There are limited ways to introduce modern drugs into the body for systemic use without puncturing the skin. Basically you can use a transdermal approach, the buccal mucosa, or the naso-pharynx/lung, a pill or liquid, or use another natural orifice. But all of these routes have limitations — degradation by the GI tract, first pass metabolism by the liver, inconvenience, dosing limits, and others. Long ago, physicians recognized that injectable methods were needed.
Think back two hundred years ago. The drugs available back then — basically botanicals — were given orally or as lotions, pastes, or enemas. But these delivery methods were not sufficient and physicians attempted to use a more direct route through the skin. The problem was that there was no way to “inject,” so early attempts used a surgical incision-and-drip method, a rather drastic approach!
Finally, in 1844, an Irish physician, Francis Rynd, invented a hollow silver needle. But other than gravity, there was no delivery mechanism, namely a syringe, until a French scientist, Charles Praviz, invented a screw-type device that used the Rynd needle. Thus the modern needle with syringe was finally available! These devices also opened up the concept of intravenous or intra-arterial drug and blood product delivery. The ability to use an injection to introduce drugs also allowed the development of large molecules that cannot be administered orally, including polypeptides and proteins — the very essence of the biotechnology revolution.
But, as much as the needle and syringe changed the delivery of medications, it was not without challenges. Original needles were very expensive and scarce and were used more than once. This necessitated resharpening. They were also rather large by current standards, and so for the past 150 years, medical science has attempted to improve this basic invention by reducing the diameter of the needle and finding ways to create a sharper and less painful needle. Further technology improvements reduced the cost so that needles could be disposed of instead of being reused.
But even these solutions were not enough. There are still concerns about the needle-and- syringe delivery method. For one, it hurts! There is no better way to train toddlers that a trip to the doctor’s office is a negative experience than to have them receive an injection at each visit. Also, the needle and syringe deliver the entire dose of the drug at one time. Sure, there are some slow-release injectables, but they are not available for all drugs. There is also the risk of needle sticks for the medical personnel using the needles, which has spawned an entire industry aimed at reducing this risk.
Break in the skin
The basic problem is that the introduction of a drug through the skin requires a break in the integrity of the skin. The stratum corneum, about 10–15 microns in depth, is a remarkably effective barrier to many compounds. Just below the stratum corneum is the pain-sensing nerves. Various attempts to increase the permeability of the skin include the use of chemical or lipid enhancers, electrical fields (iontophoresis and electroporation), and ultrasound.
They all have their role, but the idea of using a needle is still very attractive. Scientists thought they had reached the limits of miniaturization for the needle until recently. Now the concept of the microneedle is getting attention.
Basically, a microneedle is a very small needle, with a diameter and length measured in microns (one millionth of a meter). A microneedle is small enough to penetrate and make permeable the stratum corneum, but not long enough to stimulate the pain fibers.
Microneedles create smaller “holes” in the skin than even a minor abrasion, but this is enough for drugs to enter the systemic circulation.
Microneedles can be created from a variety of materials, and in many sizes and shapes, and can be either hollow or solid. They can be coated with a drug or sit atop a reservoir of drug that is delivered by way of passive diffusion or timed pumps.
The use of microneedles was first reported in 1995, when an array of needles was etched into a silicon wafer. Within several years, many articles were published that discussed the painless nature of microneedles and the delivery of insulin, growth hormone, immunizations, and other agents.
A recent development is the use of “soluble’” microneedles. Biodegradable biocompatible polymers are applied to a base material using a lithographic approach to create the “needles” of material. This method of production is much less expensive than the original, placing the microneedle in the same basic price range of the traditional needle and syringe. These polymers dissolve once they “poke” through the skin.
There are many advantages of microneedles. They can be applied as easily as a bandage. They avoid the GI problems and the variations of delivery rates caused by food absorption in the gut. They do not require a highly trained nurse. There are no “sharps” to dispose of. They prevent the reuse of traditional needles, an activity that contributes to the spread of infections, especially in underdeveloped countries and in people using illegal drugs in the United States.
Lacking FDA approval
Although none of these devices is yet approved by the FDA, numerous institutions are involved in this remarkable arena, including Purdue University, a joint venture between the University of North Carolina and Mercer University, and one between the Georgia Institute of Technology and Emory University.
A recent study by Emory and Georgia Tech, supported by the NIH, demonstrated that in an animal model, a dry form of influenza vaccine could be successfully delivered using an array of 100 microneedles just 650 microns long. The vaccination was successful. In fact, this delivery method appeared to provide a better level of immunity than the traditional needle-and-syringe method. And a Madison, Wis., company, FluGen, announced that preclinical testing using a trivalent flu vaccine will begin this year.
If these results can be replicated in humans, the researchers envision a time when you might receive your competitively priced flu “shot” in the mail and administer it yourself!
Of course, there are many challenges. Each drug may need its own custom-made microneedle device. The FDA will probably need to approve each drug–microneedle combination, and the device will come loaded with the drug from the manufacturer. But if early studies pan out, these devices will once again show the promise of Tomorrow’s Medicine!