Search

Purpose: To evaluate the use of resonant acoustic mixing (RAM) technology for homogenous blending of a morphologically challenging model API in low-dose concentrations (<0.1% w/w), and assess the potential for blend uniformity (BU) optimization. Methods: Caffeine (CAF) mixing was carried out using a LabRAM I benchtop mixer. Uniformity was assessed under a range of mixing conditions and sample preparation procedures in order to optimize system performance. The capacity for microscale mixing was evaluated from final parameters for 0.05% and 0.0125% CAF blends. Results: Upon optimization, RAM was able to accurately prepare homogeneous mixtures of <0.1% CAF in dilutions of up to 1 part per 8,000. Results from a 0.05% blend targeting 125 μg CAF dosage amounts revealed an AV score of 8.8 while a 0.0125% w/w blend accurately prepared 25 μg of CAF with 99.3% accuracy (98.7% label claim) and AV of 10.1. Microscale mixing in the 0.05% w/w blend was confirmed from plots of BU data against sample size demonstrating a slope of 0.05 within the range of 250–10 mg sample (125–5 μg CAF). L1 BU criteria only failed at the level of 2 μg CAF, despite target precision to 26 nanograms (98.7% label claim). Conclusions: This study presents the first instance of a homogenously mixed <0.1% (w/w) blend using RAM technology and demonstrate the suitability for reproducible dosing of single-digit microgram drug amounts. Uniformity is documented for API amounts 60x smaller than a recent report has shown and 10,000x smaller than achieved previously with CAF. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is an aggressive liver cancer with limited effective treatment options. In this study, we selected TLR agonists imiquimod (IMQ), gardiquimod (GARD), GS-9620 and DSR 6434, and a small molecule checkpoint inhibitor, BMS-202, for characterization of drug loading and release from radiopaque embolic beads (DC Bead LUMI) for potential use in image-guided transarterial embolization (TACE) of HCC. The maximum drug loading capacity and amount of drug released over time were determined by high performance liquid chromatography and compared with the commonly used anthracycline, doxorubicin hydrochloride (Dox). Maximum drug loading was 204.54 ± 3.87, 65.28 ± 3.09, 65.95 ± 6.96, 65.97 ± 1.54, and 148.05 ± 2.24 mg of drug per milliliter of DC Bead LUMI for Dox, GARD, DSR 6434, IMQ, and BMS-202, respectively. Fast loading and subsequent rapid release in saline were observed for IMQ, GARD, and DSR 6434. These drugs could also be partially removed from the beads by repeated washing with de-ionized water suggesting weak interaction with the beads. Aggregation of IMQ was observed in water and saline. GS-9620 partially decomposed in the solubilizing solution, so loading and release were not characterized. Compared to TLR agonists, slower loading and release were observed for Dox and BMS-202. Potential factors influencing drug loading into and release from DC Bead LUMI including steric hinderance, hydrophobicity, drug pKa, and the electrostatic nature of the beads are discussed. The maximum loading capacity of BMS-202 and Dox in DC Bead LUMI exceeded the maximum theoretical loading capacity of the beads expected from ionic interaction alone suggesting additional drug-bead or drug-drug interactions may play a role. Slightly more release was observed for BMS-202 at early time points followed by a slower release compared to Dox. Further study of these drug-bead combinations is warranted in search of new tools for locoregional delivery of immune-modulating agents for treatment of HCC via drug-eluting bead chemoembolization. [ABSTRACT FROM AUTHOR]

Achieving efficacious systemic levels of orally administered peptides is incredibly challenging due to the significant barriers to their bioavailability—their stability in the gastrointestinal tract and challenge of transepithelial transit, and variable pharmacokinetics. Even so, as the generally preferred route of administration, significant research effort in academic and industrial settings has focused on enabling the systemic absorption of orally delivered peptides. Despite several decades of research, few have ever reached the market. The recent approval of Rybelsus® (oral semaglutide) by the FDA [1], the EMA [2], and the Pmda [3] represents a significant landmark in the delivery of therapeutic peptides and is the culmination of more than 30 years research and development of the drug delivery technology enabling the product—Emisphere's Eligen™ technology—and an outstanding commitment to scientific, technical, and clinical innovation by Novo Nordisk. Following years of fundamental and applied research, an innovative clinical strategy led to the aptly named PIONEER clinical programme. This included ten Phase 3 clinical trials that demonstrated the tablet formulation to be as effective as the already approved injectable form of the drug, and more effective than competitor products in terms of its blood glucose lowering effects and weight loss. Not only is this a potentially life changing medicine for diabetic patients, it holds tremendous commercial potential for Novo Nordisk, with some analysts predicting the product to reach $5 billion in peak revenues [3]. In this "Inspirational Note," we summarize some of the public domain work that led to the achievement of this significant milestone and provide commentary on its potential future impact. [ABSTRACT FROM AUTHOR]

