatocytes in mice [Minoru Suzuki, et al., Jpn. J. Cancer Res. 91. 1058 1064, October 2000].

Carolyn Pratt Brock, Robin P. Minton and Kurt Niedenzu published an article in 1987 related to the structure and thermal motion of triphenylboroxin [Acta Cryst. (1987). C43, 1775 1779].

SUMMARY OF THE INVENTION

A primary objective of the present invention is to provide a boron-containing drug, which has a selectively high retention in cancer cells to be used as a boron source in the boron neutron capture therapy (BNCT).

Another objective of the present invention is to provide a pharmaceutical composition for boron neutron capture therapy (BNCT), which has the following advantages: a compound as a boron source in the pharmaceutical composition is able to be uniformly and stably dispersed in the pharmaceutical composition; the pharmaceutical composition is stable in serum; and the pharmaceutical composition can be selectively accumulated in cancer cells with a high concentration, as well as the boron-source compound.

In order to accomplish the objectives of the present invention, a pharmaceutical composition for BNCT prepared according to the present invention comprises a therapeutically effective amount of triphenylboroxin having the following formula (I) (see Original Patent)as a boron source and a pharmaceutically acceptable carrier, such as lipiodol.

The pharmaceutical composition of the present invention is useful for BNCT on a cancer, for examples hepatoma, breast cancer and malignant melanoma.

Preferably, the pharmaceutical composition of the present invention further comprises a promoter for enhancing uptake of said carrier by the cancer cell.

Preferably, the pharmaceutical composition of the present invention further comprises a dissolving agent for enhancing said promoter's solubility in said carrier.

Preferably, said promoter is lecithin and said dissolving agent is C10 C20 fatty acid.

Preferably, the pharmaceutical composition of the present invention comprises 0.1% to 3% boron, based on the weight of the pharmaceutical composition.

Preferably, the pharmaceutical composition of the present invention comprises 15 25 mg lecithin and 0.05 0.09 ml C10 C20 fatty acid per ml of the lipiodol. More preferably, said C10 C20 fatty acid is linoleic acid.

DETAILED DESCRIPTION OF THE INVENTION

The inventor of the present application synthesizes a hydrophobic compound, triphenylboroxin (C.sub.18H.sub.15B.sub.3O.sub.3), having the following structure (I), and is the first person using it as a boron-containing drug in BNCT (see Original Patent).

Lipiodol has been used as X-ray contrast medium and lymphography contrast medium. The present inventor and her co-workers in their previously study clearly demonstrated that hepatoma cells in culture are capable of rapidly active uptake of a large quantity of lipiodol by endocytosis with prolonged retention of the lipiodol intracellularly as long as the life span of the cells [Chou F I, Fang K C, Chung C, Lui W Y, Chi C W, Liu R S, and Chan W K. Lipiodol uptake and retention by human hepatoma cells. Nucl Med Biol (1995) 22(3): 379 386]. In this invention, the present inventor employs lipiodol as a boron-containing drug carrier in view of its capability of achieving selective and high retention in hepatoma cells. It is found that triphenylboroxin as the boron-containing drug has a property of uniform dispersion in lipiodol and is stable in lipiodol. This inventor further utilizes lecithin to enhance uptake of lipiodol by hepatoma cells, and linoleic acid to increase the solubility of lecithin in lipiodol. As a result, the pharmaceutical composition prepared in the present invention is suitable for use in BNCT on hepatoma. It is apparent that the pharmaceutical composition prepared in the present invention has a great potential for use in BNCT on other cancers such as breast cancer or malignant melanoma.
 

Claim 1 of 11 Claims

1. A pharmaceutical composition for boron neutron capture therapy comprising a therapeutically effective amount of triphenylboroxin having the following formula (I) as a boron source and a pharmaceutically acceptable carrier: ##STR00003## (see Original Patent).

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