Darren Svirskis

Electrochemically controlled drug delivery based on intrinsically conducting polymers

This paper reviews the application of intrinsically conducting polymers (ICPs) in drug delivery. ICPs are organic polymers with electrical, magnetic and optical properties usually associated with metals, whilst retaining the advantageous mechanical properties and ease of processing usually associated with polymers. Due to the inherent properties of these unique materials, electrical stimulation can be used to alter the redox state of ICPs, which in turn can modify the release rate of drug. The controlled release of drugs from ICPs has been reported in the literature since the 1980s. Following continued development, clinical applications of ICP-based drug delivery systems (DDS) have been reported recently. The next generation of controlled release technologies could utilise the biosensing properties of ICPs combined with their drug delivering abilities to develop an intelligent drug delivery system from a single material where the release rate of drug self adjusts in response to a sensed change in local body environment. This article provides an overview of ICP synthesis and properties relevant to their use as DDS, including biodegradability and biocompatibility, followed by literature on ICP-based DDS examining different methods of drug incorporation and release. The pharmaceutical applications of these systems have also been discussed. It is concluded that ICPs hold great promise in drug delivering implants where the dose can be adjusted through application of external stimulus, thus optimising benefit to side effect ratio while simultaneously ensuring patient adherence.

High surface area polypyrrole scaffolds for tunable drug delivery

Intrinsically conducting polymers such as polypyrrole (PPy) are viable platforms for efficient drug delivery, where release rates can be tuned by external electrical stimulus. In this study, the successful fabrication of 3-dimensionally ordered macroporous PPy inverse opal thin films is described, and the viability of such films for controlled drug release evaluated in vitro. The PPy inverse opal thin films were obtained by electropolymerization of PPy through the interstitial voids of a colloidal crystal template composed of poly(methyl methacrylate) colloids of diameter ∼430 nm. Chemical etching of the template yielded macroporous PPy inverse opal scaffolds. The model drug risperidone was loaded into the PPy inverse opal films, and then entrapped by electropolymerization of a non-porous PPy overlayer. The morphology and chemical composition of the PPy scaffolds were evaluated by SEM and FTIR spectroscopy, respectively. The high surface area PPy inverse opal scaffolds exhibited enhanced drug loading and releasing capabilities compared to conventional non-porous PPy films. Drug release profiles could be modified by applying electrical stimulus, which caused actuation of the porous polypyrrole films. The proposed delivery system may find use as an implantable device where drug release can be electrically tuned according to patient requirements.

Implants for drug delivery to the posterior segment of the eye: a focus on stimuli-responsive and tunable release systems.

Efficient drug delivery to the posterior segment of the eye is a challenging task for the formulation scientist. Current treatment of chronic back-of-the-eye conditions requires frequent intravitreal injections of drug containing solutions due to the short half-life and limited tissue permeation of the administered molecules. Sustained release ocular delivery systems offering reduced administration frequencies have therefore gained popularity over recent years with a few implants already on the market and many more in the pipeline. However, current implants generally release drug at a predetermined rate without the ability to alter release rates. As required drug concentrations may change over the course of treatment due to the individual patients clinical response, implants from which release rates can be tuned could optimize treatment efficacy. This article provides an overview of diseases of the posterior segment of the eye, describes currently available implants to treat such conditions and discusses advantages and disadvantages of various implant locations. Finally, stimuli-responsive drug delivery technologies that have been investigated for, or have the potential to be applied to, drug delivery to the back of the eye will be discussed. Emphasis is hereby placed on polymeric implants responsive to an electric current, light or a magnetic field to achieve tunable drug release.

