APV FOCUS GROUP DRUG DELIVERY

2.7 DUREDAS Technology (DUal RElease Drug Absorption System)
DUREDAS, as the name would suggest, is a bilayer tablet. It therefore can be used to provide immediate or sustained
release of two drugs or different release rates of the same drug in one dosage form [5-6]. The DUREDAS technology
was initially developed for OTC controlled release analgesics. In this case one layer of the tablets was formulated as an
immediate release granulate to achieve rapid onset of action, while the second released the drug slowly to provide sustained
pain relief.
2.8 Other Technologies
The PharmaZome ® and INDAS technologies were developed by Elan but are no longer actively promoted [6].
PharmZome consisted of drug-loaded microparticles in the size range 5 to 125 microns produced by either spray drying
or emulsion techniques. They could be used for taste-masking and/or to achieve controlled or delayed release, while
their particle size range conferred good mouth-feel and enabled their incorporation into formulations such as chewable
and effervescent tablets and powders for reconstitution [10].
INDAS technology (Insoluble Drug Absorption System) was a method of improving drug solubility by converting an active
into the amorphous form by a combination of energy, excipients and processing and stabilising it using a crosslinked
polymer [10]. It was superseded by the NanoCrystal technology.
3 Technologies Developed in Part by Elan
This section deals with some technologies that were initially or partially developed within Elan or its joint ventures but
are no longer part of its portfolio. Most of these technologies were divested in the wake of a dramatic fall in the company’s
share price following the US Securities and Exchange Commission’s launch of an investigation into the company's
accounting practices in 2002. As before, only technologies that have been commercialized or are in late clinical development
have been included.
3.1 Transdermal Systems
Prior to 2003 Elan had a long association with transdermal delivery systems. It developed one of the first nicotine
patches, Prostep ® , which was approved in 1992 [11]. It had a fully owned subsidiary, Elan Transdermal Technologies
Inc. (ETT), which employed 100 staff and was able to provide clients with research, development, clinical trial manufacture
and commercial production services. In 2003 ETT was sold to Nitto Americas Inc., the US subsidiary of the Japanese
giant, Nitto Denko. It still operates under the name Aveva Drug Delivery Systems (Miramar, Florida) [12].
3.2 GIPET (Gastrointestinal Permeation Enhancement Technology)
Merrion Pharmaceuticals Ltd (Dublin, Ireland) was set up in 2004 to develop technologies based on permeation enhancement
that it had acquired from Elan for oral peptide and small molecule delivery. Isis licensed similar technology
from Elan for oral gene delivery [13, 14]. As a result of advancements on the original Elan technology, GIPET, is now
the basis of the company’s pipeline of oral products, and the subject of a number of licensing and collaboration agreements
with companies such as Novo Nordisk [15].
GIPET is based on the production of enteric coated tablets or capsules containing drug formulated together with medium
chain fatty acids (typically sodium caprate) or medium-chain fatty acid derivatives or microemulsion systems based on
medium-chain fatty acid glycerides [16]. It has been shown to act as a permeation enhancer and improve the bioavailability
of Biopharmaceutical Classification System Class 3 compounds less than 10kDa in size i.e. those with good aqueous
solubility but poor membrane permeability [17]. These include alendronate, low molecular weight heparin and insulin
[16]. The enteric coating of GIPET dosage forms protects the active from degradation and prevents active and enhancer
release until the dosage form has reached the small intestine. Once in the more alkaline environment of the
duodenum, both drug and enhancer are released simultaneously. The enhancer has been shown to improve the oral
bioavailability of a variety of poorly permeable compounds by a factor of 10 to 50 [15]. The enhancer probably improves
bioavailability by a number of mechanisms including mixed micelle formation and direct effects on the intestinal wall
such as the dilation of tight junctions [16, 18].
Concerns that these effects might lead to long-lasting mucosal toxicity and result in accidental absorption of bacteria
present in the gut appear unfounded with studies carried out by Prof David Brayden (University College Dublin and ex-
Elan) and his team showing that sodium caprate did not increase the permeation of S. typhimurium across isolated rat
intestinal ileal mucosae [19]. In addition, the effects of the enhancer have been shown to be short-lived in humans with
intestinal permeability returning to normal within 40 minutes, as demonstrated by the absorption of intra-jujunally administered
polar sugars such as mannitol that are only absorbed via the paracellular route [16, 18].
Merrion’s lead product, Orazol, is a once-weekly tablet formulation of the anti-cancer bisphosphonate, zoledronic acid.
This drug is currently only available as an injectable product which must be infused once monthly [15]. Orazol is about
to enter a Phase III study that will compare its safety and efficacy as an adjuvant in the treatment of breast cancer to
placebo. The company is also investigating Orazol for the treatment of bone metastases. The company’s own pipeline
also includes a new formulation of alendronate, acyline (an oral GnRH antagonist) and MER-102 (an ultra low molecular
weight heparin). Merrion also has partnered compounds with amongst others Novo Nordisk (insulin, GLP-1 analogue and
one other), Ferring Pharmaceuticals, Rebel Pharma and a top ten Pharma (3 compounds) [15].
APV Drug Delivery Focus Group Newsletter – 2/2011 Page 10 of 15