Bridging the blood brain barrier
brain barrier is being developed in a bid to open the gates to
previously unusable compounds for the treatment of central nervous
system (CNS) disorders.
LipoBridge, under development by biotech heavyweight Genzyme's pharmaceuticals division, promises to offer a serious helping hand to firms hoping to come up with a new generation of CNS products, finally allowing therapeutic compounds otherwise unable to pass across the infamous blood brain barrier to make their way through.
The technology, presented at the Controlled Release Society annual meeting in California last week, is currently in advanced stages of pre-clinical development and could help conquer one of the major obstacles in drug delivery.
"The blood brain barrier is a physiological deterrent to the introduction of large molecules to the central nervous system," Genzyme Pharmaceuticals' Peter Hoffman said during his presentation last week.
"There are lots of compounds active against CNS disorders but a very high percentage of are discounted because they can't cross the blood brain barrier to reach the site of disease."
According to Hoffman, 99 per cent of all potential CNS are drugs are larger than 500 Daltons, and thus automatically rejected by the blood brain barrier which simply will not allow molecules this large to pass.
Although some approaches (such as trans-cranial injections or the use of carrier molecules) have been employed to try and circumvent the challenges presented by the blood brain barrier, they can lead to unpleasant side effects and can be somewhat inefficient.
However, the LipoBridge technology may be able to change all that according to its developers.
Using the company's technology, the therapeutic active agent is formulated with short chain oligoglycerolipids to facilitate transport across the blood brain barrier.
The LipoBridge formulation interferes with the barrier, temporarily opening up the tight junctions and allowing drug compounds to cross to the CNS.
The company's research has shown that it takes just a single molecule to open up the tight junctions, which remain open for a very short period of time thus reducing the risk of other unwanted molecules crossing over, and the blood brain barrier remains in tact following the drug delivery.
A typical formulation for parenteral delivery would involve 70mM of LipoBridge mixed with the desired drug compound in an aqueous buffer to form a liquid dosage form.
According to Genzyme, LipoBridge formulations have been shown to be stable at 25°C for 12 months, and 40°C for three months, providing the compound itself is stable.
LipoBridge itself forms a clear suspension of nanoparticles in water, can solubilise or stabilise some drug compounds, is non-immunogenic and is excreted unmetabolised.
According to Genzyme, as well as showing success delivering hydrophilic and hydrophobic actives, small and large molecules, and the ability to deliver in all therapeutic doses, using the LipoBridge technology can also result in a significant increase in concentration and absorption levels of the therapeutic agent than with traditional methods.
In in vivo studies with rats using the chemotherapeutic drug cytostatic A, research showed that delivery to the brain increased over a hundred fold without toxic effects, and also resulted in higher survival rates in some cases.
So far, LipoBridge formulations have been administered via the inter-arterial, intravenous and oral routes.
David Wyatt, senior director of commercial development at Genzyme Pharmaceuticals, told in-PharmaTechnologist.com that dozens of pharma firms have shown an interested in getting their hands on this promising technology.
"It offers a paradigm shift in CNS therapy," he said.
"The first company to use LipoBridge will see real dividends."
With around 23 per cent of all R&D involving searching out new treatments for CNS disorders, but 99 per cent of all potential CNS drugs currently exceeding that critical mass to make them viable for crossing the blood brain barrier, a magic ticket in the form of LipoBridge could make a vast difference to the CNS therapy landscape when it becomes available in 12-15 months' time.
Genzyme has also teamed up with UK firm Pharmidex to offer a consultancy service to companies interested in applying the LipoBridge technology to their CNS drug compounds.
The Cerense programme allows companies to evaluate whether compounds that usually exhibit poor permeability across the blood brain barrier can in fact be improved and become potential CNS therapies through the use of Genzyme's LipoBridge technology.
By combining the technology platform with Pharmidex' assessment expertise, an interested party can determine whether the patent life of an existing product could be profitably extended, or whether a previously unusable compound could be made viable, by using Genzyme's product.
"Cerense has real potential to reduce the cost, time to market, and risk inherent in developing products for the central nervous system," says Dan Hayden, senior vice president and general manager of Genzyme Pharmaceuticals of the collaboration.
