Medical Device Link.

Originally Published EMDM March/April 2005

Market Watch

Drug-Delivery Systems

Companies are rapidly exploring new technologies for a market forecast to grow at double-digit rates through the decade.

Norbert Sparrow

An electronic aerosol system developed by The Technology Partnership reportedly improves drug-delivery efficiency by as much as 90% compared with traditional inhalers.

Drugs are like commuters. To be productive, they need to get to their destination. Gridlock, a wrong turn, or some other mishap will sap their energy and diminish their effectiveness; hence, the crucial role of drug-delivery systems.

There are multiple routes to a target site, from oral or nasal delivery and injection to implantable devices and, perhaps, microthin film. Some of the recent advances in these drug-delivery systems are profiled in this article. An accompanying section features subcontractors with core expertise in the design, development, and manufacture of drug-delivery components and products.

Of Macro and Nano Economics

The medical device industry in North America and Europe generally grows by about 6% per year. That’s pretty good, but some subsectors within the device industry more than double that rate. One example is the drug-delivery market.

Drug delivery is expected to grow by 15% over the next five years, according to analysts at Research and Markets (Dublin, Ireland). That comes on the heels of double-digit growth during the past two decades, adds Michael Moradi, associate analyst at Nanomarkets LC (Sterling, VA, USA). “This [current] $40 billion industry is barely recognizable from its humble beginnings in the 1960s,” he notes. As it barrels toward the next decade, the drug-delivery systems industry will experience even more dramatic shifts, some of them spawned by nanotechnology, according to Moradi. He has authored a report examining market opportunities for nano-enabled delivery systems, which has just been published, as well as a white paper on the topic. (To obtain copies, send an e-mail to sales@nanomarkets.net.)

Although it is still an emerging technology, nano-enabled drug-delivery systems have a bright future, says Moradi. “My educated guess is that this current $100 million–to–$250 million market will grow into the single-digit billions over the next eight years.” In the meantime, however, debate rages on just what constitutes nanotechnology.

“People are very skeptical the minute they hear nano-anything,” says Moradi. “People working in the pharmaceutical industry will tell you, ‘Look, we’ve been doing this for years.’ To an extent I would agree with them,” he says.

“The way I try to characterize it is that there are a number of different disciplines that are coming together in nanotechnology that otherwise rarely talk to each other.” This breeds innovative ways of thinking, Moradi adds.

Size, of course, is one of the key differentiators. “A key concept is that materials behave differently when you get them down to the nanometre size. You are no longer subject to bulk forces like gravity to the same degree.” Nano-enabled delivery systems also have a more-refined targeting ability. That is one of the key features of a nanomagnetic particle technology, jointly developed by Biophan Technologies and Nanoset LLC, both based in Rochester, NY, USA, described by Moradi.

The core technology involves making implanted medical devices safe for use with magnetic resonance imagers and related equipment. But it also enables the bonding of drugs to nanomagnetic materials, which can then be guided magnetically to a specific location and activated, again by magnetic means.

Orthopaedics is one application under consideration. One could imagine an implant containing a “sleeper” drug that is released on demand should an infection develop.

In the United Kingdom, microfluidic engineering has led to the development of a novel method for the production of drug-bearing microspheres. The technology is derived from research conducted at Cardiff University on the manipulation and control of fluids in microcapillaries. “We can convert nanometre-size droplets into very precisely engineered microparticles, and load them with active ingredients in a precise and repeatable manner,” says Mark Barry, CEO of Q Chip (Cardiff, UK).

One of the challenges now facing pharmaceutical companies, he explains, involves particle-size and shape control. Q Chip’s microfluidic engineering technology converts aqueous beads of a precisely controlled volume into solid beads of a known diameter, explains Barry. “This is traditionally done in large-scale reactive vessels. Our reactive vessels are minuscule,” he adds.

The particles are formed in micron-scale capillaries etched in biologically inert wafers operated in large parallel arrays. “Our volume comes from forming the particles in parallel through, for example, 10 circuits. The particles can then be loaded with a precise quantity of another material.”

This capability caught the attention of UK-based Biocompatibles (Farnham, Surrey), which has licensed the technology for use in drug-delivery studies. It has the exclusive right to the intellectual property for certain applications and for a specific period of time. In the meantime, Barry is seeking other partners willing to join Q Chip in “its journey.”

Learning to Inhale

Hundreds of millions of inhalers are sold each year around the world, says Andrew Sant of The Technology Partnership (TTP; Cambridge, UK), but the performance of these devices leaves a lot to be desired. “On a good day, about 30% of what comes out of the device actually gets into the lungs,” he says. TTP, an independent technology development and licensing company, has designed an electronic aerosol system that reportedly improves efficiency by as much as 90%.

