Macro Opportunities For Microneedles

By Cindy Dubin

Pharma companies seeking painless and efficacious biologics drug delivery could find their answer in the multimillion dollar microneedle market.

Companies across the United States are investing millions of dollars to develop microneedles for drug delivery. This array of needles — from only a few to more than 1,000 — is arranged on a patch that penetrates the skin less than 1 mm. The growing interest in microneedles is being driven by several factors: patients’ demands for painless self-administration; the technology’s ability to deliver proteins and peptides; and pharma’s goal of product differentiation.

Thus, there is significant potential for this technology in the coming years. Microneedles are targeted not only to the $25 billion global vaccine market, but also to the $120 billion global biologics market, which is expected to have a compound annual growth rate of 6.7% in the next five years.

A new report from Greystone Associates, Microneedles in Medicine: Technology, Devices, Markets and Prospects, puts the microneedle drug delivery market at just under $400 million globally by 2012. In North America, growth will be driven by the anticipated approvals of Zosano’s ZP-PTH patch, while the recent European authorization of Sanofi-Pasteur’s Intanza intradermal influenza vaccine will drive growth across the pond, states the report. Microneedles are proving to be an alternative to other forms of drug delivery, particularly needles, which can be painful for patients, pose a sharps hazard, and typically are delivered by a professional. Using microneedles to deliver compounds into the highly vascularized dermis, drug companies can differentiate their offering with a patient-friendly, easy-to-apply, low-hazard system.

“Compounds delivered into the dermis by microneedles have shown faster response time compared to muscular injections because they reach blood circulation faster,” says Vladimir G. Zarnitsyn, Ph.D., research scientist II, School of Chemical and Biomolecular Engineering at the Georgia Institute of  Technology.

Microneedle Vaccinations Prove Promising
Microneedles expand the range of molecules that can be delivered transdermally. One of the more promising areas is vaccinations, because microneedles improve delivery efficiency and enhance efficacy by targeting antigen-presenting cells within the skin, explains Ann Meitz, VP of transdermal drug delivery, 3M Drug Delivery Systems.

“Given the need to vaccinate a large population, including children, in a relatively short amount of time, a microneedle-based, dissolvable flu patch is very compelling, especially if the device surrounding the microneedle could be distributed through the mail,” she says. “Studies have shown that intradermal influenza vaccination via patch can be significantly more efficacious than a traditional intramuscular injection, because specialized cells found only in the skin develop an immunological response. A vaccine administered via intramuscular injection doesn’t access these cells.”

Research at Georgia Tech included using microneedles to successfully deliver influenza vaccine in animal trials. It was found that mice vaccinated with patches responded to the flu as well as mice vaccinated with hypodermic needles. When exposed to the flu again after three months, the mice that had been vaccinated with patches cleared the infection from their lungs more effectively than the other group of mice.

The patch used in the study was covered with needles 650 microns in size that contained the vaccine. To make the vaccine part of the needles, researchers dissolved freeze-dried vaccine in poly-vinyl pyrrolidone (PVP) to ensure stability, then placed it in microneedle molds and polymerized at room temperature with ultraviolet light. When the patch is pressed into the skin, the needles dissolve into the body, leaving only a backing that can dissolve in water. The patch is left on the skin for 10 minutes.

In many parts of the world, poor medical infrastructure leads to the reuse of hypodermic needles, contributing to the spread of diseases such as HIV and hepatitis B. Dissolving microneedle patches would eliminate reuse while allowing vaccination to be carried out by personnel who have minimal training.“We want to bring this technology to healthcare, and we believe the work we did with mice will reproduce in humans,” says Dr. Zarnitsyn.

Ultimately, the ability of intradermal vaccination to outperform traditional intramuscular vaccine will need to be assessed on a vaccine-by-vaccine basis. Looking into the future, researchers speculate that hepatitis and DNA vaccines will be more efficacious delivered intradermally. “DNA vaccines hold lots of promise, and it’s exciting to think that microneedles may have a role in making those vaccines a reality,” says Meitz.

Uniformity In Manufacturing Is Key
Before microneedles find widespread use, developers must refine the techniques for optimally manufacturing them. According to researchers at Georgia Tech, microneedles can be fabricated as solid or hollow, single-needle or multineedle arrays and as biodegradable microneedles encapsulating drug compounds. Research has been conducted to show that hollow microneedles can be used to deliver insulin and lower blood glucose levels in animal models of diabetes. Dr. Zarnitsyn says this method has worked better than delivery by conventional methods, providing faster action. Microneedles also have been used to deliver drugs such as desmopressin, plasmid DNA, and oligonucleotides, as well as vaccines against hepatitis B and anthrax in animals.

