Factors in Selecting Medical Silicones
FACTORS IN SELECTING MEDICAL SILICONES
Written by: Alastair Winn
Source: Applied Silicones
Because of their inherently low toxicity, pure silicones present a low risk of unfavorable biological reactions and have thus gained widespread industrial and medical recognition and acceptance. The current health-care market supports a small group of manufacturers of silicone raw materials, companies such as General Electric, Wacker, Bayer, Dow Corning, Rhodia, Shin Etsu, Nusil Technology. The primary differences among these suppliers involve their level of testing and commitment to serving particular applications. Historically, concerns over potential liability have driven most large silicone manufacturers to aggressively exclude themselves from providing silicone intended to be used in the human body for more than 29 days. The author knows of only two suppliers willing to continue serving the long-term implantable silicone market: NuSil Technology and Applied Silicone.
Silicones as a Material of Choice for Drug Delivery Applications
Brian Reilly, NuSil Technology, email@example.com / Stephen Bruner, NuSil Technology
Presented at 31st Annual Meeting and Exposition of the Controlled Release Society,
June 12–16, 2004
This paper will investigate the benefits of using silicone in drug delivery applications. This investigation first provides an overview of how versatile of a material silicone can be to the drug delivery industry. An examination of the chemistry of silicone, the multiple material composition options and various cure chemistries demonstrates how silicone can be tailored to fit specific drug delivery applications. Then, a general investigation of the way a silicone interacts with a drug, in regards to compatibility and potential interactions, exhibits silicone’s ability to deliver pharmaceutical agents. The paper will also review factors that have made silicones the materials of choice in the medical device industry, particularly for long-term implantable devices. Examples of applications demonstrate the reasons for choosing silicone over a different material. The paper will finish with real world examples of current drug delivery applications incorporating a silicone, such as hormone replacement therapies, to manifest the benefits of using silicone in drug delivery applications.
The chemistry behind silicone essentially equates to material versatility, and this versatility allows silicone materials to be custom designed to fit drug delivery applications. The polymer chemistry that constitutes silicones allows various types of silicone polymers, which each provide varying properties beneficial to different applications. Silicone chemistry also makes a diverse set of material compositions available for a broad range of applications. Finally, silicone cure chemistry
provides options to optimize how a silicone can be used when applied to specific applications.
The term “Silicone” is actually a misnomer. Normally the suffix ‘-one’ delineates a substance has a double bonded atom of oxygen in its backbone. Scientists initially believed that silicone materials contained double bonded oxygen, hence the use of ‘silicone.’ However, silicones are really inorganic polymers, having no carbon atoms in the backbone, and therefore should be named ‘Polysiloxanes.’ The diagram below shows their typical structure:
This structure allows polysiloxanes to be used in a wide array of applications because different types of constituent groups can be incorporated onto the polymer. Different polysiloxanes can provide a variety of excellent elastomeric properties that can be chosen according to a specific use. Various types of silicones, or polysiloxanes, and their property advantages include:
Dimethyl silicones, or dimethylpolysiloxanes, are the most common silicone polymers used industrially. These types of polymers are typically the most cost effective toproduce and generally yield good physical properties in silicone elastomers and gels. The polymer pictured below contains vinyl endgroups that participate in a platinum catalyzed addition reaction (see section on Cure Chemistry for more information).
Methyl phenyl silicone systems contain diphenyldimethylpolysiloxane co-polymers. The steric hinderance of the large phenyl groups prohibit 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. Silicone polymers with diphenyl functionality are useful in bio-photonic applications (e.g., intraocular lenses) where higher refractive index materials can be useful in creating a thin lens. Creating devices with several layers of diphenyl elastomer systems may be useful in controlling release rates of certain drugs. The diagram below shows a typical structure for a methyl phenyl silicone:
Fluorosilicones are based on trifluoropropyl methyl polysiloxane polymers and used for applications that require fuel or hydrocarbon resistance. The trifluoropropyl group contributes a slight polarity to the polymer, resulting in swell resistance to gasoline and jet fuels. However, polar solvents such as methyl ethyl ketone and methyl isobutyl ketone may significantly affect fluorosilicones. 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. The diagram below shows a typical structure for a fluorosilicone:
While the polymer chemistry and structure of silicone provide the different types of silicones outlined above, they also allow those different types of silicones to appear in a wide variety of material compositions. This broad range of material compositions makes silicone a viable option to endless numbers of healthcare and drug delivery applications. Some silicone material compositions and their typical applications include:
Silicone Fluids are non-reactive silicone polymers formulated with dimethyl, methylphenyl, diphenyl, or trifluoropropylmethyl constituent groups. These materials’ viscosity depends largely on molecular weight of the polymer and steric hinderance of functional groups on the polymer chain. Fluids are typically used in lubrication and dampening applications.
Silicone Gels contain 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 and dampening.
Silicone Pressure Sensitive Adhesives (PSA’s) contain polymers and resins. These materials are designed to perform in an uncured state. PSA’s form a non-permanent bond with substrates such as metals, plastics, glass, and skin.
Silicone Elastomers fall into several categories: high consistency, liquid silicone rubbers, low consistency elastomers, and adhesives.
High consistency elastomers typically contain high viscosity polymers and high levels of reinforcing silica. These materials are clay-like in consistency in their uncured state, and offer good physical properties when vulcanized. High consistency materials can be molded into parts by compression or transfer molding, and are most commonly used for extrusion to yield tubing configurations.
Liquid silicone rubbers, or LSR’s, are elastomers containing 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 petroleum jelly. These materials can be molded into parts and require the use of liquid injection molding equipment.
