By Stephen Bruner
Drug device combinations are predicted to reach $11.5 billion in annual sales in 2010, with an average annual growth of 13% needed to meet that goal. The formation of the Office of Combination Products through the Medical Device User Fee and Modernization Act of 2002 provides regulatory support for this fast-paced industry. The role of this office is not to review product submissions but to route them properly. Routing is primarily based on the “primary mode of action” (i.e., the device primarily functions as a medical device or it provides a drug or biologic benefit). Some situations are more complex than this and require oversight from some combination of the Center for Biologics Evaluation, Center for Drug Evaluation and Research, and Center for Devices and Radiological Health. The important take away is the need for experience with both the medical device and pharmaceutical industry. Quality, engineering, and scientific experiences are key to successes and often differ drastically between medical device and pharmaceutical companies. Even the resources, such as raw materials, can differ greatly in requirements. With all of the above factors to consider, this article focuses on silicones, used in both industries as an ideal candidate to meet the design and regulatory challenges presented.
Important Regulatory DistinctionsThe FDA does not approve biomaterials used in medical devices. The Biomaterials Access Act of 1998 placed certain requirements on the device manufacturers to demonstrate that the device and the materials used in the device are safe and effective. This does not, however, mean that biomaterials are completely without regulatory support. The FDA has established Master Access Files for biomaterials used in devices. These files contain formulary information in addition to physical, chemical, and biological testing. Additionally, physical testing and some biological testing are performed on a lot-to-lot basis.
Figure 1. Groups attached to the siloxane backbone can affect solubility and diffusivity significantly
Figure 2. A polymer containing endgroups that participate in a platinum-catalyzed addition reaction
Figure 3. A typical structure for a methyl phenyl silicone
Figure 4. A typical structure for a fluorosilicone
Manufacturers with experience in both arenas provide additional value when complex devices are reviewed by different centers. Drug device combinations that require the incorporation of drugs into a biomaterial may also benefit by having this process moved to an FDA-registered facility. This provides the device manufacturer a one-stop-shop option and an alternative for an ordinarily complex process.
Silicones in Drug Device CombinationsSilicones expanded into healthcare and medical applications in the 1950s after extensive use in the aerospace industry in the previous decade. Within 20 years, a considerable body of work established that silicone oils and crosslinked siloxane systems did not give rise to harmful consequences when subcutaneous, intracutaneous, and intramuscular administrations were performed.1 After being subjected recently to a decade-plus of bio-testing, silicone is probably the most researched biomaterial on the market.
Silicones and silicone-based products are used in the pharmaceutical industry as active ingredients and excipients in pharmaceutical formulations. Simethicones, a silicone-based anti-foam agent, are used in gastro-intestinal anti-gas applications, as well as processing aids in endoscopic surgeries. As an excipient, silicones can be the delivery media of the active agent.
Silicones have already demonstrated clinical and commercial success in drug delivery applications such as Norplant and Femring. Pharmaceutical agents are not limited to hormones, according to other patent filings. Other drugs cited included antidepressants and anxiolytics; vitamins B6, D, and E; antifungal, opioid analgesics; non-opioid analgesics; and antiviral compounds.2 Recent developments in the area of microelectromechanicalsystems (MEMS) and, more specifically bio-MEMS, provide another example of the use of silicones in emerging drug delivery technologies. Bio-MEMS are micro-systems capable of diagnosis and drug delivery functions that can be implanted for long periods of time, depending on the condition and treatment. As such, bio-MEMS manufacturers need to identify materials that provide the necessary biocompatibility and drug compatibility profiles for effective use. Silicone materials are cited as candidates for hermetic sealing applications and microfluidic components, according to several patent applications filed in the last several years.
Chemical and Physical FlexibilityPhysical flexibility refers to the forms in which silicones are supplied. The range of materials provided gives design engineers a number of options in process and end use. Following is a brief description of the types of silicones available and typical uses.
Silicone FluidsFluids are non-reactive silicone polymers. The viscosity of these materials depends largely on the polymer’s molecular weight and the steric hindrance of functional groups on the polymer chain. Fluids are typically used in lubrication and dampening applications.
Silicone GelsSilicone gels are composed of reactive silicone polymers and reactive silicone crosslinkers. These materials are designed to have a very soft and compliant feel when cured. Typical applications include tissue simulation, dampening, and some transdermal pressure-sensitive adhesive (PSA) applications.
