Aphios Corporation

Betulinic Acid

Betulinic acid, a pentacyclic triterpene, is a component of the bark of the white birch tree, Betula alba. The tree is fast growing and abundant in North America and Europe. The raw material is readily available in large quantities since birch bark is considered a waste product in the pulp and paper, and furniture manufacturing industries.

Betulinic acid is a pentacyclic triterpene that has demonstrated cytotoxic activity specific for melanoma cells both in vitro and in vivo. In vitro, this melanoma-specific cytotoxicity occurs through apoptosis; however, this mechanism is not well understood. When administered intraperitoneally to athymic mice bearing human melanoma xenografts, betulinic acid is concentrated in the tumors, resulting in rapid tumor regression with no observable toxicity to the animal even at high doses (e.g., 500 mg/Kg body weight, i.p.). Direct injection of betulinic acid into the tumor of xenografts induced apoptosis within the tumors (Pezzuto et al., 1999).

Betulinic acid is relatively nontoxic, and found in the bark of white birch at concentrations of up to 1 to 2% by weight. Betulin, its non-bioactive precursor, is also found in the bark of white birch at concentrations of up to 25% by weight. Betulinic acid, the bioactive target, can be manufactured from betulin in a 2-step semi-synthetic process (Jones oxidation [CrO3/H2SO4/acetone/0°C], NaBH4 reduction and re-crystallization in methanol) with an overall yield of approximately 71% (Kim et al., 1997). This process may, however, be difficult to scale because of the solvents utilized and their expense.

Aphios Corporation has developed an improved process for manufacturing betulin and betulinic acid from birch bark. The process utilizes Aphios' SuperFluids™ CXP manufacturing technology and proprietary downstream purification processes. Research leading to these developments was made under Phase I&II Fast Track Small Business Innovative Research (SBIR) contracts from the National Cancer Institute (NCI), United States National Institutes of Health (NIH).