Current therapy for hypervascular cancers, e.g., hepatocellular carcinoma, includes occlusion of the tumor blood supply by arterial infusion of embolic microspheres (beads) suspended in iodine-based contrast under fluoroscopic guidance. Available radiopaque, imageable beads use iodine as the radiopacifier and cannot be differentiated from contrast. This study aimed to synthesize and characterize imageable beads using bismuth as the radiopacifier that could be distinguished from iodine contrast based upon the difference in the binding energy of k-shell electrons (k-edge). Radiodense bismuth beads were successfully synthesized some with uniform bismuth distribution across the beads. The beads were spherical and could be infused through clinical microcatheters. The bismuth beads could be imaged with clinical dual-energy computed tomography (CT), where iodine-based contrast could be distinguished from the microspheres. The ability to separate iodine from bismuth may enhance the diagnostic information acquired on follow-up CT, identifying the distribution of the embolic beads separately from the contrast. Furthermore, with sequential use of iodine- and bismuth-based beads, the two radiopaque beads could be spatially distinguished on imaging, which may enable the development of dual drug delivery and dual tracking. [ABSTRACT FROM AUTHOR]

Purpose: Topotecan is a camptothecin analogue with potential advantages over irinotecan for transarterial chemoembolization (TACE) of hepatic colorectal metastases including greater anti-neoplastic activity without enzymatic activation. The purpose of this study was to assess safety and tolerability of topotecan-loaded radiopaque microspheres (ROMTOP) administered by TACE in a rabbit model and to compare the in vitro elution of topotecan from microspheres to irinotecan.Materials and Methods: Topotecan was loaded into radiopaque microspheres (70-150 µm, DC Bead LUMI™, Biocompatibles UK Ltd-Boston Scientific Corporation) to the maximum capacity of 80 mg/mL of microspheres. Six healthy New Zealand White rabbits underwent hepatic TACE with ROMTOP under fluoroscopic guidance until angiographic stasis. Assessment of toxicities included regular liver function tests and complete blood counts until euthanasia 28 days post-TACE. In vitro topotecan elution from the microspheres was assessed using an open-loop flow-through system and compared to irinotecan.Results: The mean bead volume and topotecan dose delivered were 0.086 mL (0.076-0.105 mL) and 1.99 mg/kg (1.51-2.55 mg/kg), respectively. Aspartate aminotransferase and alanine aminotransferase were elevated post-embolization but resolved within 2 weeks. One rabbit died two days after TACE with pyloric duodenal perforation observed at necropsy, potentially due to non-target embolization. In vitro elution of topotecan from ROMTOP was complete in 10 h compared to 3 h for irinotecan-loaded microspheres.Conclusion: Selective embolization with ROMTOP was tolerated at a dose of 2 mg/kg (24 mg/m2) in rabbits. In vitro topotecan elution from microspheres was more prolonged compared to irinotecan. [ABSTRACT FROM AUTHOR]

Purpose: To describe first clinical experience with a directly image-able, inherently radio-opaque microspherical embolic agent for transarterial embolization of liver tumors.Methodology: LC Bead LUMI™ is a new product based upon sulfonate-modified polyvinyl alcohol hydrogel microbeads with covalently bound iodine (~260 mg I/ml). 70-150 μ LC Bead LUMI™ iodinated microbeads were injected selectively via a 2.8 Fr microcatheter to near complete flow stasis into hepatic arteries in three patients with hepatocellular carcinoma, carcinoid, or neuroendocrine tumor. A custom imaging platform tuned for LC LUMI™ microbead conspicuity using a cone beam CT (CBCT)/angiographic C-arm system (Allura Clarity FD20, Philips) was used along with CBCT embolization treatment planning software (EmboGuide, Philips).Results: LC Bead LUMI™ image-able microbeads were easily delivered and monitored during the procedure using fluoroscopy, single-shot radiography (SSD), digital subtraction angiography (DSA), dual-phase enhanced and unenhanced CBCT, and unenhanced conventional CT obtained 48 h after the procedure. Intra-procedural imaging demonstrated tumor at risk for potential under-treatment, defined as paucity of image-able microbeads within a portion of the tumor which was confirmed at 48 h CT imaging. Fusion of pre- and post-embolization CBCT identified vessels without beads that corresponded to enhancing tumor tissue in the same location on follow-up imaging (48 h post).Conclusion: LC Bead LUMI™ image-able microbeads provide real-time feedback and geographic localization of treatment in real time during treatment. The distribution and density of image-able beads within a tumor need further evaluation as an additional endpoint for embolization. [ABSTRACT FROM AUTHOR]

