Strategic aspects for the commercialization of nanomedicines.

The projected growth of the nanomedicine market mirrors the increase in commercial interest and investment in the field. Yet, amidst this optimism, research efforts have often been geared towards developing innovative materials, and less on bringing these innovations to market. In this article, we present a strategic approach of 'commercialization by design' to overcome various challenges related to commercialization. This approach shifts the focus from materials-centric development to one driven by market demands, evaluating nanomedicines considering factors like reimbursement restrictions and unmet medical needs, and aiming to generate robust evidence for regulatory authorities, Health Technology Assessment bodies and Payers alike. We highlight the linkages from the market backwards to the preclinical phase, where nanomedicines are tailored to specific clinician-identified requirements. Transitioning from a technology 'push' model to one with market 'pull' will enhance the commercial success of nanomedicines.

Detection, management, and prevention of diabetes-related foot disease in the Australian context.

Diabetes-related foot disease (DFD) is a widely feared complication among people who live with diabetes. In Australia and globally, rates of disability, cardio-vascular disease, lower extremity amputation, and mortality are significantly increased in patients with DFD. In order to understand and prevent these outcomes, we analyse the common pathogenetic processes of neuropathy, arterial disease, and infection. The review then summarises important management considerations through the interdisciplinary lens. Using Australian and international guidelines, we offer a stepwise, evidence-based practical approach to the care of patients with DFD.

Optimized production, purification, and radiolabeling of the 203Pb/212Pb theranostic pair for nuclear medicine.

TRIUMF is one of the only laboratories in the world able to produce both lead-203 (203Pb, t1/2 = 51.9 h) and 212Pb (t1/2 = 10.6 h) onsite via its 13 and 500 MeV cyclotrons, respectively. Together, 203Pb and 212Pb form an element-equivalent theranostic pair that potentiate image-guided, personalized cancer treatment, using 203Pb as a single-photon emission computed tomography (SPECT) source, and 212Pb for targeted alpha therapy. In this study, improvements to 203Pb production were accomplished by manufacturing electroplated, silver-backed thallium (Tl) targets to improve target thermal stability, which allow for higher currents during irradiation. We implemented a novel, two-column purification method that employs selective Tl precipitation (203Pb only) alongside extraction and anion exchange chromatography to elute high specific activity and chemical purity 203/212Pb in a minimal volume of dilute acid, without the need for evaporation. Optimization of the purification method translated to improvements in radiolabeling yields and apparent molar activity of lead chelators TCMC (S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) and Crypt-OH, a derivative of a [2.2.2]-cryptand.

Preclinical Evaluation of [155/161Tb]Tb-Crown-TATE-A Novel SPECT Imaging Theranostic Agent Targeting Neuroendocrine Tumours.

Terbium radioisotopes (149Tb, 152Tb, 155Tb, 161Tb) offer a unique class of radionuclides which encompass all four medicinally relevant nuclear decay modalities (α, ß+, γ, ß-/e-), and show high potential for the development of element-matched theranostic radiopharmaceuticals. The goal of this study was to design, synthesise, and evaluate the suitability of crown-TATE as a new peptide-conjugate for radiolabelling of [155Tb]Tb3+ and [161Tb]Tb3+, and to assess the imaging and pharmacokinetic properties of each radiotracer in tumour-bearing mice. [155Tb]Tb-crown-TATE and [161Tb]Tb-crown-TATE were prepared efficiently under mild conditions, and exhibited excellent stability in human serum (>99.5% RCP over 7 days). Longitudinal SPECT/CT images were acquired for 155Tb- and 161Tb- labelled crown-TATE in male NRG mice bearing AR42J tumours. The radiotracers, [155Tb]Tb-crown-TATE and [161Tb]Tb-crown-TATE, showed high tumour targeting (32.6 and 30.0 %ID/g, respectively) and minimal retention in non-target organs at 2.5 h post-administration. Biodistribution studies confirmed the SPECT/CT results, showing high tumour uptake (38.7 ± 8.0 %ID/g and 38.5 ± 3.5 %ID/g, respectively) and favourable tumour-to-background ratios. Blocking studies further confirmed SSTR2-specific tumour accumulation. Overall, these findings suggest that crown-TATE has great potential for element-matched molecular imaging and radionuclide therapy using 155Tb and 161Tb.

Cyclotron production of 103Pd using a liquid target.