Low consistency silicones are pourable systems composed of lower viscosity polymers and reinforcing fillers such as silica or resin. These systems have lower physical properties than high consistency elastomers or LSR formulations, but can be easily processed and molded by manual methods. These materials can be molded into parts by compression molding or used as cured-in-place seals or gaskets.
Adhesives are low consistency elastomers containing 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.
When a manufacturer in the drug delivery industry chooses a material for a specific application, material properties aren’t the only deciding factor. That manufacturer also has to examine how the material is used. Inconvenience in production or material by-products can make a chosen material ineffective for a specific application. Silicones, however, can be designed around various cure chemistries to accommodate different production needs. Silicone systems can cure by platinum catalyzed addition cured systems, tin condensation cure systems, peroxide cure systems, or oxime cure systems. Some of the oldest cure chemistry used with silicones utilizes an acetoxy tin condensation cure system. These systems yield a vinegar-like smell (acetic acid), a byproduct of the reaction. This discussion will focus on platinum systems, tin condensation systems, and peroxide systems.
Platinum catalyzed silicones utilize a platinum complex to participate in a reaction between a hydride functional siloxane polymer and a vinyl functional siloxane polymer. The result is an ethyl bridge between the two polymers. The reaction mechanism is pictured below:
Platinum systems are often cured quickly with heat, but can be formulated to cure at low temperatures or room temperature if necessary. The advantages of these systems include a fast cure and no volatile byproducts. The possibility of inhibiting the cure is the main disadvantage of platinum systems. Inhibition is defined as either temporarily or permanently preventing the system from curing. Some types of inhibitors are purposefully added to these systems to control the rate of cure. However, contact with tin, sulfur, and some amine containing compounds may permanently inhibit the cure. Compounds that inhibit the cure can be identified easily by attempting to cure a platinum catalyzed system in contact with the compound, as inhibition results in uncatalyzed regions of elastomer systems or inconsistency in cure over time.
Tin condensation systems involve hydroxyl functional polymers and alkoxy-functional cross linking compounds. The alkoxy functional cross linker first undergoes a hydrolysis step and is left with a hydroxyl group. This hydroxyl group then participates in a condensation reaction with another hydroxyl group attached to the polymer. The reaction can proceed without the assistance of the tin catalyst, but the presence of the catalyst boosts the rate of reaction. The reaction mechanism is pictured below:
The advantages of condensation systems include the ability to cure at room temperature (useful for temperature sensitive additives) and robust cure systems that are difficult to inhibit. The main disadvantage of condensation systems is the long cure time, as several days are often required to completely cure an elastomer.
Peroxide catalyzed systems, used mostly in high consistency elastomers (see definition below), have a reaction mechanism that involves a peroxide catalyst and either methyl groups or vinyl functional groups. The peroxide catalysts create free radical species of the methyl and vinyl that can then form covalent bonds. Pictured below is the reaction mechanism involving a peroxide catalysis of two methyl groups:
Peroxide systems are typically robust (not easily inhibited) and offer properties such as low tension set (good for balloon applications). Disadvantages include a lengthy post-curing step at high temperatures in order to remove the reaction’s byproducts. Other disadvantages include the possibility of the catalyst interacting with active agents.
The versatility of silicones as a material enables them to be a viable option for a broad range of drug delivery applications. Some of silicone’s specific properties and characteristics, such as its interactive chemistry and microporous structure, make them the material of choice for many drug delivery applications. This can be seen when looking at examples of silicones already being used in healthcare and drug delivery applications.
The siloxane polymer backbone of repeating silicon and oxygen atoms creates a potential for interaction. The two free pairs of electrons associated with each oxygen atom can form hydrogen bonds with proton donors. Silicone elastomer systems can be strengthened with silica or resin reinforcement. These systems can result in different degrees of hydrogen bonding.
Despite the ability to form hydrogen bonds, silicone is considered hydrophobic in nature. The methyl constituency on the siloxane polymer backbone creates this effect. This hydrophobicity is ideal for the solubility of pharmaceutical agents having mostly non-polar structures with alcohol or ketone structures. Below are the molecular structures for estradiol, levorphanol, and metrondiazole.
It appears the interaction between the oxygen of the siloxane backbone does have some hydrogen bonding with the alcohol functionality of many active pharmaceutical agents. This is evidenced by a rise in release rates when a fatty acid ester is used in a drug delivery device. The molecular structure of Linoleic Acid is shown below:
It is believed that fatty acid esters increase the hydrophobicity of the siloxane system (3). It can be speculated that the carboxylic acid group competes for siloxane oxygen, thereby reducing the concentration of siloxane oxygen available in the elastomer system. The exact mechanisms and interactions between the silicone polymer backbone and pharmaceutical agents are not known at this point.
The large atomic volume of the silicon atom, as well as the size and position of constituent groups, explain the virtually complete freedom of rotation around the Si-O-Si bond. Silicone polymers form helixes, and the bond angles of the silicon-oxygen bonds create large amounts of free volume in silicone elastomers. This free volume, and the high compressibility found in silicones, is associated with their permeability to gases and liquids. The gas permeability of silicone rubber is up to 100 times greater than natural or butyl rubber. Silicone rubbers swell in aliphatic, aromatic and chlorinated hydrocarbon solvents.
Silicone gaskets for industrial applications absorb lubricating oils and will tend to “wet” the surface of the elastomer system after the source of the lubrication is removed (1). NuSil Technology takes advantage of this phenomenon in the various self-lubricating elastomer formulations. Proprietary silicone fluids are incorporated into the elastomer formulation, and migrate to the surface of the molded component after cure.