In-situ phase transition from microemulsion to liquid crystal with the potential of prolonged parenteral drug delivery

This study is the first to investigate and demonstrate the potential of microemulsions (MEs) for sustained release parenteral drug delivery, due to phase transition behavior in aqueous environments. Phase diagrams were constructed with Miglyol 812N oil and a blend of (co)surfactants Solutol HS 15 and Span 80 with ethanol. Liquid crystal (LC) and coarse emulsion (CE) regions were found adjacent to the ME region in the water-rich corner of the phase diagram. Two formulations were selected, a LC-forming ME and a CE-forming ME and each were investigated with respect to their rheology, particle size, drug release profiles and particularly, the phase transition behavior. The spreadability in an aqueous environment was determined and release profiles from MEs were generated with gamma-scintigraphy. The CE-forming ME dispersed readily in an aqueous environment, whereas the LC-forming ME remained in a contracted region possibly due to the transition of ME to LC at the water/ME interface. Gamma-scintigraphy showed that the LC-forming ME had minimal spreadability and a slow release of (99m)Tc in the first-order manner, suggesting phase conversion at the interface. In conclusion, owing to the potential of phase transition, LC-forming MEs could be used as extravascular injectable drug delivery vehicles for prolonged drug release.

Electrically switchable polypyrrole film for the tunable release of progesterone

BACKGROUND Intrinsically conducting polymers, such as polypyrrole (PPy), have been utilized for drug delivery purposes as drug release rates can be tuned by electrical stimulation. Electrical stimulation can be used to switch the redox state of PPy, subsequently changing the electrostatic charge and volume of the polymer. Most literature to date has focused on the delivery of charged bioactives. This study aimed to prepare a PPy film formulation where the release rate of the uncharged drug progesterone could be electrically tuned. RESULTS & DISCUSSION In this study PPy films loaded with progesterone are described. Drug loading levels were influenced by the concentration of drug during manufacture and polymerization time. The polymer formulation was electrically conductive and electroactive, switchable between oxidized and reduced states. Drug release was influenced by the application of electrical stimulation, the greatest release was observed on application of +0.8 V (to oxidize the polymer). Triggered release was observed in response to a period of electrical stimulation (±0.8 V at 0.5 Hz). CONCLUSION This study describes the preparation of a PPy film loaded with the uncharged drug progesterone. The release rate could be tuned with electrical stimulation.

Conducting polymers with defined micro- or nanostructures for drug delivery

Conducting polymers (CPs) are redox active materials with tunable electronic and physical properties. The charge of the CP backbone can be manipulated through redox processes, with accompanied movement of ions into and out of the polymer to maintain electrostatic neutrality. CPs with defined micro- or nanostructures have greatly enhanced surface areas, compared to conventionally prepared CPs. The resulting high surface area interface between polymer and liquid media facilities ion exchange and can lead to larger and more rapid responses to redox cycling. CP systems are maturing as platforms for electrically tunable drug delivery. CPs with defined micro- or nanostructures offer the ability to increase the amount of drug that can be delivered whilst enabling systems to be finely tuned to control the extent and rate of drug release. In this review, fabrication approaches to achieve CPs with micro- or nanostructure are outlined followed by a detailed review and discussion of recent advances in the application of the materials for drug delivery.

Evaluation of vitamin D medicines and dietary supplements and the physicochemical analysis of selected formulations

ContextVitamin D is purported to offer wide ranging and numerous health benefits leading to increased interest from manufacturers of medicines and dietary supplements. Elderly patients frequently require vitamin D supplementation due to reduced sun exposure and dietary intake. There are ever increasing numbers of vitamin D formulations in the global market. However, due to a lack of regulatory restrictions for some of these products the quality of these dosage forms can be of some concern.ObjectivesTo study vitamin D formulations available in the global market and evaluate physic-chemical properties of selected formulations from the New Zealand market.MethodThe first component of this study consisted of a search for different vitamin D formulations available in selected countries. The second component of the study involved assaying selected vitamin D formulations available in New Zealand. Vitamin D was extracted from capsule, tablet and emulsion formulations and quantified using a validated High Performance Liquid Chromatography (HPLC) method.ResultsOf the 14 analysed formulations, only 60% were within 100+10 % of the label claim. The two registered, prescription formulations available exhibited vitamin D levels of 90+4% and 97±2% of the labeled amount, while non-registered, non-prescription dietary supplements had vitamin D levels ranging from 8±2% to 201±29% of the labeled amount.ConclusionsDietary supplements do not require strict regulation and showed a large variation in the percentage label claim of vitamin D. Prescription formulations which are more strictly regulated gave content values within standard acceptance ranges. Vitamin D has proven health benefits and also the potential to cause harm, therefore there is a need for tougher regulations of dietary supplements to ensure acceptable quality.

