Tiny Fat Bubbles Deliver Lifesaving Drugs
A unique drug delivery system, liposome encapsulation, holds great promise to improve the efficacy of some drugs, while reducing their side effects. With the goal of "taking one new drug into clinical trials each year," NeXstar Pharmaceuticals, Inc. (Boulder, Colo.) now has two liposomal products on the market—AmBisome, an antifungal agent, and DaunoXone, an anticancer formulation. The firm's third offering, MiKasome, is well on its way in clinical trials.
MiKasome, a liposomal formulation of the potent antibiotic amikacin, demonstrated none of amikacin's toxic effects at doses studied in Phase 1 clinical trials. Compared to conventional amikacin therapy, it maintained both a longer half-life and a more constant antibiotic level for an extended periods. Phase II studies will look at MiKasome's effectiveness in treating chronic urinary tract infections. Then next year, it will be tested for hospital-acquired pneumonia and bacterial lung infections in patients with cystic fibrosis, says the company.
The liposome-making process is relatively simple, with precedents in the milk industry. As NeXstar vice president of drug delivery research, Paul Schmidt, explains, "A colloidal suspension is made by running sterile water for injection, phospholipid molecules, and maybe some cholesterol, through a homogenizer machine. While the process is similar to homogenizing milk, we've modified it substantially to meet pharmaceutical standards. The end result is an almost clear solution of liposomes which have been formed into their little bubble-like structures."
The actual process by which these "tiny fat bubbles" hold a drug depends on individual drug characteristics. If insoluble in water, a drug will be incorporated into the lipid bi-layer structure, not in the central compartment, while a water-soluble compound will be encapsulated in the central water space surrounded by the lipid bi-layer.
Drugs are added to the liposome in one of three ways. Drugs that are not water soluble, like the amphotericin B in AmBisome, are introduced with the phospholipids, before the homogenization process. With the water-soluble amikacin in MiKasome, a passive capture technique is used. The drug is added to the water to make the colloidal suspension of liposomes, and in a secondary step, any drug not captured by the liposomes is removed from the solution. In a third process called "active loading," a chemical reaction forces a water-soluble drug into the liposome center space. For expensive drugs, like the daunorubicin in Dauno-Xone, active loading is the preferred method.
Researchers at NeXstar have found that some drugs are virtually impossible to maintain in a liposome for any length of time. One such drug, Toxol, the only drug known to be effective against ovarian cancer, requires a toxic additive to solubilize it for administration. Liposomes hold the promise of serving as a non-toxic carrier for Toxol.
Founded in 1995 from the merger of NeXagen, Inc. and Vestar, Inc., NeXstar is involved in the discovery, development and commercialization of pharmaceutical products to combat life-threatening illnesses. In addition to their liposomal technology, the company has developed novel drug-discovery processes. Their Selex combinatorial chemistry provides a method for searching enormous libraries of nucleic acids to discover drug candidates, called "aptamers," most likely to prove useful for specific therapeutic targets. The company's leading aptamer to-date is a VEGF-inhibitor (Vascular Endothelial Growth Factor), which may be beneficial to patients with macular degeneration, the leading cause of adult onset blindness.
Other products in NeXstar's portfolio include Parallel Selex, a small molecule combinatorial chemistry method that may produce small-molecule, orally available drugs, and PASS, a fast and cost-effective means of commercially manufacturing synthetic, single-stranded nucleic acid chains (oligonucleotides).
by Laurie McCarthy