Silicones expanded into healthcare and medical applications in the 1950’s after extensive use in the aerospace industry in the previous decade. Within twenty years, a considerable body of work established that silicone oils and crosslinked siloxane systems did not give rise to harmful consequences when performing subcutaneous, intracutaneous, and intramuscular administrations. In 1954 McDougall reported the cultures of various tissues of warm blooded animals, known to be extraordinarily sensitive to foreign influences, showed no deviation from the usual growth picture on contact with liquid, semisolid, and rubberlike silicone products (10). Silicones have been characterized as biologically and toxologically inert as a result of this work (1). Many applications such as pacemaker leads, hydrocephalus shunts, heart valves, finger joints and intraocular lenses utilize silicone materials.
Drug Delivery Applications
Evaluation and Fabrication
The first step in determining general compatibility of a silicone with an active agent is determining the solubility of the agent in silicone. Silicone oil can be used to determine if an agent may be soluble in a silicone elastomer system (2). Once solubility has been determined, the active agent can then be tested in the elastomer system to determine the optimal concentration or agent configuration for the target release rate per day and the total number of release days. In some devices, the drug is incorporated into a silicone matrix core or reservoir and the release rate is controlled by an outer layer of silicone (without pharmaceutical agents incorporated) on the device. (3,4,5,6,7).
A general review of those patents listed above suggests that 5% to 50% of the active agent is optimal for release rates of 10 to 500 micrograms of drug per day. These numbers are highly dependent on the type of drug, silicone, and any rate enhancing additives. The release rate is also cited on those patents above and has been characterized as essentially zero order.
Commercial applications such as Norplant (8) and Femring (9) are examples of clinically successful drug delivery applications that involve silicone materials. Patent number 6,039,968 cites a number of agents that could be used in drug eluting applications. The drugs cited included antidepressants, anxiolytics, vitamins B6, D, and E, antifungal, opioid analgesics, non-opioid analgesics, and antiviral compounds.
As presented above, an investigation of the chemistry of silicone and silicone materials, interactive characteristics, their extensive use in the healthcare industry and current drug delivery applications show the benefits of using silicone materials in a drug delivery device. The paper explored how versatile of a material silicone is and how this can benefit drug delivery. The interaction between drugs, release enhancing agents, and silicone systems was characterized by comparing molecule structures of each. The paper also demonstrated the history of silicone, in various forms, in healthcare applications since the 1950’s. Finally, commercially successful examples of products utilizing silicones demonstrate a commitment to silicone as a material of choice for drug delivery applications.
(1) W. Noll, Chemistry and Technology of Silicones, Academic Press, New York, 1968.
(2) Y. Chien, Novel Drug Delivery Systems 2nd Edition, Marcel Dekker, New York,
(3) Nabahi and Shorhre, U.S. Pat. 5,788,980 (August 4, 1998)
(4) McClay and Allen, U.S. Pat. 5,855,906 (January 5, 1999)
(5) Nabahi and Shorhre, U.S. Pat. 6,039,968 (March 21, 2000)
(6) Passmore and Clare and Gilligan and Clare, U.S. Pat. 6,416,780 (July 9, 2002)
(7) Nabahi and Shorhre, U.S. Pat. 6,103,256 (August 15, 2000)
(10) W. Lynch, Handbook of Silicone Rubber Fabrication, Van Nostrand Reinhold
Company, New York, 1978.
Comparing Silicone Pressure-Sensitive Adhesives to Silicone Gels for Transdermal Drug Delivery
By Manfred Hof, Polytec PT, Stephen Bruner and John Freedman, NuSil Technology, LLC
Presented at 33 Annual Meeting and Exposition of the Controlled Release Society July 22-26, 2006 Vienna, Austria
Transdermal, drug-delivery applications mandate the use of adequate adhesive systems to not only keep the pharmaceutical agent in contact with the intended surface, but to facilitate sustained, controlled delivery. An engineer who must determine which silicone chemistry is optimal for their device has a few options. This paper will investigate the differences in silicone pressure sensitive adhesives (PSAs) and silicone gels for transdermal drug delivery applications. The paper begins with analysis of the chemistry of silicone and silicone materials. The many variations of the chemistry demonstrate the versatility of using silicone in drug delivery applications. Further exploration of the materials demonstrates fundamental differences between silicone PSAs and silicone gels and the advantages and disadvantages of these materials in use. The findings of the study suggest that silicone gels can offer a compelling alternative to the more traditionally used silicone pressure sensitive adhesives. The paper does recognize that the tradeoffs between ease of use and physical properties need to be considered when evaluating both materials for transdermal drug delivery applications.
Since 1979, PSAs have been a mainstay in transdermal, drug delivery. PSAs, provide pharmaceutical companies the means to supply a range of active agents in a non-invasive, controlled-release system and reduce the healthcare industry’s dependence on gastrointestinal and needle-based administrations. The overriding benefits of these systems include improved patient compliance and steady drug levels within the bloodstream.
Estradiol, testosterone, and nitroglycerin are just a few of the compounds currently found in prescribed, transdermal, drug-delivery systems. Over-the-counter (OTC) products such as Dr. Scholl’s Clear Away Wart Remover, Neutrogena’s On-the-Spot Acne Treatment, and several brands of the nicotine patch are examples of how this technology has moved readily into direct consumer applications. Estimates for growth in this area are 12 percent annually(1). Some of the usual adhesives incorporated in transdermal, drug-delivery systems are polyisobutylenes (PIBs), silicones and acrylic-based PSAs. For this article, silicone-based PSAs are used for comparative purposes. Silicones are good candidates for transdermal, drug-delivery systems because they offer two major benefits to drug-device developers. First, silicones have a more than 50-year history in biomedical applications and, in that time, a considerable body of work has been assembled that characterizes silicones as biologically inert(2). In addition, silicones are ubiquitous in the medical device industry in both long-term, implantable devices and external devices. Second is the compatibility/permeability of silicones with many pharmaceutical agents, not just hormones. Other compatible drugs include antidepressants; anxiolytics; vitamins B6, D, and E; antifungals; opioid and non-opioid analgesics; and antiviral compounds (3).
