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It's all Nano Nano.

THE EMERGENCE OF NANOTECHNOLOGY IS SET TO HAVE A SIGNIFICANT IMPACT ON THE DRUG DELIVERY SECTOR AS WELL AS THE PHARMACEUTICAL MARKET OVERALL, AFFECTING ALMOST EVERY ROUTE OF ADMINISTRATION FROM ORAL AND INJECTABLE TO INHALABLE AND TOPICAL. THE REWARDS FOR PATIENTS ARE DRUGS WITH LOWER TOXICITY, IMPROVED BIOAVAILABILITY, IMPROVED COMPLIANCE AND POTENTIALLY REDUCED COST. IN THIS ARTICLE, PAUL BREEN, EXECUTIVE VICE PRESIDENT AND HEAD OF ELAN DRUG TECHNOLOGIES, PROVIDES AN OVERVIEW OF NANOTECHNOLOGY IN DRUG DELIVERY, HIGHLIGHTING RECENT SUCCESSES THAT MOVES IT FROM THE REALMS OF FANTASY INTO REALITY, AND OUTLINES THE VARIOUS APPROACHES USED BY COMPANIES TO ACHIEVE NANOPARTICULATE DELIVERY

In the late 1990s, nanotechnology gained increasing recognition as a research topic in many disciplines including the pharmaceutical sector. Since then, the buzz word in drug delivery has been nanotechnology.

Nanotechnology is a collective term for a set of technologies, techniques and processes aimed at manipulation of matter at the molecular or atomic scale (see picture on page 251. Industry analysts are predicting the drug market for nanotechnology will be worth up to US$200 billion by 2015 [1]. At present, approximately $65 billion in annual drug revenues are accounted for by pharmaceuticals with poor bio-availability which far too often result in inefficient treatment but also, more importantly, increased risks of toxicity for patients.

Because nanotechnology focuses on the very small it is uniquely suited to creating systems that can better deliver drugs to tiny areas within the body. Last year, US President George W. Bush presented his budget for fiscal 2007 with $1.28 billion of funding being dedicated to nanotechnology through the NNI (National Nanotechnology Initiative). This is triple the investment made in 2001, the first year of the NNI and brings the cumulative total to over $6.5 billion [2].

Nanotechnology in drug delivery

In the pharmaceutical industry, nanotechnology is being embraced particularly as a means of improving or enhancing the delivery of drugs, and is considered by many as key to optimising drug delivery. Reducing drugs to nanoscale has the immediate impact of making otherwise poorly soluble drugs much more bioavailable, soluble and safer.

The goal of all sophisticated drug delivery systems is to deploy medications intact, to specifically targeted sites in the body through a medium that can control the therapy's administration by means of either a physiological or chemical trigger. To achieve this goal, researchers are turning to nanotechnology.

It is well established that for every 8,000 compounds that are screened for potential development as a drug, only one actually makes it to the market place. Poor water solubility is estimated to affect more than 40% [3] of all active substances identified through combinatorial screening programs, which results in the inability to formulate these compounds effectively.

In the clinic, conventional formulations of poorly watersoluble drugs are frequently beset with problems such as poor and highly variable bioavailability, influence of patient fed/fasted state, slower onset of action than is necessary and, for parenteral products, the undesirable side-effects associated with co-solvents. Any or all of these issues can lead to suboptimal dosing, poor clinical performance and in many cases abandonment of compounds altogether.

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Nanotechnology offers the potential to address these deficiencies and provide significant value to pharmaceutical portfolios. The opportunity to apply nanotechnology to these products and provide more effective/efficient products to patients is an obvious target for pharmaceutical companies. Reviewing the number of US FDA approvals over the past number of years, NCEs accounted for only one in four products approved, with the majority of approvals being reformulations or combinations of already approved products [4]. Indeed in 2005 several major pharmaceutical companies failed to win approval for an in-house NCE.

This NCE/reformulation imbalance is expected to continue and by 2008 the contribution of sales to reformulated products (soluble and insoluble) in the US is forecast to be almost 80% of total pharmaceutical sales (5] (see figure 1).

Commercialised products

Although many pharmaceutical products utilising nanotechnology are still in development, significant achievements have been made since the first nanoparticulate product, Rapamune, was launched in the US in July 2001. Elan Corporation, using their NanoCrystal technology, developed this product, marketed by Wyeth. The original formulation of the immunosuppressant, sirolimus, was previously available only as an oral solution in bottles or sachets and required refrigeration, as well as reconstitution in water or orange juice. The new tablet developed with NanoCrystal technology provides patients with more convenient administration and storage.

Since the launch of Rapamune, a further six products have been launched in the US.

--three additional products, all of which are delivered orally, have been launched using Elan's NanoCrystal technology

--Emend by Merck in 2003, TriCor by Abbott in December 2004 and the most recent, Megace ES, by Par in July 2005;

--the first topical product, Estrasorb developed by Novavax, a topical estrogen using its micellar nanoparticulate system, reached the market in 2004;

--Abraxane, an injectable formulation of paclitaxel, was launched in the US in February 2005.

--a further oral product, Triglide, was launched in July 2005 by First Horizon (now Sciele Pharma), incorporating Skyepharma's IDD solubilisation technology.

Annual sales of these products are currently estimated to be in excess of US$1.3 billion. With analysts predicting the nano-pharma market to grow anywhere from US$80 billion to $200 billion by 2020, it is a significant market and one that pharmaceutical companies cannot afford to ignore.

Approaches

The success of nanoparticulate approaches to the formulation of poorly water-soluble compounds has created industry awareness about the value of such compounds and provided an impetus for pharmaceutical companies to develop additional nanotechnology approaches to solving the problems of drug delivery.

