A non-opioid analgesic implant for sustained post-operative intraperitoneal delivery of lidocaine, characterized using an ovine model.

Appropriate management of post-operative pain is an ongoing challenge in surgical practice. At present, systemic opioid administration is routinely used for analgesia in the post-operative setting. However, due to significant adverse effects and potential for misuse, there is a perceived need for the development of alternative, opioid-sparing treatment modalities. Continuous infusion of local anesthetic into the peritoneum after major abdominal surgery reduces pain and opioid consumption, and enhances recovery from surgery. Here we describe a non-opioid, poly(ethylene-co-vinyl-acetate) intraperitoneal implant for the sustained delivery of local anesthetic following major abdominal surgery. A radio-opaque core had the required mechanical strength to facilitate placement and removal procedures. This core was enclosed by an outer shell containing an evenly dispersed local anesthetic, lidocaine. Sustained release of lidocaine was observed in an ovine model over days and the movement modelled between peritoneal fluid and circulating plasma. While desirably high levels of lidocaine were achieved in the peritoneal space these were several orders of magnitude higher than blood levels, which remained well below toxic levels. A pharmacokinetic model is presented that incorporates in vitro release data to describe lidocaine concentrations in both peritoneal and plasma compartments, predicting similar release to that suggested by lidocaine concentrations remaining in the device after 3 and 7 days in situ. Histological analysis revealed similar inflammatory responses following implantation of the co-extruded implant and a commercially used silicone drain after three days. This non-opioid analgesic implant provides sustained release of lidocaine in an ovine model and is suitable for moving onto first in human trials.

Microneedle Systems for Vaccine Delivery: the story so far.

INTRODUCTION: Vaccine delivery via a microneedle (MN) system has been identified as a potential alternative to conventional vaccine delivery. MN can be self-administered, is pain-free and is capable of producing superior immunogenicity. Over the last few decades, significant research has been carried out in this area, and this review aims to provide a comprehensive picture on the progress of this delivery platform. AREAS COVERED: This review highlights the potential role of skin as a vaccine delivery route using a microneedle system, examines recent advancements in microneedle fabrication techniques, and provides an update on potential preclinical and clinical studies on vaccine delivery through microneedle systems against various infectious diseases. Articles for the review study were searched electronically in PubMed, Google, Google Scholar, and Science Direct using specific keywords to cover the scope of the article. The advanced search strategy was employed to identify the most relevant articles. EXPERT OPINION: A significant number of MN mediated vaccine candidates have shown promising results in preclinical and clinical trials. The recent emergence of cleanroom free, 3D or additive manufacturing of MN systems and stability, together with the dose-sparing capacity of the Nanopatch® system, have made this platform, commercially, highly lucrative.

Analysis of the Postoperative Periarticular Environment and Influence on Sustained Drug Delivery From a Gel Formulation.

Regional intraarticular delivery of local anesthetics is effective in treating postoperative pain following total knee or hip replacement. Recent research efforts have been only partially successful in achieving sustained release of the analgesic agent, in part due to limited understanding of the biological environment into which these formulations are administered. This study aimed to detail the composition and properties of postoperative periarticular fluid (PO-PAF). PO-PAF was collected from 8 patients, and the composition and physicochemical properties were determined. A number of components were identified which are lacking from phosphate buffered saline (PBS) or other synthetic media. The differences in composition led to variation in the physicochemical properties of PO-PAF compared with PBS. Notably, significantly lower surface tension (p <0.05) and higher buffer capacity (p <0.05) were observed in the biological fluid. We demonstrated that the solubility of lidocaine is almost double in PO-PAF compared to PBS (p <0.05) and that lidocaine release from a poloxamer gelling system occurred faster into PO-PAF under both sink and nonsink conditions. Collectively, these data indicate PBS is inappropriate for the in vitro evaluation of intraarticular drug delivery systems. The presented data describe that PO-PAF and will support the future development of biorelevant media to ultimately improve in vivo-in vitro correlation.

Comparing human peritoneal fluid and phosphate-buffered saline for drug delivery: do we need bio-relevant media?

An understanding of biological fluids at the site of administration is important to predict the fate of drug delivery systems in vivo. Little is known about peritoneal fluid; therefore, we have investigated this biological fluid and compared it to phosphate-buffered saline, a synthetic media commonly used for in vitro evaluation of intraperitoneal drug delivery systems. Human peritoneal fluid samples were analysed for electrolyte, protein and lipid levels. In addition, physicochemical properties were measured alongside rheological parameters. Significant inter-patient variations were observed with regard to pH (p < 0.001), buffer capacity (p < 0.05), osmolality (p < 0.001) and surface tension (p < 0.05). All the investigated physicochemical properties of peritoneal fluid differed from phosphate-buffered saline (p < 0.001). Rheological examination of peritoneal fluid demonstrated non-Newtonian shear thinning behaviour and predominantly exhibited the characteristics of an entangled network. Inter-patient and inter-day variability in the viscosity of peritoneal fluid was observed. The solubility of the local anaesthetic lidocaine in peritoneal fluid was significantly higher (p < 0.05) when compared to phosphate-buffered saline. Interestingly, the dissolution rate of lidocaine was not significantly different between the synthetic and biological media. Importantly, and with relevance to intraperitoneal drug delivery systems, the sustained release of lidocaine from a thermosensitive gel formulation occurred at a significantly faster rate into peritoneal fluid. Collectively, these data demonstrate the variation between commonly used synthetic media and human peritoneal fluid. The differences in drug release rates observed illustrate the need for bio-relevant media, which ultimately would improve in vitro-in vivo correlation.