INTRODUCTION: In this work, we present the first feasibility study on the production of the medically important radionuclide 103Pd via the 103Rh(p,n)103Pd reaction by cyclotron irradiation of a liquid target. Using a liquid target removes the time consuming and complex dissolution process of rhodium post-irradiation due to its chemically inactive nature and thereby will improve the accessibility of this radioisotope. METHODS: Liquid targets made from Rh(NO3)3·×H2O salt dissolved in de-ionized water were irradiated using a 12 MeV beam at the TR13 cyclotron at TRIUMF, Vancouver. RESULTS: A maximum EOB activity of 1.03 ± 0.05 MBq was achieved with the tested conditions, sufficient for basic radiochemistry studies. An effective separation method using anion exchange chromatography is reported using 1 M HNO3 as an eluent for rhodium (90.1 ± 2.1 % recovery) and a 1:1 mixture of 0.5 M NH3 + NH4Cl palladium eluent (103.8 ± 2.3 % recovery). The solution showed good in-target pressure stability. However, the production efficiency decreased significantly with higher solution concentrations and irradiation lengths which puts into question the scaling potential of this method. CONCLUSION: This proof-of-concept study has demonstrated the potential for using liquid targets as complementary production method of 103Pd for research purposes. The liquid target route faces several scaling challenges but can nonetheless improve the availability of 103Pd and consequently aid in widening its utility for radiopharmaceuticals.

Is this child suitable to be seen in primary care? Poor agreement between caregiver/family perception and definitions of a 'primary care-type' patient.

AIMS: To compare and evaluate the number of paediatric patients classified as 'suitable for primary care' using the Australian Institute of Health and Welfare (AIHW) method, the Australasian College for Emergency Medicine (ACEM) method, and parental judgement. METHODS: This was a prospective observational study enrolling parents/carers presenting with their children to two Victorian EDs in Victoria, Australia over a 1-week period. Trained research assistants were posted within both EDs and surveyed all eligible parents/carers whether they agreed with the statement 'I think a GP would be able to look after my child's current illness/injury'. Survey responses were linked to clinical outcomes and length of stay. Each presentation was classified as suitable for primary care using the AIHW method, the ACEM method and parental survey. Agreement between definitions was assessed using Cohen's kappa statistic. RESULTS: During the study (June 2016), 1069 patients presented to the two EDs; 677 patients were able to be classified under all three definitions (AIHW: 1069, ACEM: 991, survey: 677 patients). Only 80/677 (12%) patients met all three criteria. Agreement was slight between the parent survey and the ACEM method (K = 0.14, 95% confidence interval (CI) 0.06-0.21), and the parent survey and the AIHW method (K = 0.12, 95% CI 0.05-0.19). There was moderate agreement between the ACEM and AIHW methods (K = 0.45, 95% CI 0.39-0.51). CONCLUSIONS: There is very poor agreement on what defines a 'primary care-type' paediatric patient between the definitions used by government, professional bodies and caregivers.

Determination of distribution coefficients of mercury and gold on selected extraction chromatographic resins - towards an improved separation method of mercury-197 from proton-irradiated gold targets.

Radioisotope mercury-197g (197gHg, half-life: 64.14 h) along with its metastable isomer (197mHg, half-life: 23.8 h) are potential candidates for targeted Meitner-Auger electron therapy due to their suitable decay properties. Their production can be achieved via proton irradiation of a natural gold target, but the number of studies surrounding their separation from an irradiated gold target is limited. This study focuses on the determination of distribution coefficients (Kd) of gold (III) and mercury (II) on seven extraction chromatographic resins. Mercury Kd were measured by means of radiotracers and Inductively Coupled Plasma Mass Spectrometry (ICP_MS); values obtained from the two methods were generally in good agreement. These results can provide insight on Hg and Au chemistry and aid in the design of improved separation system(s).

A simple and automated method for 161Tb purification and ICP-MS analysis of 161Tb.

BACKGROUND: 161Tb is a radiolanthanide with the potential to replace 177Lu in targeted radionuclide therapy. 161Tb is produced via the neutron irradiation of [160Gd]Gd2O3 targets, and must be purified from 160Gd and the decay product 161Dy prior to use. Established purification methods require complex conditions or high-pressure ion chromatography (HPIC) which are inconvenient to introduce in a broad user community. This study aims to find a simpler small solid-phase extraction (SPE) column method for 161Tb purification that is more suitable for automation with commercially available systems like TRASIS. RESULTS: We first tested the distribution coefficients on TK211 and TK212 resins for the separation of Gd, Tb, and Dy, and subsequently developed a method to separate these metal ions, with an additional TK221 resin to concentrate the final product. A side-by-side comparison of the products purified using this new method with the HPIC method was undertaken, assessing the radionuclidic purity, chemical purity regarding Gd and Dy, and labeling efficiency with a standard chelate (DOTA) and a novel chelate (crown). The two methods have comparable radionuclidic purity and labeling efficiency. The small SPE column method reduced Gd content to nanogram level, although still higher than the HPIC method. An ICP-MS method to quantify 161Tb, 159Tb, 160Gd, and 161Dy was developed with the application of mass-shift by ammonia gas. Last, 161Tb produced from the small SPE column method was used to assess the biodistribution of [161Tb]Tb-crown-αMSH, and the results were comparable to the HPIC produced 161Tb. CONCLUSIONS: 161Tb was successfully purified by a semi-automated TRASIS system using a combination of TrisKem extraction resins. The resulting product performed well in radiolabelling and in vivo experiments. However, improvement can be made in the form of further reduction of 160Gd target material in the final product. An ICP-MS method to analyze the radioactive product was developed. Combined with gamma spectroscopy, this method allows the purity of 161Tb being assessed before the decay of the product, providing a useful tool for quality control.