Physicochemical characterization of asulacrine towards the development of an anticancer liposomal formulation via active drug loading: stability, solubility, lipophilicity and ionization.

To facilitate the development of a liposomal formulation for cancer therapy, the physicochemical properties of asulacrine (ASL), an anticancer drug candidate, were characterized. Nano-liposomes were prepared by thin-film hydration in conjugation with active drug loading using ammonium sulphate and post-insertion with Poloxamer 188. A stability-indicating HPLC assay with diode array detection was developed for the determination of ASL concentrations. The U-shaped pH-solubility profile in aqueous solutions, with a lowest solubility at pH 7.4 (0.843 μg/mL), indicated that ASL is an ampholyte, and dilution or neutralization of acidic drug solutions used in clinical trials with physiological fluids may cause drug precipitation. The basic pKa value measured by absorbance spectroscopy was 6.72. The logD value at pH 3.8 was 1.15 which increased to 3.24 as pH increased to 7.4. ASL was found to be the most stable in acidic conditions and degraded most rapidly in alkaline conditions. An extra-liposomal pH of 5.6 during drug loading was found to be optimal to achieve the highest drug loading (DL) of 4.76% and entrapment efficiency (EE) of 99.9%. At this pH, >90% of ASL was ionized conferring high drug solubility (1mg/mL) and acted as a reservoir of unionized ASL to be transported into liposomal cores. As a suspension the optimized liposomes showed great physicochemical stability for five months at 4°C. In summary, the obtained physicochemical parameters provided insightful information useful to maximise DL into the liposomes, and explain a tendency of drug precipitation of pH-solubilized formulations following intravenous infusion.

Systematic review of the systemic concentrations of local anaesthetic after transversus abdominis plane block and rectus sheath block

Background. Safe and efficacious modalities of perioperative analgesia are essential for enhanced recovery after surgery. Truncal nerve blocks are one potential adjunct for analgesia of the abdominal wall, and in recent years their popularity has increased. Transversus abdominis plane block (TAPB) and rectus sheath block (RSB) have been shown to reduce morphine consumption and improve pain relief after abdominal surgery. These blocks typically require large volumes of local anaesthetic (LA). We aimed to synthesize studies evaluating systemic concentrations of LA after perioperative TAP and RSB to enhance our understanding of systemic LA absorption and the risk of systemic toxicity. Methods. An independent literature review was performed in accordance with the methods outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. An electronic search of four databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and PubMed) was conducted. Primary articles measuring systemic concentrations of LA after single-shot bolus TAPB or RSB were included. Results. Fifteen studies met the inclusion criteria. Rapid systemic LA absorption was observed in all studies. Of a total of 381 patients, mean peak concentrations of LA exceeded toxic thresholds in 33 patients, of whom three reported mild adverse effects. The addition of epinephrine reduced systemic absorption of LA. No instances of seizure or cardiac instability were observed. Conclusions. Local anaesthetic in TAPB and RSB can lead to detectable systemic concentrations that exceed commonly accepted thresholds of LA systemic toxicity. Our study highlights that these techniques are relatively safe with regard to LA systemic toxicity.

Polypyrrole Film as a Drug Delivery System for the Controlled Release of Risperidone

Conducting polymers are finding applications in medicine including drug delivery systems, biosensors and templates for the regeneration of nervous pathways. We aim to develop a novel system where the drug release rate can be controlled by electrical stimulation. Polypyrrole (PPY) is being used as a drug delivery system due to its inherent electrical conductivity, ease of preparation and apparent biocompatibility. Risperidone is an atypical antipsychotic drug used in the treatment of psychosis and related disorders, including schizophrenia. PPY was synthesised using p‐toluene sulfonic acid as a primary dopant, in the presence of risperidone. A validated high performance liquid chromatography (HPLC) analytical method was used to quantify risperidone release. It has been demonstrated that the release rate of risperidone can be altered through the application, or absence, of electrical stimulation. Technology such as this would find use in drug‐delivering implants where the dose could be adjusted through appl...