Silicones’ compatibility and permeability with pharmaceutical agents is a function of the siloxane-based polymers and resins used to formulate these systems, and the siloxane polymer backbone of repeating silicon and oxygen atoms creates an interaction potential. The two free pairs of electrons associated with each oxygen atom can form hydrogen bonds with proton donors, often resulting in different degrees of hydrogen bonding with reinforcing fillers. Despite its ability to form hydrogen bonds, silicone is considered hydrophobic in nature. The methyl constituency on the siloxane polymer backbone creates this effect. A vinyl-terminated, dimethyl polysiloxane can be seen in Figure 1.
Figure 1. A vinyl-terminated, dimethyl polysiloxane’s hydrophobicity is ideal for the solubility of pharmaceutical agents.
This hydrophobicity is ideal for the solubility of pharmaceutical agents having mostly non-polar structures. Another characteristic of silicone systems is the large atomic volume of the silicon atom itself, which – along with the size and position of constituent groups – explains the virtually complete freedom of rotation around the Si-O-Si bond. Silicone polymers form helixes, and the bond angles of the silicon-oxygen bonds create large amounts of free volume in silicone elastomers. This free volume, and the high compressibility found in silicones, is associated with their permeability to certain gases and liquids. The gas permeability of silicone rubber is up to 100 times greater than natural or butyl rubber.
In the specific case of drugs or active pharmaceutical molecules, release rates in silicones are determined by the drug’s solubility in a silicone and the diffusion coefficients of those drugs in silicones through the Higuchi equation(4,5)(equation 1 corresponds to a matrix device, and equation 2 corresponds to a reservoir device):
Equation 1 : Q = (Dsil (2A – Csil) Csil t)1/2
Equation 2 : Q = ((Dsil Csil)/ hsheth)*t.
“Q” is the cumulative amount of drug released per device-unit area, “A” is the drug loading, “Csil” is the drug solubility in the silicone, “Dsil” is the diffusivity of the drug in the elastomer, “hsheath” is the thickness of the sheath in cm, and “t” is the time in days. Determination of these values is aided by additional research in this area that relates the molecular weight and melting point of the drugs to release rates (4), as well as demonstrates that the addition of fatty acid esters improve release rates of certain drugs(6). Silicone polymer chemistry can be modified to include different groups on the backbone. For example, trifluoropropyl methyl dimethyl siloxane copolymers are used in applications in which solvent resistance is required, while diphenyl silicone polymers are used in elastomeric formulations, when a high-refractive index is necessary (intraocular lenses or UV and heat protection). The diphenyl and trifluoropropylmethyl functionality may also affect drug solubility and, in turn, affect release rates. The concentration of these groups on the backbone can be easily altered and optimized for specific compounds. A diphenyl polysiloxane structure is seen in Figure 2.
Figure 2. A diphenyl polysiloxane structure can be easily altered and optimized for specific compounds.
Silicone PSAs incorporate a high-molecular-weight polydimethylsiloxane polymer and a tackifying silicone resin dispersed in a solvent system. The solvent provides the system with viscosity control, as silicone components are virtually impossible to process at room temperature with standard coating equipment. If containing a catalyst, silicone PSAs typically crosslink by curing after removing the solvent. Two systems are currently available: platinum-catalyzed and peroxide-catalyzed. Platinum catalyzed systems are common in PSAs and utilize vinyl functional polymers, such as those pictured above, and hydride functional crosslinking polymers to cure in the presence of the catalyst. Figure 3 diagrams the cure mechanism of a platinum system. Curing of these PSAs is achieved through multi-zone ovens. The solvent is eliminated by a gradual increase in temperature from 60°C to 90°C.
Figure 3. Platinum cure mechanism.
Peroxide-cure system employs benzoyl peroxide, or 2,4-dichlorobenzoyl peroxide, as a catalyst to drive a free-radical reaction and achieve cure. Curing is normally performed in a multi-zoned oven. Solvent removal is achieved through a gradual increase in temperature, starting at 60°C to 90°C to ensure that the peroxide catalyst does not cure while solvent is present. The temperature is then increased to 130°C to 200°C, eliminating the peroxide through decomposition. The reaction mechanism is pictured below in Figure 4. A high-crosslink-density PSA can be better achieved through peroxide curing due to the ability to increase peroxide levels up to 4 percent.
Figure 4. Peroxide cure reaction mechanism.
Tape and adhesive-backed component fabricators take the liquid PSA and either wet coat in sheet form, for small applications, or in roll form (pilot coaters and full-width production coaters), when large quantities are required. The PSA may be applied on one or both sides of a substrate – such as Kapton®, Mylar®, Nomex®, foils, foams, and rubbers – or it can be coated directly onto a release film. Coat weights on supported film range from 0.0003” to more than 0.010” thick. When the adhesive is coated directly onto a release film, this is called an unsupported PSA transfer film. Common post-production processes include die cutting and laser cutting for later use in component assembly, and automated pick-and-place solutions for difficult-to-apply parts and materials(7).
