Transdermal delivery of hydrophilic drugs

New technologies have enabled the transdermal delivery hydrophilic drugs, with many benefits to the patient. Lee Schafer, from medical r&d company Dermatrends, explains

Roughly half of all the ethical drugs on the market today possess a molecular affinity for water. This affinity manifests itself in a tendency to dissolve in, mix with, or absorb water. Drugs with these characteristics are referred to as hydrophilic drugs. Drugs that are hydrophobic, on the other hand, repel water and have an affinity for oils, making them lipophilic. Now, new technologies are available that allow hydrophilic drugs to be absorbed through the skin rather than the GI tract.

Transdermal delivery through the skin has a number of advantages over oral delivery for hydrophilic drugs. Transdermal delivery leads to better absorption, greater flexibility in how the drugs are administered, and more choices for patients in how they receive these important drugs.

poor absorption

The advantage of transdermal delivery of hydrophilic drugs versus oral delivery lies in the molecular nature of the GI tract. As a lipid membrane, the GI tract possesses hydrophobic properties, thus the more hydrophilic a drug is, the more likely it is to absorb poorly through the GI tract. A well known example of this problem is sodium alendronate, a bisphosphonate, which needs to be administered in very large doses because only 0.64 % is absorbed when taken orally.

This problem of poor absorption can sometimes lead to situations where, once a hydrophilic drug has been developed, it then becomes necessary to develop a complementary prodrug that will increase absorption in the GI tract in order to make the drug effective. This prodrug increases both the cost of the drug and may carry side effects of its own. There have even been cases where development ceased on a drug because the problem of poor absorption could simply not be overcome. In other cases, hydrophilic drugs that absorb poorly must be injected, causing patient discomfort.

Delivery of hydrophilic drugs through a transdermal patch avoids all GI tract issues. However, owing to the hydrophobic nature of the skin and its role as a barrier for keeping unwanted substances out of the body, there have been challenges in this approach. Until recently, for transdermal delivery of hydrophilic drugs to be effective, it was necessary to use an active delivery system to breach the skin barrier, thereby allowing the drugs to absorb. Two examples of such technologies are microporation, which uses miniature drug-coated needles to puncture the skin, and thermal patches, which use heat to open passages in the skin.

Dermatrends, an r&d company focused on alternative delivery systems, has developed a passive transdermal patch that can overcome issues related to permeation. Laboratory tests have shown that its patented enhancer can deliver hydrophilic drugs through the skin, and the company hypothesises that this is accomplished by opening a temporary water channel that allows the drugs to be absorbed into the body without rupturing or excessively irritating the skin.

The patch with enhancer system has been tested in Dermatrends' laboratories in vitro and found to effectively deliver hydrophilic drugs with a molecular weight of up to 1400 AMU and daily dosage requirements in excess of 100 mg (with acceptable patch sizes).

better compliance

There are also reasons to believe that transdermal delivery may be preferable to oral delivery for a large number of patients for several reasons.

First, transdermal delivery potentially improves patient compliance compared with oral delivery. This is because there are no restrictions around the time that the drug should be administered or whether or not the patient may eat afterwards. In particular, multi-day patch delivery offers ease of use and is convenient, without the requirement to remember to take a drug at a specific time.

Second, there is increased bio-availability, which means that smaller doses may be used for the same drug, helping to minimise side effects. Third, the problem of first pass metabolism is avoided, as well as the peaks and troughs created by oral delivery and GI tract absorption.

A final benefit of transdermal delivery versus oral or injection is that dosage may be stopped abruptly by simply removing the patch if adverse side effects are experienced.

While transdermal delivery of hydrophilic drugs does appear to offer solutions to some common problems, it is important to remember that it is not without some challenges, ranging from medical limitations to cosmetic concerns. To begin with, the existing patches on the market are limited to small molecular weight drugs with very small daily dosages. The largest commercially available molecule delivered so far has been oxybutynin with a molecular weight of 357 AMU.

limiting factor

Permeation of the higher molecule drugs has been a limiting factor in the past. Dermatrends' enhancer system could allow delivery of much larger molecule drugs in the future. Dermatrends has successfully delivered vitamin B12, which has a molecular weight of 1380 AMU. Other systems may also be in development at other companies, all striving to increase the number of drugs that can be delivered effectively through the skin.

Dermatrends' belief is that the molecular size of the potentially deliverable drugs is likely to increase with further research; however, the largest molecular compounds, such as those used in vaccines, will continue to be problematic for today's methods.

Finally there are some challenges currently around patch placement. The rate of absorption will vary depending on the thickness of the skin, and where it is placed, the temperature of the skin, and the age and skin condition of the patient. In addition, the place that the patch is used must be changed to avoid irritating the skin.

The increased efficacy of transdermal technology should appeal to drug manufacturers, doctors and patients alike. However, while some patients might find wearing a patch easier than taking a pill, the reverse also may be true. The question of whether active patients would prefer to wear patches under their clothing versus swallowing a series of pills is open to debate. There are other cosmetic issues, such as whether applying the transdermal patch to different points on the skin would leave a temporary mark. There is also the possibility of an allergic reaction by a small number of patients, making this form of delivery unsuitable for a certain segment of the population.

The role of the consumer may prove crucial in determining whether transdermal technology will be a widely accepted alternative delivery system for hydrophilic drugs now on the market. This highlights the importance of improving existing transdermal technology to make it more versatile and consumer friendly.

improved permeation

Currently Dermatrends seeks to improve the permeation of its transdermal patch with enhancer in order to allow higher doses of a drug to be delivered via a smaller patch. It is also working to reduce irritation levels and create better and longer lasting adhesion, and is working in partnership with companies to carry out additional testing on specific compounds.

Transdermal technology promises to increase radically the effectiveness with which hydrophilic drugs are administered by reducing the need for injection as well as reducing the dosage required by bypassing the GI tract.

One potential application that possesses both medical and consumer promise is the use of a transdermal patch to treat muscle pain. Dermatrends has used its transdermal patch with enhancer system to successfully deliver sodium diclofenac, a pain medication, through the skin. It is likely that consumers would respond well to the concept of being able to place a patch containing a pain relief drug directly on the affected area. This would allow the drug to be delivered more quickly, leading to faster relief.

vitamin supplement

Another example of how transdermal technology could be used would be as a needle-free means of administering vitamin B12. Currently millions of children located in poorer countries around the world are believed to suffer from B12 deficiency, as well as several million people in North America. The symptoms of a B12 deficiency include fatigue, weakness, nausea, constipation, flatulence, loss of appetite and weight loss. A B12 deficiency can also lead to difficulty in maintaining balance, depression, confusion, poor memory, and soreness of the mouth or tongue. Inexpensive transdermal patches distributed by relief agencies operating inside these countries could go a long way towards alleviating this problem.

Finally there is an opportunity to work with existing development stage drugs that had previously been shelved due to excessive difficulties when administered orally. Dermatrends believes that, with the new transdermal technologies available, there is a real opportunity to bring new hydrophilic drugs to market that were previously not commercially viable because of their poor bioavailability.

The development of more effective transdermal delivery systems for hydrophilic drugs should increase the number of hydrophilic drugs available to patients. These systems will also make it easier for pharmaceutical companies to develop and bring new hydrophilic drugs to market, because they will no longer need to worry about the problems caused by oral delivery.

While it is likely that the first uses of transdermal patches will be in specialised areas, the long term potential of the technology is to solve the issues around oral delivery of hydrophilic drugs, while minimising side effects and providing continuous therapeutic blood levels of the drug. With time, transdermal delivery has the potential to become the preferred means of delivering many hydrophilic drugs.