[Dan McCann]

From corporate powerhouses such as 3M to small startups like TheraJect, companies across the U.S. are investing millions of dollars to develop microneedles for drug delivery.

Most of the focus is on devising microneedles incorporated into transdermal patches. Ranging from about 100μm to 1,000μm in length and 50μm to 250μm in diameter, the needles are lined in arrays of 50 to 1,500 or more. They’re designed to puncture only the outer skin layer (stratum corneum) and, stopping short of nerve endings, provide a channel to deliver drugs that otherwise would require hypodermic needles.

The prospect of a painless device that provides the convenience of self-administration joined with the eff ectiveness of hypodermic needles has obvious appeal—on both the clinical and financial fronts. Medtech Insight, a medical marketplace research firm in Irvine, Calif., estimates that U.S. sales of drug devices—including injection/infusion, needleless transdermal and inhalation systems—totaled $18 billion in 2008.

And microneedle developers are ready to make wide inroads into the market. If they do, it will be by way of microneedles supplanting established techniques, said George Perros, managing director of market research firm Greystone Associates, Amherst, N.H. “Instead of using a syringe to inject a drug, you use a transdermal patch because it has a microneedle array that’s helping to encourage the skin to allow that drug to go through.”

Three types of microneedles are used for delivering drugs: solid titanium or stainless steel devices that are coated with drugs, hollow titanium or stainless steel microneedles that carry the drugs inside and dissolvable microneedles, which are composed of biodegradable polymers mixed with drugs.

None of these are on the market yet. All the companies contacted for this article reported that they are in various stages of development— either preparing to submit their products to the U.S. Food and Drug Administration for safety and eff ectiveness studies or about to begin the agency’s Class III clinical trials, the last step before going to market.

While some devices appear to be nearing commercialization, no one would specify when that might occur. Likewise, company officials were guarded about their manufacturing processes, primarily for proprietary reasons.

What is clear is that the race is on: Company executives were explicit in their commitment to get their products to market as soon as possible, and they were well apprised of their competitors’ progress.

Transdermal basics

The microneedle projects underway build upon previous technology. Adhesive patches coated with drugs that absorb through the skin—called passive transdermal systems—have been used for years to administer nitroglycerin (for angina), nicotine (for smoking cessation), estrogen (for osteoporosis, menopause) and fentanyl (for pain).

This method is ideal for small-molecule drugs, but those are in the minority. Many of the latest biopharmaceuticals are the heavier, large-molecule medicines, which can neither bypass the stratum corneum nor be delivered eff ectively via tablet.

“Excitement about the [microneedle] patch stems from the fact that as you start to see more sophisticated drugs, particularly ones with higher molecular weights—vaccines, proteins, peptides, macromolecules of all kinds—it becomes difficult to administer them as a tablet, [which] is every pharmaceutical company’s first choice of a delivery system,” said Richard Dalby, a professor in the Department of Pharmaceutical Sciences at the University of Maryland, School of Pharmacy.

The problems with large molecules in tablets are twofold, Dalby explained. Tablets are recognized as food and, consequently, are either degraded by stomach acid or digested; if it’s the latter, by the time they reach the gastrointestinal track their molecular weight is so high they cannot enter the blood stream.

The other option, needle injection, is so widely regarded as inconvenient and a source of anxiety that it is considered “a delivery system of last resort for most people,” said Dalby.

University researchers

Given the limitations of traditional drug delivery methods, university researchers in the 1990s took the lead in investigating the potential for microneedle patch technology. Among the more prominent has been the Georgia Institute of Technology’s Laboratory for Drug Delivery, headed by Mark Prausnitz.

An article written by MICROmanufacturing Contributing Editor Victor Cassidy and posted on this magazine’s Web site (www.micromanufacturing. com) earlier this year, details one of the lab’s latest projects, a microneedle patch designed to deliver fl u vaccines, developed with the Emory School of Medicine in Atlanta.

The two-part patch consists of a 20mm-dia. disk composed of medicalgrade foam tape topped with an adhesive, upon which rests a sheet of microneedles. The 10mm×10mm stainless steel sheet features 50 vaccine-coated needles measuring 700μm long×160μm wide × 50μm thick.

Researchers used CAD to design the microneedles on the sheet and then downloaded the program into a laseretching system that cut out the needles.

Using a microscope, researchers manually bent the microneedles perpendicular to the steel sheet. (They are working on a method to automate the procedure.) The patch then was electropolished to remove slag and sharpen the needles. At that point, researchers sterilized the patch, coated the needles with medicine, attached the patch to the disk and packaged it.

When applied to the skin with gentle finger pressure, the microneedles penetrate the stratum corneum; as the drugs dissolve and diff use, they’re absorbed by the capillaries and conveyed throughout the body. The adhesive on the disk keeps the patch attached to the skin much like a bandage, which can be removed after a minute or two.

Last year, Apogee Technology Inc., a drug delivery device company based in Norwood, Mass., purchased Georgia Tech’s microneedle patch technology.

Coated with drugs

Other manufacturers pushing forward with coated microneedle technology include 3M and Zosano Pharma Inc., Fremont, Calif., a spinoff of Johnson & Johnson’s Alza Corp.

Peter Daddona, Zosano’s chief scientific officer, said the company began work on its drug-coated microprojection technology about a decade ago. The patch is approximately the size of a U.S. quarter, consisting of a 5-sq.-cm adhesive patch that includes a 2-sq.-cm microprojection array with about 1,500 microprojections, averaging about 200μm long and about 100μm in tip width. The patch is applied with a plastic spring-loaded applicator, a lot like an ink stamp used by attendants at amusement parks.

