Window of opportunity

Geoff Tovey discusses the use of alternatives to injections to administer drugs, and ensure that they reach their intended destination

With US$20bn (€20.2bn) of currently patented drugs coming off patent within two years, there is a need for drug companies to prolong the value of their products to maintain profit levels. One of the ways of managing product lifecycles is to move to a drug delivery system. This can be done with the help of a drug delivery company, and can generate royalty income for 15 years or so. However, perhaps not surprisingly, pharmaceutical companies are reluctant to share r&d work on their NCEs with external companies. The other perceived difficulty is that using a drug delivery system (DDS) is often seen as a failure of the NCE, whether this be a solubility issue or other ADME problem.

There are exceptions to this attitude, notably where the drug cannot be administered without a delivery system. This is often the case with the oral delivery of peptides and proteins, something that is growing with the explosion in the nutraceutical market.

While there have been developments in the dosage form of oral drug delivery over the past 20 years, including fast dissolvers, electrostatic coat and supercritical fluid methods, the delivery of large biotech molecules remains elusive. Drug delivery technologies are an essential tool for pharma and biotech companies.

Already more than 10% of all pharma sales are in a drug delivery system, and this is expected to grow at double digit rates for the next five years at least.

injection alternatives

The need for a good DDS is simply that drugs and new molecules in r&d are now more potent, selective and complex. However, they are also often less stable with respect to time and conditions, hence many drugs are administered by injection. With a significant number of patients either having a fear of injections or preferring the oral route, the search for new DDSs is imperative. In 2001, 15% of the industry's r&d was focused on DDSs, with 50% of that on the oral route.

The delivery of a protein by a non-invasive route is certainly a prominent goal within the pharmaceutical industry. It would greatly increase patient compliance and expand the market for release agents. However, the challenges are formidable, as reflected by the fact that although insulin has been used clinically for more than 70 years, it is still given exclusively by daily injection. Possible non-invasive routes include nasal, buccal, rectal, vaginal, transdermal, ocular and pulmonary.

There are two potential barriers to drug absorption: permeability and enzymatic barriers. The nasal and pulmonary routes tend to show the greatest promise. The oral route would be the most popular route, but despite extensive investigation, strategies to prevent degradation and poor absorption in the GI tract have proved to be of limited value, particularly for macromolecular proteins. Of course, the best absorption occurs in the area in which absorption is meant to take place in the body. So the duodenum, which has a large, highly absorptive area, is the ideal place for administering drugs. Further down the GI tract, and into the colon the body is interested in the uptake of water, and is not designed for drug uptake. The best absorptive processes take place in the upper GI tract, but the degree of effectiveness is drug dependant.

The solubility/permeability paradigm, as it is known, is set out in figure 1. When the dosage form is administered, it has to overcome two barriers before reaching the systemic circulation. First the drug has to be dissolved to form a drug solution, and then it has to pass through the barrier cells into the blood. Simply stated, this is achieved in various stages.

The drug is conveyed to the absorption site. Dissolution may occur at or before reaching this site. This is followed by absorption through the membranes and then away from the absorption site into general circulation.

One way to subdivide the drugs in terms of oral needs is to look at their biopharmaceutical classification (figure 2). For Class I drugs, with high solubility and permeability, problems can still occur. The DDS has to ensure that the drug is kept within the therapeutic range (figure 3). Figure 3a shows that the drug is so readily absorbed that its concentration goes above the therapeutic range. Figures 3b and 3c show some sort of DDS has been added to reduce the absorption to levels that are within the therapeutic range.

Such effects are also a function of the contact time, a person's metabolism, and food impact, i.e. whether the patient has fasted or not.

Class II drugs have limited solubility, but once this has been overcome the permeability is high, meaning that the drug can pass through the GI barrier cells and into the blood stream without problem. Class II technologies are centred on getting the drug from the dosage form into solution, as shown in figure 4 (highlighted in red). This can be achieved by using solid dispersions, microemulsions, and stabilised sub-micron size reduction processes.

The Class III drugs are those that have permeability problems, but no solubility issue (figure 4, highlighted in blue). The problems associated with limited permeability are shown in figure 5. There may be an overall problem or the drug may be site specific. It may be that the drug is absorbed into the GI barrier cells, but is then destroyed before it can pass into systemic circulation. Finally it may just efflux, and not enter the cell at all.

Again there are DDSs that can overcome these problems. Methods include oral vaccine systems, biodegradable micron/submicron systems, M-cell targeting/adjuvants, GI receptor targeting and activation, novel absorption promoters, gastro retentive systems and device/dosage forms.

Class IV drugs remain the most difficult to absorb non-intravenously, as they exhibit both poor solubility and poor permeability. However, drugs in this group do exist, including the anti-cancer drug Taxol.

As more advanced drugs are produced, the need to deliver them to the specific site becomes more important, as does the solubility/permeability paradigm. Expanding knowledge in this area requires a range of integrated models to have any chance of success, and for many compounds this may be an unrealistic goal. A broad technology base is needed to focus on addressing all aspects of drug absorption - physiological and physicochemical, as well as pharmaceutical.

However, there are always business pressures and these must be understood. The early application of technology to leverage product opportunities is essential in justifying continued investment. This is also true for IP.

challenges ahead

The knowledge so far obtained suggests that many new drugs will need tailor-made delivery systems, and that the gestation of such a system can take as long as a new drug to formulate. There are challenges that can be overcome by making the use of material sciences.

New material science technologies have improved options to target or modulate the rate of drug delivery (see below).

Other methods for new momenta in drug delivery include improved stability in hostile environments, and technologically advanced delivery systems, all of which are aimed at increasing patient compliance and, hence, reducing the cost of non-compliance.