To extend the platform of clinically utilised chemoembolic agents based on ion-exchange systems to support the delivery of anionic drugs, a series of PVA-based beads was produced with different levels of (3-acrylamidopropyl)trimethylammonium chloride (APTA) in their formulation. The beads were characterised to confirm composition and the effect of formulation variation on physical properties was assessed. Suspension polymerisation was shown to successfully produce uniformly spherical copolymer beads with APTA content up to 60 wt%. Equilibrium water content and resistance to compression both increased with increasing APTA content in the formulation. Confocal laser scanning microscopy was used with model drugs to demonstrate that by increasing APTA content, compounds between the molecular weight range 70–250 kDa could permeate the microsphere structures. Interaction with anionic drugs was modelled using multivalent dyes. Dyes with multi-binding sites had increased interaction with the polymer, slowing the release and also demonstrating a reduced rate of elution from beads with higher charge density. The model drug release studies demonstrate that these systems can be engineered for different potential anionic drugs for local therapeutic delivery in the clinic. [ABSTRACT FROM AUTHOR]

Clinical use of DC BeadTM loaded with doxorubicin (DEBDOXTM) or irinotecan (DEBIRITM), for the treatment of primary and secondary tumours of the liver respectively, is showing great promise. Recently there has been a tendency to select smaller bead size ranges to treat tumours in an effort to allow more drug dose to be administered, improve tumoural penetration and resultant drug delivery and tumour coverage. Herein we describe the development and performance characterisation of a new DC Bead size range (DC BeadM1TM, 70–150 lm) capable of an increased bead delivery in the distal vasculature, corresponding to greater tumour coverage and drug dose delivered. Both unloaded and drug loaded DC BeadM1 were shown to have a greater density of distal volume of penetration although the ultimate distal level of penetration was the same as that of the 100–300 lm beads in an in vitro penetration model. Elution of doxorubicin was slower than irinotecan elution, but it was similar when comparing the same drug elution from 70 to 150 lm compared to 100–300 lm beads. Radiopaque versions of 70–150 and 100–300 lm beads were prepared in order to evaluate distribution ex vivo using l-CT and doxorubicin distribution using epifluorescent microscopy. Liver distribution of the radiopaque versions of the beads was shown to be more distal and efficient at filling smaller vessels with the DC BeadM1 and correspondingly more beads were found per vessel histologically with a larger area of drug coverage with the smaller size range. This study indicates that the smaller (70–150 lm) beads should permit an increased dose of drug to be administered to both hypervascular and hypovascular tumours as compared to 100–300 lm beads. [ABSTRACT FROM AUTHOR]

DC Bead is a drug delivery embolisation system that can be loaded with doxorubicin or irinotecan for the treatment of a variety of liver cancers. In this study we demonstrate that the topoisomerase I inhibitor topotecan hydrochloride can be successfully loaded into the DC Bead sulfonate-modified polyvinyl alcohol hydrogel matrix, resulting in a sustained-release drug eluting bead (DEBTOP) useful for therapeutic purposes. The in vitro drug loading capacity, elution characteristics and the effects on mechanical properties of the beads are described with reference to our previous work with irinotecan hydrochloride (DEBIRI). Results showed that drug loading was faster when the solution was agitated compared to static loading and a maximum loading of ca. 40–45 mg topotecan in 1 ml hydrated beads was achievable. Loading the drug into the beads altered the size, compressibility moduli and colour of the bead. Elution was shown to be reliant on the presence of ions to perform the necessary exchange with the electrostatically bound topotecan molecules. Topotecan was shown by MTS assay to have an IC for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 μM compared to 28.1 and 19.2 μM for irinotecan at 48 and 72 h, respectively. The cytotoxic efficacy of DEBTOP on PSN-1 was compared to DEBIRI. DEPTOP loaded at 6 & 30 mg ml, like its free drug form, was shown to be more potent than DEBIRI of comparable doses at 24, 48 & 72 h using a slightly modified MTS assay. Using a PSN-1 mouse xenograft model, DEBIRI doses of 3.3–6.6 mg were shown to be well-tolerated (even with repeat administration) and effective in reducing the tumour size. DEBTOP however, was lethal after 6 days at doses of 0.83–1.2 mg but demonstrated reasonable efficacy and tolerability (again with repeat injection possible) at 0.2–0.4 mg doses. Care must therefore be taken when selecting the dose of topotecan to be loaded into DC Bead given its greater potency and potential toxicity. [ABSTRACT FROM AUTHOR]