Whatever the drug, a key challenge in manufacturing microneedles is ensuring the presence of a significant drug load on the very small needles, as well as making certain the load is robust enough to penetrate the skin, explains Zarnitsyn. The processing techniques incorporate one or more technologies that enable the precise machining, extrusion, casting, and forming of an array or grid of microneedles. Methods for manufacturing microneedle devices include micromolding, microfabrication, and microshaping.

Manufacturing microneedles is all about setting specifications that can be maintained through design, fabrication, and verification testing. For drug-coated microneedles, it is the selection of a stable, coatable drug formulation and the coating process that applies a consistent amount of drug per microneedle array. “The FDA calls this drug content uniformity,” says Peter Daddona, chief scientific officer at Zosano Pharma, Inc. “The specification for coated drug amount is set by the United States Pharmacopeia [USP] for the manufacturing process, and it is a very tight specification.”

Zosano began working on its drug-coating microprojection technology about 10 years ago. The patch, which is the size of a quarter, contains up to 1,500 titanium microneedles 0.22mm in length and is applied with a plastic spring-loaded applicator. Manufacturing the arrays involves the use of a photomask and chemical etch to devise the designs in titanium sheets. “Our manufacturing process is robust, reproducible, and generic enough to handle a variety of compounds,” says Daddona.

The company’s lead product, which is entering Phase 3 studies, is the ZP-PTH patch for treating osteoporosis. As an alternative to daily injections, the product delivers PTH 1-34, teriparatide (PTH), a compound that stimulates formation of new bone and reduces the risk of fractures. 

Just as Zosano has perfected its manufacturing technique, 3M’s microneedle systems draw upon the company’s experience in microreplication and precision coating, which ensures consistency in manufacturing precisely molded parts, says Meitz. High-speed robots accommodate smooth part transfer from mold to inspection and packaging, while “real-time” visual inspection of microneedles in-process verifies that the parts meet quality specifications. Graphical display outputs of individual parts oversee quality control of microneedle patches.

3M’s platform of microneedle-based drug-delivery technologies include the solid Microstructured Transdermal System (sMTS), which contains 200 to 1,300 structures for delivering vaccines and highly potent proteins or peptides. 3M’s hollow Microstructured Transdermal System (hMTS) contains just 18 needles arranged across an array that is about the size of a U.S. dime. The hMTS is designed to provide high-volume (0.5-2 mL) delivery of liquid formulations. “Microneedle technologies that rely on coating the antigen on the microneedle can be limited in the dose they can deliver,” says Meitz. “Vaccines with a very high dose [>1 mg] can be challenging to coat. These dose limitations can be overcome by a microneedle-based system that can deliver higher volumes of liquid formulations, such as hMTS.”

Painless, Potent, And Different
Whether delivering liquid or dry formulations, there is no denying that getting large molecules into the body via oral methods has proven inefficient leaving injections as the viable alternative. But patients and caregivers are seeking less painful drug delivery options. Pharma is left with the challenge of responding with painless yet potent products. Microneedles may prove to be the answer in delivering these new compounds.

In addition, the pros say that as a transdermal delivery mechanism, microneedles offer increased compound stability, improved patient convenience, and better potency and may prove a cost-effective drug delivery option. According to the researchers at Georgia Tech, if mass-produced, the dissolvable microneedle patches are expected to cost about the same as conventional needle-and-syringe techniques and may lower the overall cost of immunization programs by reducing personnel costs and waste disposal requirements.

There is also the possibility of market patent value that microneedles bring to pharmaceutical companies. Some might be looking to extend patent protection for compounds whose patents are about to expire. Finding an alternative delivery method for a franchise molecule is a way to do that. There is also value in discovering a drug delivery system during Phase 1 or 2 development when other options have failed.

“We expect that as more biopharmaceutical products are developed, the demand for needlefree injection systems is going to grow,” says Meitz. “Pharmaceutical companies need to find ways to differentiate their products. Physicians want to see products that increase compliance and keep patients away from the clinic, and patients want administration that is convenient and painless.”