Drug Delivery Report

By Kevin Bottomley
Managing Consultant, PharmaVentures Ltd, Magdalen Centre, Oxford Science  Park, Oxford OX4 4GA, UK

Introduction

First references  to nanotechnologies and drug delivery date back to the late 1970s,  as a means of improving drug bioavailability, either by enhancing aqueous solubility, prolonging  exposure and/or targeting drug compound delivery. When a technology  is determined as validated is often a debatable point but, for nanotechnology and drug delivery, evidence supports  both the technical
and commercial validation of this technology,  both for improving active ingredient  exposure and targeting delivery of therapeutics. So what is the evidence supporting validation of nanotechnology for drug delivery and what
are the prospects  for this technology?
Nanotechnology refers to the generation of therapeutic relevant matter  of between 1 and 100 nanometers. For drug delivery this includes generation of small crystalline drug forms, enhancing the exposed crystalline surface area and thereby improving aqueous solubility. Nanotechnology can also improve delivery of the active drug ingredient
to the site of therapeutic action. This can either be
by associating drug nano-particles with a carrier such as plasma albumin to improve organ targeting, or by encapsulating the active material in liposomes, to enhance compound half life and improve targeting.

Nanocrystals

The market leading technology  for the production of nano- crystalline drug forms is Elan Corporation's NanoCrystal® technology.  NanoCrystal®   particles are small particles of drug substance, produced by milling the drug substance using a proprietary, wet-milling technique.
To date,  there are four drugs on the market which have specifically exploited NanoCrystal®.
•  Rapamune®  (sirolimus) from Wyeth  received marketing approval from the US Food & Drug Administration
(FDA), in 2000.
•  Emend®  (aprepitant)  Merck, approved  by the FDA in
2003
•  TriCor®  (fenofibrate) Abbott Laboratories, launched  in
December 2004
•  Megace® ES (megestrol), Bristol-Myers  Squibb, approved  in July 2004 by the FDA
This is evidence of the technical validation of this technology  and its contribution  to providing effective therapeutics. With respect  to commercial validation, in total there are 25 published references  to deals involving third party access to this technology  (both while owned by Elan and when the technology  was developed  by Nanosystems LLC (of Eastman Kodak Co.) (Table 1). There is little information  about  individual deal values but a pointer is the deal between NanoSystems and Merck in 1998,  which has the potential  for NanoSystems to receive US$30 M in development payments,  in addition to unspecified royalties.
A related but competing technology  is Dow  Pharma's
Bioaqueous Solubilization Service, based on technology licensed from the University of Texas at Austin in
2002.  This allows generation of small crystalline forms of drugs using non-milling approaches, specifically SFL (Spray Freezing into Liquid) and EPAS (Evaporative Precipitation into Aqueous Solution). In 2004,  Dow Pharma announced a technology  access deal with Bristol-Myers  Squibb, which included fees, milestones and royalties contingent on the development of markets drugs availing of the technology.  Baxter and SkyePharma  (Dissocubes®  and NanoEdge®  respectively) and other service providers also offer proprietary technologies for the preparation of nanocrystals.

 Targeting Drug Therapies

Nanotechnology can provide a technical solution for delivering effective anticancer  agents. Liposomes: phospholipid  bilayers which encapsulate a drug, can ensure both effective exposure and targeting of the chemotherapy agent  (Table 2). These structures  provide a wrapper  for hydrophilic drugs, reducing metabolism.  The first examples of this class of therapy were licensed in the mid 1990s and, since then,  there have been a large number  of drugs which use this nanotechnology to enchance their therapeutic effectiveness.  These include DaunoXome®,  Caelyx® and Myocet®, liposome formulated versions of daunorubicin. Since the first introduction of these  drugs, the liposome technology  has developed  and matured to include surface presented polyethylene glycol (PEG) to reduce metabolism of the therapeutic, thereby increasing the half-life of
the therapeutic and exposure to the drug. Typical deal structures  include fees, milestones and in a low minority of examples undisclosed royalties. As with nanocrystals, liposomes are a mature  validated technology.

Abraxane®

Another clinically validated nanotechnology is exemplified by Abraxane from Abraxis. Abraxane (paclitaxel), approved  by the FDA in January 2005 for the treatment
of chemotherapy refractory metastatic breast cancer, uses drug nano-particles stabilised by albumin, to enhance
the exposure of the active compound, at the tumour.
This drug is the product  of Abraxis' nanoparticle  albumin bound  technology  and provides clinical validation of nanotechnology to both target  and enhance the exposure of the drugs. Targeting of drugs using nanotechnology techniques  by limiting systemic exposure can also reduce general drug induced toxicities.

Summary and Potential future developments

Drug delivery nanotechnologies exemplified by nanocrystals, liposome and nano-particle-protein conjugates are mature  technologies clinically and commercially validated. From the assembled  evidence, nanotechnologies are a valuable adjunct to the development of new therapeutics. While nanotechnology is a buzzword  which suggests  exciting need developments in clinical therapies, it is clear that  in the context of drug delivery, this is now a successfully validated technology, both therapeutically  and clinically.
The future is exciting, not only with respect  to the continued development and maturation of these established  technologies, but there is also the prospect of new technologies which promise enhanced benefits in both control of drug targeting and exposure by enhancing both efficacy and safety. Currently in clinical trials are technologies which exploit micelles, monolayer
equivalents  of liposomes; dendrimers,  regularly branched water soluble nanoparticles which can act as a carrier for hydrophobic  active compounds; and nanoshells,  nanoscale partials, which can be used to actively or passively target pathologies (such as cancers) within the body, and then release therapeutic agents.