LifeGuide

[Treatment Horizons]

by Chael Needle

Par Pharmaceutical Companies, Inc., has submitted a New Drug Application to the FDA seeking marketing clearance for megestrol acetate oral suspension NanoCrystal Dispersion (NCD). This NCD formulation—an extension of Par’s currently marketed appetite stimulant, megestrol acetate oral suspension (the generic version of Bristol-Myers Squibb’s Megace Oral Suspension)—hopes to be indicated for the treatment of anorexia, cachexia, or any unexplained, significant weight loss in AIDS-diagnosed individuals alongside past formulations.

This formulation uses NCD technology to make megestrol acetate more bioavailable (or more easily accessed by the body’s system) than other formulations currently on the market. NanoCrystal Dispersion “is a newer technology to the pharmaceutical industry,” says Dr. Robert A. Femia, executive vice president of Scientific and Regulatory Affairs at Par. “This technology has been used in other areas of manufacturing unreleated to pharmaceutical compounding. But recently it’s been recognized as potentially having a benefit for compounds that are water insoluble, and not necessarily well-absorbed.”

Water insoluble, not necessarily well-absorbed—this describes the active ingredient in megestrol acetate oral suspension, at least in the currently marketed drug’s tablet or oral suspension forms. In pharmacokinetic (how a drug is absorbed, distributed, metabolized, etc., by one’s body) studies, the researchers, led by Dr. Femia, have found that NCD technology dramatically reduces the particle size of the active ingredient, from the micrometer particle size, say, down to the nanometer particle size.

 Says Dr. Femia: “When you reduce particle size, you also dramatically increase total surface area of the drug per unit weight of the drug. This facilitates dissolution of the drug substance, which in turn offers the opportunity to dramatically increase the bioavailability of the drug substance, since, for something to be bioavailable, the dosage form must have good dissolution characteristics.”

Increasing the opportunity for the drug to become more permeable and bioavailable affects dosing. Instead of a 20 mL a day dose required for the current oral suspension, only a teaspoon of liquid a day is required with the NCD formulation. Also, “the NCD technology affords a more solution-like drug product, which is nowhere near as viscous as the currently available oral suspensions. Because of that, we believe that it will in itself facilitate patient compliance—a teaspoon is a less burdensome dose than a 20 mL cup of a rather viscous and, according to some, rather soapy-tasting solution.”

 Researchers also found that the currently available products showed a “tremendous” food effect—in this case, a fed state allows the drug to stay in the blood at higher levels and work better. The NCD formulation, however, achieves comparably high blood levels but under fasting conditions as well as fed conditions. The NanoCrystal Dispersion formulation’s pharmacokinetics seem to be far less dependent on the presence of food than currently available oral suspension versions of this drug substance.

“Consider the implications of the disease state of cachectic wasting—the individuals are more or less in a naturally fasted state in that they are not very motivated to eat. If a drug has a tremendous food effect but yet the individuals taking the drug are not motivated to eat, then you have a potential issue in terms of onset of efficacy and the ability of the individuals to remain compliant (as they don’t necessarily see results in the time frame they would like),” says Dr. Femia.

As Par awaits word from the FDA, Dr. Femia notes that they have an ongoing study in people with AIDS to assess the onset of efficacy of the NCD-based drug product compared to those currently available oral suspensions as evidenced by weight gain. Par is also considered pairing this technology with other pharmaceutical products but this is still in the early planning stages.

Chael Needle wrote about recent resistance studies in the April issue.