Sterilization of Drug-Loaded Composite Coatings for Implantable Glucose Biosensors.

BACKGROUND: An anti-inflammatory drug-loaded composite coating (dexamethasone-loaded poly (lactic-co-glycolic acid) [PLGA] microspheres/polyvinyl alcohol [PVA] hydrogel) was previously developed to counter the foreign body reaction to a fully implantable continuous glucose monitoring biosensor. The long-term sensor functionality was ensured in the presence of the drug-loaded composite coating thus facilitating better diabetes control and management. In order to advance such a drug-device combination product toward clinical testing, addressing sterilization remains a key step due to the heterogeneity of the product components. The main objective of this research was to investigate the effect of two terminal sterilization techniques: gamma radiation and ethylene oxide (EO) on the stability of the anti-inflammatory coatings as well as retention of the glucose sensing ability of the implantable sensor. METHOD: The composite coatings, their individual components, and the glucose-sensing elements of the biosensor were subjected to low-temperature gamma radiation and EO cycles. Detailed characterization was conducted on all components before and after sterilization. RESULTS: Exposure to gamma radiation affected dexamethasone crystallinity and glucose response linearity of the sensing element, whereas physical aging of microspheres in composite coatings was observed poststerilization with EO. Despite these effects, dexamethasone drug release from coatings was not significantly affected by either technique. CONCLUSION: The research findings indicate that both sterilization techniques are feasible for the sterilization of the dexamethasone-loaded PLGA microspheres/PVA hydrogel composite coatings, while EO was preferred for the sterilization of the glucose-sensing element of the biosensor.

Effect of implant formation on drug release kinetics of in situ forming implants.

In situ forming implants are attractive long-acting implant dosage forms due to their: i) ability to control drug release; ii) simple manufacturing process; and iii) minimally invasive administration. In situ forming implants are typically made of a drug, solvent, and a biocompatible polymer that controls drug release. Once injected in the subcutaneous tissue, they form solid depots through solvent/non-solvent exchange and phase separation of the biodegradable polymer (such as poly (lactic-co-glycolic acid), PLGA and poly (lactic acid), PLA). However, the mechanism of implant formation and the changes in their microstructure that determine drug release behavior are not fully understood. Furthermore, there is no standardized in vitro release testing method for in situ forming implants due to limitations in recreating bio-relevant and reproducible implant formation in vitro with controllable implant shape, dimensions and surface-to-volume ratio. In the present study, bio-relevant implant formation was recreated in vitro by testing five different methods to determine their effect on drug release kinetics, reproducibility, and internal microstructure formation. The leuprolide acetate formulation Eligard® was used as a model in situ-forming implant, consisting of lyophilized leuprolide acetate, and PLGA dissolved in N-methyl pyrrolidone. The results revealed that the in vitro implant formation method is a crucial step in the dissolution testing process that significantly impacts the release profile of in situ forming implants. An implant formation method that utilizes dissolvable polyvinyl alcohol (PVA) films allowed for initial drug burst release control by modulating implant dimensions (i.e. surface area) and resulted in reproducible in vitro release profiles. In addition, implant formation was shown to affect the internal microstructure of in situ forming implant and was the main factor controlling the release profile which consisted of an initial release phase followed by a release plateau (lag phase) and then a second erosion-controlled release phase.

Flow-through cell-based in vitro release method for triamcinolone acetonide poly (lactic-co-glycolic) acid microspheres.

The main objective of the current research was to develop a compendial flow-through cell apparatus based in vitro release testing method for sustained-release triamcinolone acetonide-loaded poly (lactic-co-glycolic) acid (PLGA) microspheres. Media-based and instrument-based parameters, such as surfactant type, concentration, media volume, flow rate, and testing temperature, were investigated. In addition, a detailed exploration was performed to reveal polymer degradation encompassing pore formation, channeling, and triamcinolone acetonide release from microspheres using freeze-fracture scanning electron microscopy. The developed USP apparatus 4 method demonstrated more than 85% drug release from the microspheres in 12 days and showcased reproducibility between different microsphere batches. Large medium volume (15 times saturation solubility) at low surfactant concentration was identified as a critical media-based parameter, with potential application in testing of other sensitive poorly soluble drugs. At 35 °C, drug release via pore channeling to the surface was evident, whereas at 39 °C, drug release slowed due to polymer plasticization. It was demonstrated here for the first time that elevated temperature-accelerated testing does not work for all PLGA-based microsphere products.