Development, Validation and Application of a Stability Indicating HPLC Method to Quantify Lidocaine from Polyethylene-co-Vinyl Acetate (EVA) Matrices and Biological Fluids.

An efficient and cost-effective quantification procedure for lidocaine by HPLC has been developed to estimate lidocaine from an EVA matrix, plasma, peritoneal fluid and intra-articular fluid (IAF). This method guarantees the resolution of lidocaine from the degradation products obtained from alkaline and oxidative stress. Chromatographic separation of lidocaine was achieved with a retention time of 7 min using a C18 column with a mobile phase comprising acetonitrile and potassium dihydrogen phosphate buffer (pH 5.5; 0.02 M) in the ratio of 26:74 at a flow rate of 1 mL min-1 with detection at 230 nm. Instability of lidocaine was observed to an oxidizing (0.02% H2O2) and alkaline environments (0.1 M NaOH). The calibration curve was found to be linear within the concentration range of 0.40-50.0 µg/mL. Intra-day and inter-day accuracy ranged between 95.9% and 99.1%, with precision (% RSD) below 6.70%. The limit of quantification and limit of detection were 0.40 µg/mL and 0.025 µg/mL, respectively. The simple extraction method described enabled the quantification of lidocaine from an EVA matrix using dichloromethane as a solvent. The assay and content uniformity of lidocaine within an EVA matrix were 103 ± 3.60% and 100 ± 2.60%, respectively. The ability of this method to quantify lidocaine release from EVA films was also demonstrated. Extraction of lidocaine from plasma, peritoneal fluid and IAF followed by HPLC analysis confirmed the utility of this method for ex vivo and in vivo studies where the calibration plot was found to be linear from 1.60 to 50.0 µg/mL.

Injectable thermosensitive gelling delivery system for the sustained release of lidocaine.

BACKGROUND: Patients undergoing arthroplasty require appropriate postsurgical pain relief. Analgesia is typically achieved through bolus doses of short-acting local anesthetics and with oral analgesics such as opiates, which are associated with systemic side effects. By formulating an injectable thermosensitive gelling system containing lidocaine, sustained and local delivery can be achieved following a single administration. RESULTS: Poloxamer-based thermosensitive gelling formulations were prepared. Altering the weight ratios of poloxamers affected the sol-to-gel transition temperature, mechanical and rheological properties and in vitro drug release. Desirable formulations gelled between 28 and 33°C providing sustained release of lidocaine over 48 h. CONCLUSION: Thermosensitive gelling systems are promising for sustained drug release following patient administration and may be beneficial in addressing postoperative pain.

Controlled release drug delivery systems to improve post-operative pharmacotherapy.

Over 230 million surgical procedures are conducted worldwide each year with numbers increasing. Pain, undesirable inflammation and infection are common complications experienced by patients following surgery. Opioids, non-steroidal anti-inflammatory drugs (NSAIDs), local anaesthetics (LAs) and antibiotics are the commonly administered drugs peri-operatively to manage these complications. Post-operative pharmacotherapy is typically achieved using immediate-release dosage forms of drugs, which lead to issues around fluctuating plasma concentrations, systemic adverse effects and poor patient adherence. Controlled release (CR) systems for certain medicines including opioids, NSAIDs and antibiotics have demonstrably enhanced treatment efficacy in the post-surgical setting. However, challenges remain to ensure patient safety while achieving individual therapeutic needs. Newer CR systems in the research and development pipeline have a high level of control over medicine release, which can be initiated, tuned or stopped on-demand. Future systems will self-regulate drug release in response to biological markers providing precise individualized therapy. In this review, we cover currently adopted CR systems in post-operative pharmacotherapy, including drug eluting medical devices, and highlight a series of examples of novel CR technologies that have the potential for translation into post-surgical settings to improve medication efficacy and enhance post-surgical recovery.

Application of Carbopol/PVP interpolymer complex to prepare mucoadhesive floating granule.

Novel mucoadhesive floating granule was prepared using Carbopol/PVP interpolymer complex to deliver hydrophilic drugs in a controlled manner. Acetaminophen was used as a model drug. Maximum floatability of the granules was obtained at the ratio of 1/1, where 95 % of the granules floated for 12 h. As the concentration of sodium bicarbonate increased, both the floating duration and the release rate of the drug increased. The granules without sodium bicarbonate floated only for 2 h and floating onset time was 15 min. The release rate of drug gradually increased as the drug content in the granule increased. As the drug content in the granules increased, duration of adhesion decreased. However, the decrease in adhesion duration was minimal up to 40 % of drug content. The release rate from the granules prepared by dry granulation method was faster than that by wet granulation. The granules prepared by dry granulation method led to formation of highly porous structure; whereas, that by wet granulation method showed non-porous structure. The optimum size of the granules to retard the release of the model drug was within the range of 3-4 mm. Based on both mucoadhesive and buoyant properties, the floating granules are expected to reside in the upper part of the stomach for sufficient period of time and release the drug in a sustained manner.