Conventional devices have severe limitations, says Sant. “The breakup mechanism is entirely chaotic, and the droplet size range is incredibly broad,” he notes. Because of the devices’ inherent inefficiency, patients must inhale relatively large quantities of a drug to ensure that an adequate amount reaches the lungs. To be at all effective, explains Sant, an inhaler requires low-velocity droplets sized between 1 and 10 µm. If the particles are any larger, or if they are delivered at a high velocity, the medication will simply impact the throat. Any smaller, and they won’t reach the lungs. The breakthrough of TTP’s TouchSpray system, he adds, is the ability to consistently produce droplets of a given size. It has been successfully used in the eFlow electronic nebulizer marketed by Pari (Starnberg, Germany). TTP is now extending the reach of this technology by offering to license its use in other drug-delivery applications.

“TouchSpray is a propellant-free electronic device,” explains Sant. The core component is a low-profile piezoelectric actuator that incorporates a thin, perforated stainless-steel membrane. The actuator is driven at ultrasonic frequencies that cause the membrane to vibrate. “The droplets are forced through the membrane; their size is in direct relation to the hole size,” says Sant. Millions of precisely sized droplets can be ejected per second.

TTP recently announced the development of a “cousin technology” called Reverse Taper TouchSpray. “It uses a different physical mechanism to form the droplets,” says Sant. Fluids containing dense suspensions of insoluble compounds can be administered by means of an inhaler device thanks to this technology. “Atomizing a liquid that is loaded with solid particles in suspension can be challenging,” says Sant. The Reverse Taper achieves this result without clogging, even if the particles are larger than the hole size, explains Sant, because of the shape of the nozzle.

A Model Nose

The benefits of using the nasal cavity to deliver drugs are well known. Drug uptake through the nasal cavity’s highly vascularized subepithelial layer enables therapies to pass quickly into the bloodstream for rapid onset of effects. The nasal route also bypasses the body’s first-pass metabolism, reducing the likelihood of drug degradation.

To gain a better understanding of the particle deposition process and ultimately improve drug uptake, drug-delivery device specialist Bespak plc (Milton Keynes, UK) has launched an extensive research programme. One tool it is using is an anatomically correct model of the nasal cavity that was developed with magnetic resonance imaging and computed tomography systems. By studying the factors influencing nasal deposition and optimizing spray characteristics, the firm hopes to develop more-efficient nasal devices.

If the results of this research are validated by in vivo studies, they could lead to the development of drug-delivery technologies that better target specific tissues in the nasal cavity with an accurate, repeatable dose.

Optimized nasal devices can make the nasal passage a major route for the delivery of systemic as well as locally acting drugs, according to Bespak.

Drug-Eluting Thin Film Research Hots Up

Researchers in the United States are investigating alternative drug-delivery methods that may, one day, allow diabetics to take insulin through heat-controlled drug implants. The research group, led by Andrew Lyon, associate professor at the Georgia Institute of Technology (Atlanta, GA, USA), tested insulin release using microthin films during an 18-month period. The group used a multilayering procedure to assemble the films from microparticles, which allowed for greater control over drug release than using bulk material.

“This is another great example of how layer-by-layer polymers can be used to create film structures and properties not easily realized by other techniques,” says Michael Rubner, professor of polymer materials science and engineering at the Massachusetts Institute of Technology (Cambridge, MA, USA).

The films were loaded with insulin that released after they were heated to 31°C, six degrees below human body temperature. The release was stable, and the films continued to emit insulin for more than a month.

Although the results were encouraging, Lyon and his team are working to increase the release point to above human body temperature. That would help prevent overdoses, which could occur if body temperature rises too high.

“It could be catastrophic if [a patient with an implant] ran a marathon or ran a fever,” Lyon says. “We don’t want the release to be affected by changes in body temperature.”

Accidental overdoses are not the only risks associated with implantable drug-delivery systems. Inflammation, the rejection of the implant, and the formation of scar tissue around the implant itself can decrease the efficacy of the drug delivery, Lyon says. There is also the issue of going under the knife every time an implant needs to be refilled. “Who would want to undergo periodic microsurgeries to fill their prescription?” asks Lyon.

The next step for Lyon and his team is to find a way to get a bigger pulse out of the film and more tightly regulate when the film is activated. These issues must be resolved before heat-controlled drug implants can have any practical use.

“The near-term impact [of this research] on the population is minimal,” Lyon says. Ronald Siegel, head of pharmaceutics at the University of Minnesota (Minneapolis, MN, USA), also cautions against building up Lyon’s discoveries. The findings are encouraging, he says, but they don’t mean that diabetics or patients undergoing hormone therapy will receive their dosages with implantable drugs anytime soon. Brendan Gill contributed to this article.