High molecular weight alginate beads with 59% mannuronic acid content or 68% guluronic acid were prepared using a droplet generator and crosslinked in calcium chloride. The alginate beads were compared to current embolisation microspheres for compressibility and monitored over 12 weeks for size and weight change at 37°C in low volumes of ringers solutions. A sheep uterine model was used to analyse bead degradation and inflammatory response over 12 weeks. Both the in vitro and in vivo data show good delivery, with a compressibility similar to current embolic beads. In vitro, swelling was noted almost immediately and after 12 weeks the first signs of degradation were noted. No difference was noted in vivo. This study has shown that high molecular weight alginate gel beads were well tolerated by the body, but beads associated with induced thrombi were susceptible to inflammatory cell infiltration. The beads were shown to be easy to handle and were still observable after 3 months in vivo. The beads were robust enough to be delivered through a 2.7 Fr microcatheter. This study has demonstrated that high molecular weight, high purity alginate bead can be considered as semi-permanent embolisation beads, with the potential to bioresorb over time. [ABSTRACT FROM AUTHOR]

Despite some progress in therapy, the prognosis of patients with malignant gliomas remains poor. Local delivery of cytostatics to the tumour has been proven to be an efficacious therapeutic approach but which nevertheless needs further improvements. Drug Eluting Beads (DEB), have been developed as drug delivery embolisation systems for use in trans-arterial chemoembolisation. We tested in a rat model of malignant glioma, whether DEB, loaded with doxorubicin or irinotecan, may be used for local treatment of brain tumours. Unloaded and drug loaded DEB were implanted into the brains of healthy and tumour bearing BD IX rats followed by histological investigations and survival assessment. Intracerebral implantation of unloaded DEB caused no significant local tissue damage, whilst both doxorubicin and irinotecan DEB improved survival time significantly. However, a significant local toxicity was found after the implantation of doxorubicin DEB but not with irinotecan DEB. We concluded that irinotecan appears to be superior in terms of the risk-benefit ratio and that DEB may be used for local treatment of brain tumours. [ABSTRACT FROM AUTHOR]

DC BeadTM is a FDA cleared embolisation device for the treatment of hypervascular tumours and arteriovenous malformations. This product is currently evaluated in a number of centres in Europe as an embolic device for transarterial chemoembolisation (TACE). The beads consist of poly(vinyl alcohol) microspheres modified with sulfonic acid groups and are available at different size ranges varying from 100 to 900 μm in diameter. The beads were shown to actively sequester doxorubicin hydrochloride (dox) from solution in a time dependent upon the dose of the drug and size of the beads. Drug uptake was by an ion-exchange mechanism, and in the absence of other ions in solution, the beads could load a maximum of around 40 mg dox/mL hydrated beads, with >99% of drug being sequestered from the solution. A loading of 25 mg dox/mL beads was recommended as providing a practical therapeutic dose and optimum handling characteristics. There was a decrease in equilibrium water content of the beads with increasing dox loading, which resulted in a decrease in the average diameter of the beads and an increase in the compressive modulus. The deliverability properties, however, were not affected after drug loading. Using a variety of microscopic methods, the drug was shown to be distributed throughout the bead structure, but concentrated in the outer 20 μm surface layer, a feature related to the method of synthesis. This study characterises the properties of DC Bead loaded with dox with respect to important characteristics in embolisation and demonstrates the potential of this drug device combination for the treatment of hypervascular tumours such as hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Since the first reports on foam sclerotherapy, multiple studies have been conducted to determine the physical properties and behavior of foams, but relatively little is known about their biological effects on the endothelial cells lining the vessel wall. Moreover, a systematic comparison of the biological performance of foams produced with different methods has not been carried out yet. Herein, a 2D in vitro method was developed to compare efficacy of commercially available polidocanol injectable foam (PEM, Varithena) and physician-compounded foams (PCFs). Endothelial cell attachment upon treatment with foam was quantified as an indicator of therapeutic efficacy, and was correlated with foam physical characteristics and administration conditions. An ex vivo method was also developed to establish the disruption and permeabilisation of the endothelium caused by sclerosing agents. It relied on the quantitation of extravasated bovine serum albumin conjugated to Evans Blue, as an indicator of endothelial permeability. In our series of comparisons, PEM presented a greater overall efficacy compared to PCFs, across the different biological models, which was attributed to its drainage dynamics and gas formulation. This is consistent with earlier studies that indicated superior physical cohesiveness of PEM compared to PCFs. [ABSTRACT FROM AUTHOR]

The article “The effect of cationically modified phosphorylcholine polymers on human osteoblasts in vitro and their effect on bone formation in vivo”, written by Jonathan M. Lawton, Mariam Habib, Bingkui Ma, Roger A. Brooks, Serena M. Best, Andrew L. Lewis, Neil Rushton and William Bonfield, was originally published Online First without open access. After publication in volume 28, issue 9, page 144 it was noticed that the copyright was wrong in the PDF version of the article. The copyright of the article should read as “© The Author(s) 2017”. [ABSTRACT FROM AUTHOR]