Silicone PSAs are not without their drawbacks. As stated above, most PSAs are dispersed in a solvent system to provide viscosity control. The solvent can be problematic and limiting to transdermal, drug-delivery systems. Environmental concerns regarding Volatile Organic Compounds (VOCs) and plant-safety initiatives are costly factors that must be considered. In addition, solvent systems are dynamic, and evaporating solvent can impact viscosity, leading to process variations. PSAs can also limit the transdermal system design, as these materials are typically used in multilaminate, reservoir designs. PSAs that utilize peroxide systems, as mentioned above, require an elevated temperature and may negatively impact active agents. This limitation may require that the PSA is processed in a separate step.
Silicone Gel Technology
Silicone gels share the same basic siloxane polymer chemistry as silicone PSAs but lack the silicone resin credited with supplying adhesive strength to the system. Silicone gels are typically composed of two types of siloxane polymers: vinyl-functional polysiloxanes and hydride-functional polysiloxanes. Silicone gels are low-viscosity materials that are not dispersed in solvent systems. These materials do not contain reinforcing fillers, such as silica or silicone resins, found in silicone elastomer systems. As a result, they offer little tensile or tear strength. Typically, gels used in thin-film applications use reinforcing fabrics to add strength.
The tack and adhesion of silicone gels have proven sufficient in transdermal, adhesive-type applications. The testing discussed later in this article illustrates the superior tack properties of silicone gels compared to silicone PSAs. Pfizer’s Scar Solution and Smith & Nephew’s Cica Care are OTC examples of silicone gels used in transdermal applications to treat hypertrophic and keliod scarring.
Silicone gels cure in the presence of platinum catalysts to solid forms that do not flow. Gels can be formulated to cure completely at low temperatures, which may be ideal for pharmaceutical agents that are unstable a higher temperatures. These materials can be utilized in mulitlaminate, reservoir or monolayer, drug-in-adhesive delivery systems.
Comparative Adhesive Properties
The discussion above provides some basic differences between silicone PSAs and gels from chemistry to supplied forms. The following data was compiled to determine the key property differences between silicone PSAs and gels (and differences in silicone gels with dissimilar compositions). The two properties tested in this study were 90-degree peel strength (NuSil Technology Test Method TM087 Reference ASTM D1876) and tack testing (NuSil Technology Test Method TM103 Reference ASTM D429 Method D)(8).
Because pressure-sensitive system properties are influenced by the thickness or amount of adhesive, care was taken to ensure identical amounts of silicone were used. The materials were prepared per the applicable test method and specific material cure recommendations. Four materials were tested; Table 1 describes the material and characteristics:
Results and Discussion
The testing was performed in triplicate for each material, results appear in Table 2:
Table 2. Test Results.
From the data, it is apparent silicone gels offer higher tack, but lower peel strength, than PSAs. It also appears that gels containing phenyl functionality gave higher tack and peel results than the dimethyl gel. The timing of the study prevented a multiple lot measurements of tack and peel but more research is underway to determine the statistical differences between these products. Despite the small sample size, these results are consistent with industry knowledge of these types of products.
The discussion and data presented above provide transdermal, drug-delivery system designers with another choice in pressure-sensitive-type, silicone-based adhesives. Silicones’ historic healthcare use and drug solubility make both silicone PSAs and tacky gels good candidates for certain drug-delivery applications. From the data, it appears silicone gels offer higher tack, but lower peel strength, than PSAs. It also appears that gels containing phenyl functionality gave higher tack and peel results than the dimethyl gel. When considering these results – alongside factors such as drug-release rates, VOC elimination and reservoir/matrix delivery designs it is clear that, no matter which chemistry you choose, tradeoffs must be expected.
The authors would like to thank Susan Rhodes of Akron University for her content contributions and expertise in PSA technology, Jim Lambert for his research contributions, and NuSil Technology LLC’s technical healthcare group and commercial testing services for their work.
(1) L. Townsend Ferguson, Adhesives In Transdermal Drug Delivery Systems,
http://www.adhesivesmag.com/CDA/ArticleInformation/features/BNP_Features_Item article posted 11/01/05
(2) W. Noll, Chemistry and Technology of Silicones, Academic Press, New York, 1968.
(3) Nabahi and Shorhre, U.S. Pat. 6,039,968 (March 21, 2000)
(4) K. Malcolm, D.Woolfson, J. Russell, P.Tallon, L. McAuley, D. Craig, Influence of Silicone Elastomer Solubility and Diffusivity on the In Vitro Release of Drugs from Intravaginal Rings Journal of Controlled Release 90 (2003) 217-225
(5) S. Mojtaba Taghizadeh, A. Mashak., A. Jamshidi, M Imani, Study of Progesterone Release Mechanisms from a Silicone Matrix by a New Analytical Method Journal of Applied Polymer Science, Vol 91, 3040-3044 (2004) © 2004 Wiley Periodicals, Inc.
(6) Nabahi and Shorhre, U.S. Pat. 5,788,980 (August 4, 1998)
(7) B.Reigler, J. Meyer Low Outgas Pressure Sensitive Adhesives for Aerospace Applications, presented at SAMPE Conference, June 2004, NuSil Technology
(8) NuSil Technology’s Test Methods are available by request at www.nusil.com
ADDING COLOR TO MEDICAL DEVICES
Summer L. Sivas, Ace Hilmission, Steve Bruner, and Brian Reilly
NuSil Technology LLC
Medical device companies continue to support the healthcare community by distinguishing models, sizes and improving the aesthetics of the device with the addition of color. Color in medical devices offers a number of benefits in marketing the device. Adding color can help differentiate the product in a competitive marketplace, and the addition of corporate colors can also create a strong tie to the company’s brand. Another factor to consider is the migration of medical devices to home use, emphasizing the need for aesthetics to improve use compliance and other factors.1
Many applications — such as cosmetic implants, pacemaker leads, hydrocephalus shunts, heart valves, finger joints and intraocular lenses — utilize silicone materials. Adding color to silicone materials that are extruded, molded or calendared is a common manufacturing process for medical devices that utilize silicone parts. Processing and consistency are two major challenges when incorporating pigments into silicone. Typically, coloring silicone materials involves incorporating powdered pigments directly into an uncured elastomer via milling or mixing. Pigments are typically not soluble in silicone, which leads to processing problems. If the pigments are not dispersed homogenously, color variations will result in the cured part. Particulate contamination, handling and additional cleaning of equipment can also add considerable delays in production time, as well as costly maintenance.