Silicone PSAsSilicone PSAs are composed of polymers and resins. These materials are designed to perform in a cured and uncured state. PSAs form a non-permanent bond with substrates such as metals, plastics, glass, and skin.
Silicone ElastomersSilicone elastomers fall into several categories: high-consistency, liquid silicone rubbers (LSRs), low-consistency elastomers, and adhesives.
High-consistency elastomers are typically composed of high-viscosity polymers; high levels of reinforcing silica; and, at times, crosslinking polymers. High-consistency materials can be molded into parts by compression molding or extruded into tubing configurations.LSRs are elastomers that contain medium-viscosity polymers and moderate amounts of silica. The cured elastomers have good physical properties. They tend to have an uncured consistency like that of Vaseline. These materials can be molded into parts and require the use of liquid injection molding equipment.
Low-consistency silicones are pourable systems that are composed of lower-viscosity polymers and reinforcing fillers such as silica and resin. These systems have lower physical properties than high-consistency or LSR formulations but can easily be processed and molded by hand. These materials can be molded into parts by compression molding or can be used as cured-in-place seals or gaskets.
Adhesives are low-consistency elastomers that contain lower-viscosity polymers, reinforcing silica, and adhesion promoters. Silicone adhesives are designed to adhere silicones to various substrate surfaces, including metals, glass, and certain plastics.
Chemical FlexibilityIn drug device combinations that utilize the permeation characteristics of silicones in the delivery of the pharmaceutical agents, flexibility in the basic chemistry offers advantages. Device configurations can range from reservoir designs to a drug-in-elastomeric matrix. The key to these designs is the permeation of drugs and, specifically, the rate in which the drug permeates. Permeability of active agents is dependent on two factorssolubility and diffusivity. Both solubility and diffusivity in silicones can be significantly affected by groups attached to the siloxane backbone (Figure 1).
A brief description of some common types of polysiloxane derivatives can be helpful.
Dimethyl silicones, or dimethylpolysiloxanes, are the most common silicone polymers used industrially. These types of polymers are typically the most cost effective to produce and generally yield good physical properties in silicone elastomers and gels. The polymer pictured in Figure 2 contains vinyl endgroups that participate in a platinum-catalyzed addition reaction.
Methyl phenyl silicone systems contain diphenyldimethylpolysiloxane co-polymers. The steric hindrance of the large phenyl groups prohibits significantly high concentrations of diphenyl units on the polymer chain. The phenyl functionality boosts the refractive index of the polymers and silicone systems that use these polymers. Creating devices with several layers of diphenyl elastomer systems may be useful in controlling release rates of certain drugs. Figure 3 shows a typical structure for a methyl phenyl silicone.
Fluorosilicones are based on trifluoropropyl methyl polysiloxane polymers and used for applications that require a slightly hydrophilic elastomer. The trifluoropropyl group contributes a slight polarity to the polymer. While some fluorosilicones contain 100% trifluoropropylmethylpolysiloxane repeating units, other systems contain a combination of the fluorosiloxane units and dimethyl units to form a co-polymer. Adjusting the amount of trifluoropropyl methyl siloxane units in the polymerization phase provides optimal performance in specific applications. Figure 4 shows a typical structure for a fluorosilicone.
ConclusionThe rapid expansion of the drug device combination market will bring about rapid development of products in this area. If the device’s primary mode of action is somewhere in between a drug and device, it is likely that the combination device will be subject to an extensive review. Biomaterial or raw material manufacturers with both device and pharmaceutical experience should be in the best position to provide answers and solutions when navigating the complexity of this industry. Silicones have emerged as biomaterials and pharmaceutical agents and have proven to be successful in the drug delivery world. Given the flexibility in supplied forms and chemistry, drug delivery engineers should look to evaluate silicones for the next-generation drug delivery device.
References1 W. Lynch, Handbook of Silicone Rubber Fabrication, Van Nostrand Reinhold Company, New York, 1978.2 Nabahi and Shorhre, U.S. Pat. 6,039,968 (March 21, 2000)
Stephen Bruner has over ten years of experience in silicone chemistry and is currently the marketing director for NuSil Technology. He has a BA in chemistry from the University of Colorado and a Masters in business administration from Pepperdine University. Bruner can be reached at 805-684-8780 or email@example.com .