Advantages of Manufacturing Silicone Drug-Eluting Components via Ultraviolet Light Vulcanization Process
Combination products offer several advantages when compared with drug delivery via oral, injection, and infusion methods. All drug-device type combination products exhibit one or more of the following attributes. First, they provide controlled release of the active pharmaceutical ingredients (API) instead of bolus-type delivery; API concentrations can be consistently maintained within an optimal therapeutic range. Second, drug-eluting devices, particularly implanted devices, allow for a targeted delivery of the API. This targeted approach, when contrasted with systemic administration, permits higher therapeutic dosages to be delivered while minimizing adverse side effects. Third, combination products have been shown to improve patient compliance. Most healthcare practitioners now agree that within our aging population, compliance becomes less certain and therefore more important.Elastomers play an important role as a matrix or reservoir in many drug-eluting combination products. Silicone rubber in particular provides excellent release characteristics for numerous small molecule drugs. However, most silicone elastomers, especially those with physical properties suitable for long-term in vivo durability, are vulcanized at elevated temperatures that may cause rearrangement and subsequent inactivation of the drug molecule. The following study indicates that low-temperature vulcanization of silicone-drug mixtures using UV light provides a superior alternative to traditional thermal processes. More specifically, this study will show that Specialty Silicone Fabricators (SSF) (Paso Robles, CA) has developed a process to mold drug-eluting components using UV light and a 60- durometer liquid silicone rubber (LSR) developed and manufactured by Momentive Performance Materials (MPM) (Columbus, OH). This low-temperature process produced viable components in a fraction of time required to produce thermally cured components.
Silicone: Pros and Cons as Drug-Eluting Matrix
As a class of biomaterials, silicones offer the combination product designer several unique advantages over other materials. First, silicones, specifically elastomers, have a long history of use in the body. Biocompatibility and biostability of silicones have been well established in over 50 years of human implantation. Second, polymers and filler can be modified such that specific drugs will release at specific rates. Third, because of their helical conformation and weak intermolecular attraction, silicone elastomers exhibit high free volume. This in turn contributes to the exceptional permeability of polydimethylsiloxane (PDMS) elastomers. It has been shown that silicone elastomers are 25 times more permeable to oxygen than natural rubber and over 4000 times more permeable than polyvinylchloride. Compared with polyethylene, silicone is 1000 times more permeable to progesterone.
Despite these positive attributes, the fabrication of silicone drug components can be challenging. The advantages of UV-initiated vulcanization can be best appreciated when compared with other types of silicone cure systems currently used in healthcare applications.
In the broadest sense, silicones can be divided into two groups: those that must be heat-cured and a second group that vulcanizes at room temperature, commonly referred to as RTVs. RTVs are typically tin-catalyzed and include acetoxy, alkoxy, and oxime cure systems. Cure times are generally quite slow, from 30 minutes for alkoxy materials to 72 hours for acetoxy, and vary depending on part geometry and ambient conditions. Physical properties are marginal and in most cases, if not encapsulated, RTVs are insufficiently durable for implantation.
Thermally cured silicones include platinum and peroxide systems. Both systems can be formulated to produce elastomers with excellent physical properties. Peroxide systems must be heated to temperatures that are sufficient to cause free radical formation of the peroxide initiator. Vulcanization temperatures of 200 °C are typical. Platinum-catalyzed systems, also referred to as addition systems, vulcanize via hydrosilation, whereby hydrogen on a crosslinker reacts with vinyl groups on other polymer chains. The reaction is heat-accelerated and cure temperatures of 150 °C are common. Platinum-catalyzed systems can be formulated to cure at lower or even room temperature but reaction rates are reduced. The dependence of reaction rate on temperature agrees well with the Arrhenius equation. Reaction rates are doubled for a temperature increase of 10 °C.
Many active pharmaceutical ingredients (API) are altered at elevated temperatures. While platinum-catalyzed silicones may be vulcanized at various time/temperature parameters, low temperature fabrication, molding for example, may require such lengthy cycle times as to be economically non-viable. The purpose of this research was to demonstrate that a material and process have been developed that address the silicone drug vulcanization challenges inherent in currently available RTVs and thermal cure materials.
This research had 5 primary objectives: (1) Demonstrate the ability to vulcanize silicone elastomers containing various API at various concentrations using UV light; (2) For one of the API, dexamethasone sodium phosphate (DSP), vulcanize via both UV and thermal processes, and compare and contrast; (3) Produce test articles, cylindrical plugs, from silicone-DSP sheets vulcanized via both UV and thermal process; (4) Perform API elution rate analysis on both sets of DSP test articles; (5) Confirm that UV and thermal curing processes leave DSP unaltered.
Test Methodology UV Vulcanization
Test articles in this study were cylindrical plugs, similar in size and shape to those used on cardiac pacing leads. Extrusion and molding were both considered as possible fabrication methods. A viable extrusion process utilizing UV light for rapid in-line vulcanization had been demonstrated by an SSF-MPM team in 2010. While attractive, an extrusion process was ruled out due to the high volume demand of even small barrel extruders.
Attention then focused on developing a molding process. Rather than mold individual plugs, the team focused on forming and vulcanizing a slab from which plugs could be removed via a punching process. This process eventually proved very effective in producing representative test articles for both UV and thermal vulcanization. (See Fig. 1)