The key to color consistency is the accurate addition of pigment(s) to the elastomer and the homogeneous dispersion of those pigments in the elastomer system. An ideal dispersion breaks down the pigments into their primary particle size using high-shear mixing and then disperses the particles homogenously throughout the silicone polymer. This process takes a high level of expertise and high-quality mixing equipment. Colorability is also affected by high pigment powder concentration. The highly filled elastomers tend to be more opaque, drastically changing the color. Another aspect influencing colorability is the thickness of the device, especially for transparent colored silicones.
A more effective alternative to adding color pigments to a silicone polymer directly is to incorporate a color masterbatch prior to the curing stage of the molding or extruding process. In a silicone, color masterbatch pigment is already dispersed in a functional silicone polymer. Typical low-grade masterbatches are simply powders wet-out to be non-dusting materials. While in color-dispersion masterbatches, the pigments are broken down and distributed homogenously in the polymer. The silicone polymers used in the color masterbatches have vinyl functionality and will partake in the cure or tie in with the elastomer system. This leads to two benefits: a reduced effect on the cured physical properties and no “bleeding out” or increase in extractables, which can be experienced when non-functional polymers are used.
NuSil silicone color masterbatches were co-developed with Gayson SDI for coloring low-consistency silicone rubbers (LSRs) and high-consistency silicone rubbers (HCRs). They are offered in an array of both solid colors, including white, black red, orange, yellow green, dark blue and blue and an addition line of transulescent colors are available for coloring LSRs. Colors also can be customized or color-matched to fit a variety of device needs. For coloring LSRs used in the injection molding of silicone parts, a low-viscosity masterbatch can be introduced via a third line prior to the dynamic mixing stage. For HCRs used in tubing extrusion, calendaring and transfer molding applications, a high-viscosity gum polymer masterbatch can be added directly to the elastomer on a two-roll mill during the softening/mixing step. NuSil will also supply most any of its silicone products pre-colored as a ready to use material eliminating any color processing.2
The benefits of using a color masterbatch or colored silicone dispersion will help eliminate particulate contamination in cleanrooms and reduce the costly cleaning time associated with processing powdered pigments. The exceptional color precision will also ensure unparalleled color consistency and improve device esthetics.
REGULATORY CONSIDERATIONS FOR COLOR IN MEDICAL DEVICES
What differentiates NuSil’s color masterbatches from other color options in the medical device market is its level of biological testing and support. Silicones expanded into healthcare and medical applications in the 1950s after extensive use in the aerospace industry and have undergone a steady growth in use and importance ever since.3,4 During the last 20 years, a considerable body of work has established that siloxane systems do not give rise to harmful consequences and have been characterized as biologically inert.5
Pigment masterbatches require regulatory support comparable to that provided for the elastomers into which they are incorporated.2 NuSil’s line of color masterbatches are supported by U.S. FDA Class VI testing and many ISO-10993 standards. The USP Class VI testing consists of systemic toxicity, intracutaneous reactivity, seven-day muscle implantation, genotoxicity, pyrogenicity and sensitization testing. These products are supported by a comprehensive Master Access Files (MAF) submitted to the United States Food and Drug Administration (FDA). NuSil’s products are also documented quality system certified as conforming to ISO 9001 and adhere to Good Manufacturing Practice.
The benefits of adding color to medical devices are numerous. Several considerations must be taken into account when adding color to silicone materials used in a device. Processing and, more specifically, concentration accuracy and clean up, are important initial factors to consider. Color consistency in the cured part depends on the optimal filler concentration, material thickness, and cure conditions. Regulatory requirements, as they relate to materials used in medical devices, should be a concern throughout the entire process. When adding color to a material, keeping these factors in mind will ultimately serve to smooth a complicated process.
1. K. Marshall Plastic Material Innovations Help Shape Healthcare Industry. Medical
Design Technology, 2008.
2. Peignot, P., Sivas, S. L., Bruner S. Adding Color to Medical Devices Using Pigment
Masterbatch. Presented at Silicone Elastomers Conference, Munich Germany, March
3. Compton RA. Silicone manufacturing for long-term implants. Journal of Long-Term
Effects of Medical Implants 1997;7(1):1-26.
4. McMillin CR. Elastomers for biomedical applications. Rubber Chemistry And
5. Yoda R. Elastomers for biomedical applications. Journal Of Biomaterials Science,
Polymer Edition 1998;9(6):561-626.
Drug Delivery Summary
Silicones have been cited as materials regularly used in drug delivery devices. These drug delivery devices incorporating silicones primarily fall into three major categories:
• Implanted delivery devices
• Mucosal delivery devices
• Transdermal delivery devices
Implanted drug delivery devices include spinal treatment devices, ocular treatment devices and contraceptive devices. These delivery configurations typical utilize silicone tubing or molded configurations. The silicone is used to either hold or precisely deliver the drug to a specific location. Liquid silicone rubbers or high consistency silicone rubbers can be molded into precise configurations required by these applications.