The microneedles are made of titanium “because it’s a known biocompatible material that is used in joint replacement and it’s chemically very compatible,” said Daddona. “Choice of materials is important; you have to be mindful of potential leachables, and chemical reactions that could occur on the surface of your material with the drug.”

Drug formulation, Daddona continued, is also a key element of the drug-coated-microneedle-patch technology. For instance, engineers and scientists have to ensure the medicine remains intact and bioavailable as it passes through the stratum corneum. “Sometimes, the drug itself has film-forming characteristics; [if not] you have to add incipients that facilitate filmforming,” said Daddona.

Manufacturing the microneedle arrays involves using a photomask and chemical etch to devise the designs in titanium sheets. “We have a forming process to create the 3-D projection array,” Daddona continued, “[and] what I would consider a proprietary coating process to put the drug in aqueous liquid form on the tips of the microprojections.”

Using a standard titanium etching procedure was key to finding the microneedle array that best suited its needs, he added. “We chose this manufacturing process because, particularly in the early stages, when you’re trying to optimize array designs, we felt we had fast cycle times for looking at the design variables and how they would aff ect performance. So very quickly we could get to a place where we had something we knew would work for the drugs we’re developing.”

In conjunction with their patch technology, Zosano researchers also are developing pharmaceutical products to be incorporated in the microneedle platform. One drug in development, for instance, would be used to treat osteoporosis. Unlike a current osteoporosis medicine on the market, which calls for dailysubcutaneous injections for 18 months or more, the Zosano ZP-PTH patch would be minimally invasive.

“This [micropatch] technology has been clinically tested in more than 400 subjects with several compounds,” said Daddona. “Our most advanced product— ZP-PTH for the treatment of osteoporosis— has just completed a successful Phase II clinical study, and we’re gearing up to enter Phase III. Our goal is to get the first commercial microprojection delivery technology onto the market … and we’ll be cost-competitive.”

3M micropatch

This past July, officials from 3M Drug Delivery Systems, St. Paul, Minn., a division of 3M Co., announced it had successfully designed a proof-of-concept, coated-microneedle patch called the solid microstructured transdermal system (sMTS).

During a poster session at the annual meeting of the Controlled Release Society in New York City, John K. Simons, Ph.D., 3M’s microstructured transdermal project manager, outlined in vivo data on the patch’s depth of penetration, timed release and drug delivery.

The sMTS consists of more than 1,000 microneedles that penetrate about 120μm and can deliver large-molecule drugs systematically within 10 minutes.

According to Simons, “these studies demonstrate that our sMTS technology can quickly and eff ectively deliver molecules not typically compatible with traditional transdermal technologies into the bloodstream.”

3M spokesperson Stephanie Sanderson reported that the sMTS is in the preclinical stage of development.

Hollow, dissolving microneedles

At Valeritas Inc. (formerly Biovalve Technologies Inc.), Parsippany, N.J., engineers are at work making transdermal patches with hollow microneedles made of titanium or stainless steel, said Ronald Nardi, Ph.D, chief scientific officer and vice president, R&D.

“We have a technology that allows us to make a mask that will then produce an array of short needles (200μm to 500μm) in that matrix,” he said. The needles are filled with either a gel or liquid containing the drug. Once the needles have penetrated the skin, the drug can be expressed either by a spring mechanism or manually.

A deposition technology is used to make the needles. Starting with a hollow template, workers coat the metal onto the template to produce the hollow needles.

Another of the company’s microneedles, which can be composed of titanium or stainless steel, has a fl at side with a slot in the middle to house the drug. A drug film is deposited in the needle slot and when the patch is applied, the film dissolves and delivers the drug. Those needles are produced with an etching process, and the slot is a through-hole in the fl at part of the needle.

The company plans to submit Investigational New Drug (IND) applications for several drug delivery products to the FDA early next year.

Similarly, Sung-Yun Kwon, founder and chief technical officer of TheraJect Inc., Fremont, Calif., also expects to meet soon with FDA officials. Topping the agenda will be two transdermal patches, the VaxMat and the DrugMat, which incorporate dissolving microneedles.

Both feature an array of microneedles formulated to deliver drugs (DrugMat) or vaccines (VaxMat), which dissolve and diff use upon penetration. Varying in length from 100μm to 1,000μm, the microneedles are composed of a sugar matrix, said Kwon.

“First we prepare a micromold. Then the hydro-gel containing the drug is poured on the mold and dried. The hydro-gel becomes solid, then is cut and assembled with an adhesive patch that’s like a bandage.”

The adhesive stays on the skin, but within minutes the microneedle portion in the center disappears. “Unlike other drug delivery technology,” said Kwon, “with dissolving material there’s no chance of cross contamination or a sharps hazard.”

Kwon said he will have an initial meeting with the FDA sometime this year or early 2009. “We are now designing how to mass produce our products, but so far we can make the microneedle for [the FDA’s] Phase I study,” he said.

Down the stretch

Just who will win the race to market with a microneedle patch is up in the air. Still, it probably won’t be long before a number of the new drug delivery systems are available. At that point, new questions will arise: Which microneedle patch is most eff ective for delivering which drugs? Which systems are most patient friendly? Which ones can be mass produced most easily and at least cost? And the race will enter a new phase.

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About the Author: Daniel McCann is senior editor of MICROmanufacturing magazine. He can be reached at dmccann@jwr. com or (847) 714-0177.