Piezo Bimorph Materials Enable Disturbance-Free Drug Release

Unlike traditional electrical solenoid systems, piezo bimorph products do not produce an electric field to achieve drug release in delivery devices. Consequently, the products developed by Morgan Electro Ceramics (München-Unterföhring, Germany) maintain a disturbance-free environment.

In lieu of a conventional metal inner layer, the piezo bimorphs use a carbon fibre that reportedly improves deflection and force properties while boosting performance and reliability by as much as 30%. An integrated safety electrode ensures operation even in harsh applications. The products are available in sizes ranging from 15 to 45 mm long and 2 to 15 mm wide. The maximum peak-to-peak deflection is 3 mm.

An optional humidity-resistant coating ensures that warm, damp, or humid conditions do not have an adverse effect on device performance.

The firm offers a range of piezoelectric and dielectric materials used to manufacture transducers, sensors, and related products. Application engineering services are available.

Injection Moulding Firm Banks on Clean Future

In the years ahead, a company’s ability to offer clean production processes will gain even more clout as a negotiating point between OEMs and subcontractors. That is the analysis of Wilden AG, an injection moulding firm active in the design and manufacture of plastic systems for the pharmaceutical, medical device, and diagnostic industries. To cement its competitive edge, the company recently announced that it would double cleanroom capacity by 2010 to 20,000 m2. The expansion will affect plants in Europe, the United States, China, and the United Arab Emirates.

Increased demand for cleanroom production capabilities will also be driven by innovations in materials science, according to Burkhard Stolz, head of Wilden’s diagnostics business area. Currently, a second-stage sterilization of injection-moulded parts is generally required. This may be eliminated, he notes, as production shifts to a Class A sterile environment. “The bioburden of a product is evolving more and more into a standard for the manufacture of diagnostics products,” says Stolz.

The company produces parts, assemblies, and finished devices at 13 facilities worldwide. It recently announced the construction of a new technical centre in Wackersdorf, Germany, that will consolidate the company’s technical expertise in a single location.

Drug-Delivery Products Benefit from Firm’s Moulding and Automated Assembly Expertise

A company relies on its expertise in injection and blow moulding and multicomponent automated assembly to supply drug-delivery systems, metering pumps and valves, and plastic primary packaging. Rexam Pharma (Suresnes, France) operates four facilities in Europe that follow GMP guidelines and are certified to ISO 9001 and ISO 13485.

In the parenteral field, the firm has developed a proprietary Safe ’n’ Sound safety system for prefilled syringes, as well as transfer sets, autoinjectors, and injectable vials. Pumps, valves, and applicators for spray delivery are designed via digital simulation techniques to provide the best solutions for formulations. The company also boasts significant in-house expertise in the development and manufacture of dry-powder inhalers and pressurized metered dose inhalers. A multidose asthma inhaler manufactured by the firm comprises 14 injection-moulded parts, 11 assembled parts, and 3 loose parts.

In addition, the firm offers ophthalmic primary packaging, custom and standard pill jars, pumps and associated systems for dermal and transdermal applications, and tamper-evident tubes.

Company Has a Nose for Development of Drug- Delivery Products

A developer and manufacturer of drug-delivery technologies and medical devices has carried out extensive research into targeting specific tissues in the nose. Bespak plc (Milton Keynes, UK) has notably developed an anatomically correct model of the nasal cavity to evaluate particle deposition. It has also instituted a product introduction process to provide its customers with flexible, efficient, and time-sensitive services.

Bespak uses the model of the nasal cavity, which was developed using magnetic resonance imaging and computed tomography techniques, to study the many factors that influence nasal deposition. Supplemented by in vivo studies, the findings could provide the basis for developing more accurate and repeatable delivery technologies, according to the firm.

The company also recently announced a research programme in collaboration with the University of London’s School of Pharmacy to study site-specific delivery of antibodies in the respiratory tract. Bespak will provide its expertise in aerosol technology and testing, as well as its capabilities in the production of prototype devices. The partners believe that the programme offers the potential to advance the effectiveness of inhaled antibodies.

In addition, the manufacturer has focused efforts on delivering a spectrum of services that efficiently meets the needs of its customers. The Bespak Product Information Process (BPIP) is described as a stage-gated methodology that provides a basis for continued project review. It allows for a project of any size and complexity to be broken down into manageable checklists of deliverables. By providing a platform for fact-based decision-making from design and development to manufacturing, BPIP can accelerate time to market at agreed levels of risk and generate cost savings, according to the firm.

Moulding Firm Invites MDI Developers to Step Up to the Counter

Dry-powder inhalers are equipped with a device that indicates the amount of remaining medication. In the past, metered dose inhalers (MDI) have not included a counting mechanism. That is changing, according to Sanner Plastics Technology (Bensheim, Germany), as public and regulatory pressure mounts to design MDIs that include a remaining-dose counter. The firm has developed a solution in the form of a self-contained unit that can be fitted onto existing mouthpieces.