Transmucosal drug delivery devices can include silicone elastomer systems with the drug incorporated into the silicone matrix. After the device is placed in contact with the mucosal membrane, the drug elutes from the device at a controlled rate. A non-medicated sheath is cited (References 12,11,7) as a means to control the initial burst of drug from the device. Drugs can be incorporated into liquid silicone rubbers and molded into various configurations.
Transdermal delivery devices are primarily skin patches in configuration. The drug may be incorporated directly into the adhesive of the patch or may exist as a separate layer. Silicone pressure sensitive adhesives have been used in these applications because of the low skin sensitization, oxygen and drug permeability properties they offer. Silicone materials used in medical device configurations can also be treated with drug infused coatings.
NuSil Technology offers a complete line of off the shelf silicones and offers customized versions of the following materials types:
Two types of liquid silicone rubbers are cited as candidates for transmucosal drug delivery systems, non-acetoxy RTV silicones and platinum catalyzed silicones.
Drugs or Active Agents
The table below is a list of drugs cited (References 5-14) as candidates for incorporation into a silicone transmucosal drug delivery device. These same citations list typical amounts of 5 to 15% by weight of the drug for release rates of 10 to 500 micrograms per day in a 30 to 60 day time frame. Rate enhancing additives can improve release rates significantly (Reference 9) and are listed below the table. Release rates are essentially zero order. Particle sizes, where applicable, are cited as below 200 microns for the most effective release rates. References for these drugs are listed in the references section under transmucosal drug delivery.
Rate Enhancing Additives
Silicone polymers are relatively hydrophobic and it’s thought the list of compounds below can increase the rate of release. The typical amount by weight added to the elastomer system is cited at 5 to 20%.
NuSil Technology / Drug Delivery
NuSil Technology is actively involved in the development of custom materials for the drug delivery industry. Our customers range in size from Fortune 500 to start-up ventures. NuSil’s focus on silicone materials and chemistry can help customers prototype devices quickly. We have worked extensively with major pharmaceutical customers to supply materials for several commercially successful drug delivery devices on the market today.
Please contact a NuSil Technology technical sales representative regarding additional resources on silicone’s use in drug delivery applications at 805-684-8780.
Transdermal Drug Delivery:
(1) Woodward, J.T and Metevia, V.L. Transdermal Drug Delivery Devices with Amine-Resistant Silicone. U.S. Patent 4,655,767
(2) Studen, J.R., Method and Composition for the Treatment of Scars. U.S. Patent 6,337,076
Implanted Drug Delivery Devices:
(3) Segal, M., Patches, Pumps, and Timed Release FDA Consumer (October 1991)
(4) DiCosmo, F. and Ditizio and Valerio Drug Delivery via Therapeutic Hydrogels U.S. Patent 6,228,393
Transmucosal Drug Delivery Devices:
(5) Woolfson AD, Malcolm RK, Gallagher R (2000) Ther. Drug Del. Carr. Sys., 17, 509-555
(6) McCullagh, SD, Woolfson AD, Malcolm RK, Gallagher R (2001) Novel Silicone Crosslinkers for Intravaginal Drug Delivery British Pharmaceutical Conference Abstract
(7) Nabahi, Shorhe Intravaginal Drug Delivery Device U.S. Patent 6,039,968
(8) Malcolm RK, Woolfson AD, Elliott G, Shepard M Intravaginal Drug Delivery Devices for the Admistration of an Antimicrobial Agent U.S. Patent Application 2030059456
(9) McClay A Intravaginal Drug Delivery Devices for the Admisnstration of 17.bets.-oestradiol Precursors U.S. Patent Number 5,855,906
(10) Zimmerman I, Windt F, Reck HJ Vaginal Ring U.S. Patent 4,822,616
(11) Passmore C, Gilligan C Intravaginal Drug Delivery for he Adminisrtation of Testosterone and Testosterone Precursors U.S. Patent 6,416,780
(12) Nabahi, Shorhe Intravaginal Drug Delivery Device U.S. Patent 6,103,256
(13) Nabahi, Shorhe Intravaginal Drug Delivery Device U.S. Patent 5,788,980
(14) Saleh SI, Nash HA, Bardin WC, Harmon T Intravaginal Rings with Insertable Drug Containing Core U.S. Patent 6,126,958
Warnings About Product Safety:
NuSil Technology believes that the information and data contained herein is accurate and reliable; however, it is the user’s responsibility to determine suitability and safety of use for these materials. NuSil Technology can not know the specific requirements of each application and hereby makes the user aware that is has not tested or determined that these materials are suitable or safe for any application. It is the user’s responsibility to adequately test and determine the safety and suitability for their application and NuSil Technology makes no warranty concerning fitness for any use or purpose. There has been no testing done by NuSil Technology to establish safety of use in any medical application.
NuSil Technology has tested its materials only to determine if the product meets the applicable specifications. (Please contact NuSil Technology for assistance and recommendations when establishing specifications.) When considering the use of NuSil Technology products in a particular application, you should review the latest Material Safety Data Sheets and contact NuSil Technology for any questions about product safety information you may have.
No chemical should be used in a food, drug, cosmetic, or medical application or process until you have determined the safety and legality of the use. It is the responsibility of the user to meet the requirements of the U.S. Food and Drug Administration (FDA) and any other regulatory agencies. Before handling any other materials mentioned in the text, you should obtain available product safety information and take the necessary steps to ensure safety of use.
NuSil Technology disclaims any expressed or implied warranty against the infringement of any patent. NuSil Technology does not warrant that the use or sale of the products described herein will not infringe the claims of any United States patents or other country’s patents covering the product itself or the use in combination with other products or in the operation of any process.
