Emerging and Novel DDTs
DDTs presented that have the potential to make significant contributions to the challenges imposed by insoluble and/or low-permeability compounds include: gastric-retention systems, protein PEGylation, microspheres, drug-device combinations for inhalation or enhanced transdermal delivery, and novel materials.
Although some of these technologies have been utilized for years, recent improvements have enhanced their utility.
Gastric retention, the use of DDT to prolong the residence and release of orally administered drug substance in the upper GI tract, has long been considered a desirable mechanism to increase the duration of action of small molecule therapeutics that have a narrow absorption window in the upper GI tract. Historical results have not met this need.
Bret Berner, Ph.D., vp, product development of DepoMed (Menlo Park, CA), says, "In the past, some gastric-retention technologies attempted to use large particles or devices, potentially resulting in adverse effects on GI function. Our formulations provide particles 1213 mm in diameter, just too large to cross the pylorus in the fed stomach.
"We obtain about six hours of gastric residence, which enables 89 hours of drug delivery and once-daily dosing for many drugs administered 34 times daily in other formulations."
DepoMed's most advanced products are once-daily formulations of metformin for type 2 diabetes and ciprofloxacin for urinary tract infections. Each has been studied in over 1,000 patients and both products have received approval by the FDA.
While no one was claiming oral delivery of peptides and proteins, the long-awaited inhaled formulation of insulin may be close to market. The NDA for Exubera developed by Nektar Therapeutics (San Carlos, CA) and Pfizer was submitted in March. Many other inhaled formulations of insulin and other peptides and proteins are in development.
Dr. Wilding is one of many who believe that the first approval of a protein delivered with a novel delivery will favorably impact the market. "A green light for Exubera could change the perceived risk profile for novel delivery technologies, leading to a resurgence of interest in pulmonary technology for systemic delivery and more investment in transdermal, nasal, and buccal technologies," he said.
PEGylation technology has improved the delivery of injectable proteins. Annual worldwide sales of PEGylated drugs total about $6 billion. According to Mary Bossard, Ph.D., director of biopharmaceutical research, at Nektar, PEGylation has been shown to enhance bioavailability, optimize pharmacokinetics, reduce toxicity, and improve solubility and stability.
Nektar's Advanced PEGylation is based on PEGs selected from a broader range of molecular weights (560 kDa), functional groups, and improvements in attachment chemistry. PEGASYS, once-weekly alpha-interferon for the treatment of hepatitis C, was developed by Roche using Nektar's Advanced PEGylation to compete with Schering's PEG INTRON, a PEGylated alpha interferon.
PEG Intron was one of the first PEGylated therapeutic proteins and was an improved formulation of non-PEGylated Intron A, recombinant interferon alpha 2b.
"PEGASYS is made with a 40 kDa branched mPEG-NHS reagent. One PEG molecule is bound to a lysine on each alpha-interferon, providing high in vivo efficacy. PEG INTRON is also mono-PEGylated, but uses a 12kDa PEG with binding to 14 different sites, primarily histidine residues.
PEGASYS provides higher and more uniform blood levels," according to the firm. PEGASYS captured 60% of the market within two years of launch, virtually all at the expense of PEG INTRON.
Epic Therapeutics' (Norwood, MA) Promaxx is an aqueous-based formulation technology that produces microspheres for inhalation or injection with over 95% drug loading. The manufacturing process can be controlled to produce microspheres from 0.4 to 50 microns in diameter within a narrow particle size range that can contain proteins, nucleic acids, or small molecules, says Larry Brown, Sc.D., CTO of Epic.
Epic has developed Promaxx formulations of insulin, alpha-1-antitrypsin, and hGH for pulmonary delivery. Most of the development has been conducted with dry powder inhalers, a limited amount with HFA-based inhalers.
The target particle size depends on the desired site of uptake. For example, microspheres 13 microns in diameter containing insulin are targeted to the alveoli for systemic delivery.