Sterilization of implantable polymer-based medical devices: A review.

This review article is focused on the sterilization techniques used for polymer-based implantable medical devices as well as the regulatory aspects governing sterile medical devices. Polymeric materials are increasingly used in implantable devices due to their biodegradable and biocompatible nature. Patients and medical staff often prefer long-term implantable devices and these can be achieved using high molecular weight polymers. Sterilization of polymer-based implantable devices is critical. Since all implantable devices must be sterile, the effect of the sterilization method on the different device components (such as, the polymer, the drug, the electronics, etc.) has to be considered. A comprehensive summary of the established sterilization methods is provided along with the possible effects on polymers. In addition, novel sterilization methods are also discussed.

Foreign Body Reaction to Subcutaneous Implants.

Subcutaneously implanted materials trigger the host's innate immune system, resulting in the foreign body reaction. This reaction consists of protein adsorption on the implant surface, inflammatory cell infiltration, macrophage fusion into foreign body giant cells, fibroblast activation and ultimately fibrous encapsulation. This series of events may affect the function of subcutaneous implants, such as inhibition of drug diffusion from long-acting drug delivery depots and medical device failure. The foreign body reaction is a complex phenomenon and is not yet fully understood; ongoing research studies aim to elucidate the cellular and molecular dynamics involved. Recent studies have revealed information about the specific role of macrophages and their differential activation towards pro- and anti-inflammatory states, as well as species differences in the timing of collagen deposition and fibrosis. Understanding of the diverse processes involved in the foreign body reaction has led to multiple approaches towards its negation. Delivery of tissue response modifiers, such as corticosteroids, NSAIDs, antifibrotic agents, and siRNAs, has been used to prevent or minimize fibrosis. Of these, delivery of dexamethasone throughout the implantation period is the most common method to prevent inflammation and fibrosis. More recent approaches employ surface modifications to minimize protein adsorption to 'ultra-low' levels and reduce fibrosis. However, the diverse nature of the processes involved in the foreign body reaction favor the use of corticosteroids due to their wide spectrum action compared to other approaches. To date, combination approaches, such as hydrophilic coatings that reduce protein adsorption combined with delivery of dexamethasone are the most effective.

Drug Distribution in Microspheres Enhances Their Anti-Inflammatory Properties in the Gottingen Minipig.

The foreign body reaction (FBR), one of the body's defense mechanisms against foreign materials, results in loss of implant biocompatibility. A popular strategy to prevent FBR is the constant release of dexamethasone in the tissue surrounding the implant. However, FBR prevention has not been sufficiently studied in large animal models, which offer a better representation of the human subcutaneous tissue physiology. Accordingly, a long-term strategy to prevent FBR to subcutaneous implants in a large animal model is necessary to translate the existing research for clinical applications. Here, a poly(lactic-co-glycolic) (PLGA) microsphere/poly(vinyl alcohol) (PVA) hydrogel composite coating for one-month prevention of FBR in Gottingen minipigs was developed. A modified PLGA microsphere formulation process is presented, that utilizes coprecipitation of dexamethasone and PLGA. Traditional methods result in heterogeneous distribution of large drug crystals in the microsphere matrix, which in turn results in low drug loading since the drug crystal size is close to that of the microspheres. The modified microsphere preparation method showed homogeneous distribution of dexamethasone, which in turn gave rise to increased drug loading, low burst release, and minimal lag phase. Elimination of the lag phase was dictated from previous work that compared FBR between rats and minipigs. The ability of the coatings to improve implant biocompatibility was successfully tested in vivo via histological examination of explanted tissue from the area surrounding the implants. The biocompatible coatings presented here are suitable for miniaturized implantable devices, such as biosensors, that require constant communication with the local microenvironment.