The counter is placed on the open end of the MDI sleeve. As the device is depressed to release the drug, the remaining quantity of medication is shown through a window in the transparent sleeve.

The counter is designed to slip onto the sleeve of any marketable MDI following a simple modification. A tamper-evident mechanism prevents exchange of the drug-containing cartridge by the patient.

The firm is currently seeking partners to further develop this device.

Sanner provides injection moulding, extrusion, and assembly services at facilities in Europe, the United States, China, and Brazil. Class 100,000 cleanrooms are on-site, and quality systems are certified to ISO 9001: 2000 and ISO 13485:2000.

Drug-Eluting Coating Technology to Reach Market This Year

Biocompatible polymer coatings that can be engineered to release pharmaceutical agents according to preset elution profiles are scheduled to reach the market this year. Coating technology developer Hemoteq GmbH (Würselen, Germany) notes that products developed and manufactured for various clients are close to reaching that milestone.

Several biodegradable and biostable coating platforms have been developed to suit a range of applications, including drug-eluting stents for patients with coronary heart disease. The company’s biomimetic nanocoating Camouflage has the potential to further benefit patients, says the firm. A very thin layer of synthetic basecoat that resembles the outermost layer of living cells masks the drug-eluting device from the body’s defense system.

Modular Approach Speeds Development of Delivery Systems

A company that specializes in the development, manufacture, and marketing of metered dosage systems produced its first nasal spray pump more than 30 years ago. Pfeiffer (Radolfzell, Germany) jointly developed the device with Thomae, a subsidiary of Boehringer Ingelheim. Today, the firm continues to innovate not only in nasal delivery systems but also in oral and topical drug delivery technologies.

One recent development is a mechanical multidose system for the nasal application of preservative-free solutions. The pump design allows drug manufacturers to eliminate preservatives in their products. (Since May 2004, in a number of European countries pharmaceutical companies are required to declare the presence of preservatives.) The system combines a sterilizable pump and a filter membrane vent developed by W.L. Gore & Associates that provides reliable viral and bacteriological protection.

Moulder of MDI Products Expands Operations

MDI parts are moulded by a firm that has been supplying devices to the pharmaceutical industry for more than 30 years. Anticipating continued strong demand for its outsourcing services, Nemo S.A. (Barcelona, Spain) recently moved to a new 10,000- m2 plant with a 2000-m2 cleanroom. The firm also purchased hybrid injection moulding machines.

Citing MDI applicators as a core activity, the company offers a range of inhaler options. Products include one-piece actuators for standard 10-, 14-, and 19-ml aluminium cans and valves and two-piece actuators with transparent sleeves that fit 17-, 22-, and 28-ml devices. The company also offers nasal and throat actuators with a pump and aerosol mechanism that revolves 360°, single-dose ampoules, and dialysis cartridges.

Product design and development assistance is available, and the firm can also provide advice on aesthetic and ergonomic matters. The company is certified to ISO 9001 and ISO 14001, and it operates in accordance with GMP guidelines.

Design Bureau Stresses User Sensitivity

Sensitivity to the needs of potential device users is a key consideration at DCA Design International (Warwick, UK), which describes the design and development of drug-delivery devices as a core area of expertise. To ensure device safety and satisfactory ergonomics, the firm’s industrial designers scrutinize human factors and risk at the beginning of a project. The broad and seasoned expertise of its staff enables the company to realistically predict where trends may lead. This can be especially useful in the development of medical devices, notes the firm, which may take several years to reach the marketplace.

In-house specialist skills include mechanical engineering, electronics hardware and software engineering, and prototyping. A dedicated team of medical device development experts provides regulatory knowledge and project management. These resources enable the firm to undertake the design and development of products ranging from high-volume disposables to advanced electronic devices.

The bureau is equipped with a prototyping facility as well as a test laboratory where mechanical, electrical, and environmental testing can be conducted.

Needle-Free and Custom Components Offered to OEMs

Disposable IV components that facilitate needle-free access are designed for OEM use by Cardinal Health, Alaris Products (San Diego, CA, USA). The valve technology developed by the company features a high flow rate, low priming volume, and straight-through fluid path equivalent to an 18-gauge needle. Free of latex and DEHP, the SmartSite valves have a smooth and easy-to-swab surface and are chemically resistant. The product line includes luer-lock, y-body, and t-connector valve ports; straight tubing pockets; vial access devices; and access pins. The firm performs 100% in-line production testing.

The engineering staff uses CAE tools such as 3-D modelling, mould-flow analysis, and FEA to design and develop custom products. Technical support is provided throughout the development process to assist with SmartSite or custom product configurations. The firm also has expertise in assembly with high throughput and test fixture design.

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