The approaches fall into two broad categories, namely attrition--grinding particles down to sub-micron size, and controlled crystallisation-which is in effect growing them.

Attrition: The NanoCrystal technology, from Elan's Drug Technologies group, is an example of an approach using attrition (see Figure 2j. It involves wet-milling micron drug crystals to a nanometer size and stabilising these particles against agglomeration by adsorption of stabilisers on their surface. Baxter Healthcare is also developing microfluidisation/ homogenisation techniques to prepare sub-micron particulates to injectable drug delivery.

Controlled crystallisation: Controlled crystallisation is principally achieved using supercritical fluid technology. This technology has been used in the food industry for many years, for example in decaffeinating coffee, but has yet to be used for an approved drug.

Two main approaches of controlled crystallisation are in development: RESS (rapid expansion of supercritical fluid), and GAS (gas anti-solvent recrystallization). RESS is used for compounds that are soluble in supercritical fluids. The resultant solution is subjected to a rapid reduction in pressure and/or a rapid elevation in temperature, causing the solute to emerge from solution. If the conditions are optimised then submicron particles can be generated. Companies developing RESS approaches to crystallisation include Lavipharma, which has a proprietary supercritical fluid technology that can change the shape and dispersal of the particles by adjusting the engineering parameters.

GAS processing is used for compounds that are not soluble in supercritical fluids. In this process, the compound is first dissolved in an organic solvent and is then re-crystallised by admixing with the supercritical fluid. Again, if the conditions are optimal, submicron particles can be generated. Bradford Particle Design's SEDS (Solution Enhanced Dispersion by Supercritical Fluids) is an example of GAS.

Besides GAS and RESS there are a number of hybrid approaches to controlled crystallisation including Eurand's Biorise technology, and a range of approaches from Eiffel Technologies.

Challenges

Successful approaches to the formulation of poorly water-soluble nanoparticulate compounds must be able to deliver nanoparticles effectively in small quantities, in the 10-50 mg range for clinical trials, as well as large scale for commercial requirements. The nanoparticles must also be suitable for secondary processing into finished dosage forms, be that for oral, parenteral or pulmonary delivery.

Converting nanoparticle-sized suspensions into solid dosage forms using conventional processing equipment (secondary processing) and retaining the benefits of the suspension is a major challenge in realising the commercial potential in poorly water-soluble drugs.

For solids, four major processing approaches using conventional equipment are being utilised: spray coating in fluid bed driers; spray granulation in fluid bed driers; high-shear granulation; and spray drying. The powders are then blended with additional excipients and compressed into tablets or capsules.

However, each delivery route does present its own challenges. For example, although a liquid suspension can be administered via injectable and pulmonary routes, sterilisation of injectable products and obtaining a narrow particle size range for pulmonary delivery may prove too difficult for some nanoparticulate technologies to achieve.

Furthermore, combining nanoparticulate technologies with other already established drug delivery technologies may bear rewarding results. Combining the technology with other oral drug delivery technologies such as oral controlled release, delayed release, and pulsatile release, will provide both broad and novel delivery opportunities.

For nanotechnology to have a significant impact on poorly water-soluble molecules it must be:

--capable of being rapidly utilised in discovery at the milligram scale with a standardised cost-effective approach;

--scalable up to commercial production and use GRAS (generally regarded as safe) excipients;

--capable of being formulated into conventionally acceptable dosage forms, such as tablets, using conventional secondary processing equipment

--provide proprietary protection

Future

We have come a long way since the physicist Richard Feynman in his lecture "There's plenty of room at the bottom" first laid out the concept of nanotechnology in 1959 [6] The era of nanotechnology in the pharmaceutical industry has begun with the approval and launch of the first drugs in the US. Over the next decade the benefits of enhancing the dissolution rate of poorly water-soluble drugs through nanoparticulate technologies will be more greatly appreciated.

The use of nanotechnology in the discovery arena may also prove a fertile path and significantly speed the rate of drug development by preventing the need for difficult formulation or even medicinal chemistry work. In addition, nanotechnology will allow the use of previously unusable insoluble compounds at the early screening stage. New classes of molecules for development into pharmaceuticals may also result from this technology. The next applications of the technology such as biologically-active nanoparticles for both disease detection and elimination may not just be a pipe dream. Future developments in nanotechnology will be interesting to observe.

References

[1.] Susquehanna Financial Group LLLP; Griffin Securities Inc

[2.] National NanoTechnology Initiative website, Sept 2006.

[3.] Lipinski C "Avoiding investment in doomed drugs", Current Drug Discovery 2001

[4.] FDA Website, accessed September 1st, 2006

[5.] BCC Report "US ethical drug market, Strategies for Sustained Growth", April 2004.

[6.] www.its.caltech.edu/~fenyman/ plenty.html

Megace ES Case Study--patient benefits through nanotechnology

Megace was on the market for the treatment of anorexia and significant weight loss in patients with AIDS. However this compound, which was used to stimulate appetite, was a thick viscous liquid that was difficult to swallow and had to be taken with food. Using the NanoCrystal technology, a superior, more palatable product with a significantly lower dose than the original product was formulated. The viscosity was reduced 16-fold, the volume swallowed reduced by 75% and probably most significantly, it could be taken with or without food--a significant benefit for those with poor or no appetite.

FOR MORE INFORMATION

NanoCrystal technology

www.elan.com/EDT
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Title Annotation:DRUG DELIVERY
Author:Breen, Paul
Publication:Pharma
Date:May 1, 2007
Words:1873
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