Understanding the Role of Silicones in Controlled Release Applications
Nathan Wolfe, Technical Sales
Alex Kurnellas, Technical Writer
As one of the most widely researched biomaterials to date, silicone has an approximate 50-year legacy of use in the healthcare industry. This history of biocompatibility has made silicone a material of choice for both long and short-term implantable device applications. The last twenty years have seen the emergence of targeted release and combination product applications. These technologies evolved as the result of pharmaceutical and medical device manufacturers seeking novel ways to achieve their therapies. So, raw materials that were formerly chosen for their performance capabilities in medical device applications are now tasked with maintaining those requirements but also with meeting a host of new performance expectations that are specific to drug delivery applications. Faced with these new challenges few raw materials have succeeded in transitioning quite as well as silicone. This is because silicones possess certain dynamic characteristics which allow them to be compounded in with a host of actives. These same unique characteristics also allow them to release those actives from a molded/extruded device in a predictable way – whether that application is for transdermal, transmucosal, short or long-term human implantation. This article will highlight key attributes of certain silicones as well as key considerations when selecting a silicone.
When designing a drug delivery application with silicone, the first question to be answered relates to the product’s basic design. Generally speaking there are two configurations to choose from: matrix and reservoir.
A matrix design is where the active is mixed homogenously into the silicone and then molded, extruded, etc. into the desired geometry. A good example of this might be a central venous catheter impregnated with actives intended to combat infection. Reservoir configurations are the other primary device design. A reservoir device is one where an active is concentrated in a void in the center of a molded silicone part. A good example of this would be several early-generation contraceptive devices that were implanted just under the skin; small silicone tubes were molded or extruded, cured, filled with active and then sealed with silicone adhesives. It’s important to understand the impact that the design of a part or device has on how the active will be released. Generally speaking, matrix designs release the most active initially and then the release rate tapers off whereas reservoir devices will exhibit an initial spike and then normalize into a lower but consistent release rate.
If it is decided that a matrix design is ideal, there are a number of considerations that must be evaluated. The first order of business is to establish that the active in question is appropriately soluble in silicone. As most silicones are hydrophobic in nature it is important to either know or establish the extent to which the active in question is hydrophobic/lipophilic. If an active is extremely polar and, subsequently, hydrophilic, it will not readily dissolve into most traditional silicone formulations. As a direct result of insolubility a matrix design would no longer be an option. Once solubility is established the next question has to do with how one wishes to process the part/device in question. If the design relies upon heat curing the molded or extruded silicone part then the matrix design may not be an option if the active in question is heat sensitive. Here again, understanding the chemical characteristics of the API is key and the specific temperature threshold must be determined. Perhaps the desire is to mold a matrix design and the drug is found to be robust relative to temperature, there still remains the potential that the platinum catalyzed, heat accelerated silicone will be inhibited by the active in question; it has been observed that some actives common to combination products are chemically very similar to an inhibitor often used to control the work time (pot life) of platinum systems. This can result in excessive work times or even failure of a part to cure. In such instances one option is to mold with rapidly curing moisture sensitive cure chemistries. However, it’s important to note that these concerns are specific to matrix designs and not reservoir. All this having been said, it’s understandable to wonder how an active moves, (or diffuses) through a cured silicone medium at all. To better understand this phenomenon it is necessary to cover some basics of silicone chemistry.
To start with, silicone is an inorganic polymer, having no carbon atoms in its backbone. However, because the pendant groups off this backbone do contain carbon atoms it is fair to classify silicone as an “organo-polysiloxane”. It is these organic pendant groups that make silicone hydrophobic. A typical
silicone polymer structure is shown below.
The constituent if the polymer is functional or non-functional. If a polymer only contains non-functional pendant groups (methyl, fluoro and/or phenyl), the polymer is essentially nonreactive, not easily crosslinked and generally only used as a fluid. While non-functional silicone fluids can be used as excipients to facilitate the diffusivity and ultimate elution of certain APIs through a device or part molded from a silicone elastomer, this article limits its scope to drug delivery applications relying simply on curable silicone chemistry.
Accordingly a closer look will now be taken at silicone gels, liquid silicone rubber elastomers (LSRs) and high consistency rubber elastomers (HCRs).
Silicone gels are polymers – similar to fluids – except that they contain reactive groups, which allow the polymers to crosslink. Because the degree of crosslinking (or crosslink density) tends to be minimal and because these materials tend to have little or no filler (silica, resin, diatomaceous earth, etc.) silicone gels cure into a soft and compliant gel-like rubber. Typical applications include tissue simulation.
Liquid silicone rubbers, or LSR’s, are elastomers containing medium viscosity polymers and moderate amounts of silica. They tend to have an uncured consistency like that of petroleum jelly and the cured elastomers have good physical properties. These materials can be molded into parts and require the use of liquid injection molding equipment.
High consistency elastomers typically contain high viscosity polymers and sometimes contain higher levels of reinforcing silica. These materials are clay-like in consistency in their uncured state, and offer good physical properties when vulcanized. High consistency materials can be molded into parts by compression or transfer molding and are most commonly used for extrusion to yield tubing configurations. All of the above silicones rely upon the same basic repeating siloxane polymer and for each the pendant groups may be customized. Gels are loosely crosslinked, with little or no filler. LSRs have more crosslinking and more filler. Lastly, HCRs, are basically the same as LSRs except their polymers are of a much higher molecular weight. Due to the fact that all of the above rely on the same basic siloxane polymer they all benefit from a unique characteristic that is inherent to these polymers – a lot of empty space. Specifically, the large atomic volume of the silicon atom, as well as the size and position of the applicable pendant groups, result in bond angles that yield a high degree of free volume. This free volume then provides what may be considered “microporous pathways” for liquids and gasses (including water vapor) to migrate through a cured silicone medium.