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)
Momentive Performance Materials developed and supplied the silicone for this study, a UV-curable, two-part, 60-durometer LSR. The UV light source used in this research, a CoolWave 2-610 conveyor system, was provided by the Nordson Corporation of Amherst, OH.
Various UV transparent materials and mold designs were evaluated as tooling options and incremental improvements were made throughout the study. The final tool, shown in Fig 2, includes top and bottom 8-mm PMMA plates and a center screw that provided uniform torque across the slab, thereby minimizing thickness variability. The plates were separated by a 2 mm stainless steel spacer.
Four Active Pharmaceutical Ingredients (API) were included in the study. The API included Dexamethasone Sodium Phosphate (DSP), a steroidal anti-inflammatory immunosuppresant glucocorticoid; Doxycycline Hyclate, a tetracycline antibiotic; Diclofenac, a non-steroidal anti-inflammatory; and Fluocinolone Acetonide, a corticosteroid. Molecular weights ranged from 295 to 516 g/mol.
Compounding processes were optimized for each of the four API-silicone mixtures. The general approach was to place 10–20 grams of silicone and the appropriate amount of powdered API in a 50 mL plastic container. The contained material was then subjected to low-frequency, high-intensity acoustic energy as well as dual asymmetric centrifugal shear forces. The homogenized API-silicone mixture was then transferred to a 10 cc syringe and centrifuged.
Each of the 4 API-silicone mixtures were secured in the PMMA mold then placed on a conveyer belt that transported the mold through the UV chamber. Each pass through the chamber provided 10 seconds of UV exposure. Because the UV chamber was fitted with a unidirectional top mounted lamp, it was necessary to rotate the mold, top to bottom, with each pass. Vulcanization was determined via durometer measurements with complete cure defined as a value greater than 55. Results are summarized in Table 1 as follows. Two points should be considered when interpreting this data. First, UV lamp intensity is highest at the midpoint of the curing chamber. Exposure times required for API-silicone vulcanization would be reduced by stationary positioning of the mold directly under the UV light source. Second, it was shown that vulcanization was directional and that material closest to the UV lamp cured more quickly. It is expected therefore that UV light sources positioned above and below the mold would reduce curing time by 50 percent.
Research then turned to the thermal vulcanization of a silicone- dexamethasone mixture. While it is known that silicone components containing this drug are used in the cardiology sector, details of the thermal curing processes used are not known. The compound is comprised of 4 cycloalkane rings and as such is expected to have limited thermal stability. A sample of the DSP was therefore evaluated via differential scanning calorimetry, DSC, to determine drug stability at elevated temperatures.
The DSC profile, provided by IASIS Molecular Sciences, (Fig. 3) reveals a steady rising slope with a first inflection beginning at 130 °C and a clear melting exotherm at 216 °C. A conservative molding temperature of 120 °C was chosen to insure thermal stability of the drug. A rheometer test was then performed on a 60-durometer, platinum-catalyzed LSR, supplied by Momentive Performance Materials. At 120 °C, the trace showed that the LSR began vulcanization quickly around 2:40. T90 was calculated at 3:03.
DSP was then added at 15.0% to the MPM 60 durometer LSR, placed in a stainless steel mold, and press cured for 6 minutes at 120 °C. Durometer of 60 confirmed complete cure.
Fifteen cylindrical plugs, roughly 2 mm in height with an outer diameter of 1.9 mm, were removed from both the UV and thermally cured DSP slabs. Both sets of test articles were sent to IASIS for drug elution rate testing. IASIS randomly selected 7 test plugs from each set of 15 supplied. Test plugs from each set were placed into 7 cuvettes containing phosphorus buffered solution (PBS) at 37 °C. DSP concentration was analyzed over 72 hours using an Agilent-8453 UV spectroscopic device with temperature control and multi-cell kinetics function. Elution rates are shown in Fig. 4.
With the exception of outliers in cells 7 and 8, elution results for test plugs cured via UV light fell in a tight range between 38.47 μg and 42.43 μg. It is likely that the higher elution of the outliers was due to non-micronized DSP particles on the surface of test articles 7 and 8, causing a pronounced burst effect within the first 5 hours of testing. Elution values for thermally vulcanized test plugs ranged from 41.97 μg to 48.39 μg. Both test groups reached a steady state condition at approximately 30 hours.
Finally, Fourier Transform Infrared Spectroscopy (FTIR) as well as proton and carbon Nuclear Magnetic Resonance (NMR) analysis was performed to confirm the identity of DSP. Results for both UV and thermally vulcanized material confirmed that DSP was unaltered by processing.
This research met the five stated objectives:
- Four API were compounded and subsequently vulcanized using UV light. API concentrations ranged from 1.0 to 15.0%. Furthermore it was demonstrated that silicone with low concentrations of API, 1.0 and 1.3%, could be vulcanized within 40 seconds of exposure to UV light. Silicones containing higher concentrations of API, DSP at 15.0% and fluocinolone acetonide at 10.0%, were vulcanized within 100 seconds. It is believed that equipment modifications to the UV curing chamber, such as stationary positioning of the mold as well as top and bottom lamps, would reduce curing time by more than 50 percent.
- Silicone-DSP was cured via both UV and thermal methods. UV curing time was 100 seconds. Thermal cure cycle was 6 minutes.
- A process was developed and demonstrated that produced nearly identical test articles from both UV and thermally cured elastomers.
- Elution rate testing of UV and thermally cured test articles showed similar results.
- FTIR and NMR analysis showed that the UV process, as described above, did not alter the DSP molecule.
Low-temperature vulcanization of silicone-drug mixtures using UV light provides an alternative and potentially superior fabrication method to traditional thermal processes. Furthermore, it is expected that this UV-light-activated process will greatly expand the utility of silicone elastomers in drug-eluting applications and will increase the candidate pool of active pharmaceutical ingredients (API) that may be used in such combination product components.