June 23, 1998 "Microneedles" much thinner than the diameter of a human hair could be the basis for a new drug delivery technique able to administer small quantities of high-potency medications through the skin without causing pain.
Arrays of the microneedles could improve administration of existing medications, allow development of new therapeutic compounds and open the door for microprocessor-based systems for delivering drugs continuously or in response to body needs. Produced with fabrication techniques originally developed for the microelectronics industry, the tiny needles can avoid causing pain because they penetrate only the outermost layer of skin that contains no nerve endings.
Researchers at the Georgia Institute of Technology believe their microneedles would be especially useful with large protein-based molecules, such as those produced through new biotechnology processes. Such drugs often cannot be taken orally, but must be administered frequently enough to make traditional needle injection impractical or unpleasant.
"We envision microneedles being 'user-friendly' for patients, similar to the current transdermal patches that are in common use," said Dr. Mark R. Prausnitz, assistant professor in Georgia Tech's School of Chemical Engineering. "We expect in its final design that a microneedle array would be quite easy to use. Patients would just peel a liner off and stick it onto the skin. They would not see any needles, and there should be no pain associated with it."
Details on the work will be presented June 22 at the 25th International Symposium on Controlled Release of Bioactive Materials. A paper has been accepted for publication in the Journal of Pharmaceutical Sciences. In addition to Prausnitz, the research team includes Dr. Mark G. Allen, associate professor in Georgia Tech's School of Electrical and Computer Engineering, and Graduate Students Sebastien Henry and Devin McAllister.
The first use for the microneedle arrays would be for one-time injections. However, Prausnitz believes the arrays could also be left attached to the skin to provide continuous administration of medication under the control of microprocessor-based equipment.
"This system could provide constant communication between the drug reservoir and the inside of the body," he explained. "Using a microprocessor to control a pump would allow the device to be programmed to deliver a drug at variable rates. The pump could also be controlled by the patient or a clinician."
If microneedle arrays were also used to withdraw bodily fluid for analysis, the microprocessor-based equipment could automatically administer drugs based on the body's need. Such a feedback system would be useful in regulating the blood sugar levels of persons suffering from diabetes, Prausnitz noted.
Using reactive ion etching microfabrication techniques originally developed for integrated circuits, the researchers have so far built solid silicon microneedle arrays 10 millimeters square. The existing needles are 150 microns long and leave holes about one micron in diameter when removed from the skin.
Prausnitz and Allen expect further development will reduce the length and diameter of the microneedles, make them hollow to increase the rate of drug delivery, and permit mass fabrication of arrays at least a centimeter square. If the diameter of the microneedles can be reduced, the holes they produce could be small enough to exclude bacteria, eliminating a potential source of infection.
Prausnitz expects that with high-volume production, the microneedle arrays would be competitive in cost with existing disposable drug delivery techniques.
"I do believe that microneedle technology offers great potential for delivering drugs through the skin, avoiding the barrier presented by the outer stratum corneum," said Dr. John C. Ansel, professor in the Department of Dermatology at Emory University School of Medicine and chief of Dermatology Services at the Atlanta Veterans Administration Medical Center. "The fact that it is virtually painless and does not pose a significant risk for infection is a major advance in this area of drug delivery."
The major challenge ahead, he cautioned, will be to demonstrate in a clinical setting that this approach can effectively deliver therapeutic quantities of various drugs safely and economically.
Most drugs now are delivered orally, or through injections. To be orally administered, drugs must resist decomposition in the body's gastrointestinal tract, be readily absorbed through the intestinal wall, and survive attacks by enzymes in the liver. Conventional hypodermic needles get drugs directly into the bloodstream, but cause pain, create the potential for infection, and require medical training to use.
A limited number of compounds, such as nicotine, can be readily absorbed by the skin. Techniques are being developed for improving transdermal drug administration using chemicals, electricity and ultrasound to make the skin more permeable. However, Prausnitz believes the microneedles could be both simpler and more effective for delivering drugs through the skin, providing the benefits of needle injection without the disadvantages of conventional needles.
By eliminating the constraints imposed by other delivery techniques, the microneedle arrays could give drug developers more freedom to select compounds without concern for how they might be administerered.
Through limited laboratory testing, the researchers have demonstrated that their microneedles can significantly increase absorption of a drug compound through the skin by as much as 25,000-fold. Once the microneedles penetrate the outer layer of skin known as the stratum corneum, they can carry medications into deeper areas of the skin where the compounds diffuse, are absorbed by capillaries and carried into the bloodstream.
"We'd like to have needles that just penetrate that outer barrier, but not much farther, to avoid hitting nerves and causing pain," Prausnitz said. "Preliminary testing on humans has shown that insertion of microneedles into the skin does not cause pain."
Before the microneedles could be used to administer drugs to humans, the researchers must demonstrate their safety and effectiveness through extensive animal and human testing. Potential problems could arise, Prausnitz warns, if high levels of drug under the skin cause local inflammation, or if the body reacts to the needle material itself.
Using existing silicon material, the tips of a very small number of the needles can break off in the skin. Whether the minute amount of silicon left behind may cause problems, or whether needle breakage could be eliminated with the use of other materials or improved needle design, must also be studied.
The research has been sponsored by Georgia Tech internal research funds.
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