A pragmatic regulatory approach for complex generics through the U.S. FDA 505(j) or 505(b)(2) approval pathways.

The diverse nature of complex drug products poses challenges for the development of regulatory guidelines for generic versions. While complexity is not new in medicines, the technical capacity to measure and analyze data has increased. This requires a determination of which measurements and studies are relevant to demonstrate therapeutic equivalence. This paper describes the views of the NBCD Working Group and provides pragmatic solutions for approving complex generics by making best use of existing U.S. Food and Drug Administration's abbreviated approval pathways 505(j) and 505(b)(2). We argue that decisions on the appropriateness of submitting a 505(j) or 505(b)(2) application can build on the FDA's complex drug product classification as well as the FDA's much applauded guidance document for determining whether to submit an ANDA or a 505(b)(2) application. We hope that this paper contributes to the discussions to increase the clarity of regulatory approaches for complex generics, as well as the predictability for complex generic drug developers, to facilitate access to much-needed complex generics and to promote the sustainability of the healthcare system.

Publisher Correction: On the issue of transparency and reproducibility in nanomedicine.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Publisher Correction: On the issue of transparency and reproducibility in nanomedicine.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Report of the AAPS Guidance Forum on the FDA Draft Guidance for Industry: "Drug Products, Including Biological Products, that Contain Nanomaterials".

To guide developers of innovative and generic drug products that contain nanomaterials, the U.S. Food and Drug Administration issued the draft guidance for industry titled: "Drug Products, Including Biological Products, that Contain Nanomaterials" in December 2017. During the AAPS Guidance Forum on September 11, 2018, participants from industry, academia, and regulatory bodies discussed this draft guidance in an open setting. Two questions raised by the AAPS membership were discussed in more detail: what is the appropriate regulatory pathway for approval of drug products containing nanomaterials, and how to determine critical quality attributes (CQAs) for nanomaterials? During the meeting, clarification was provided on how the new FDA center-led guidance relates to older, specific nanomaterial class, or specific product-related guidances. The lively discussions concluded with some clear observations and recommendations: (I) Important lessons can be learned from how CQAs were determined for, e.g., biologics. (II) Publication of ongoing scientific discussions on strategies and studies determining CQAs of drug products containing nanomaterials will significantly strengthen the science base on this topic. Furthermore, (III) alignment on a global level on how to address new questions regarding nanomedicine development protocols will add to efficient development and approval of these much needed candidate nanomedicines (innovative and generic). Public meetings such as the AAPS Guidance Forum may serve as the place to have these discussions.

Ion quantification in liposomal drug products using high performance liquid chromatography.

A simple, straightforward analytical method based on liquid chromatography has been optimized to quantify total, internal, and external ions in drug-loaded liposomal products. The quantification of ammonium and sulfate ions in Doxil is detailed; although, the methodology has been extrapolated to quantitate a variety of ions, including calcium, acetate, and others in several different liposomal formulations. Total ion concentrations were measured after disruption of the liposome via lyophilization, to liberate all components. External ion concentrations were made following membrane centrifugation, without disruption of the liposome structure, where the permeate fraction was analyzed for external ion quantities. The internal ion fraction was derived from mass balance of the total and external ion measurements. High performance liquid chromatography (HPLC), equipped with different separation columns, and coupled to a charged aerosol detector, was employed for all ion quantifications. The analytical measurements were confirmed using simple stoichiometry based on the drug crystallization of doxorubicin within the liposome interior. The method presented herein is quick, highly accurate, and has significantly improved lower limits of detection and quantification over other traditional methods. As more follow-on versions of Doxil are being developed, this facile approach to ion quantitation can be used to help establish compositional similarity to the reference listed drug.

Evaluating Nanomedicines: Obstacles and Advancements.

Continued advancements in nanotechnology are expanding the boundaries of medical research, most notably as drug delivery agents for treatment against cancer. Drug delivery with nanotechnology can offer greater control over the biodistribution of therapeutic agents to improve the therapeutic index. In the last 20 years, a number of nanomedicines have transitioned into the clinic. As nanomedicines evolve, techniques to properly evaluate their safety and efficacy must also evolve. Characterization methods for nano-based materials must be adapted to the demands of nanomedicine developers and regulators. This second edition book provides updated characterization protocols designed to address the clinical potential of nanomedicines during their preclinical development. In this chapter, the characterization challenges of nanoparticles intended for drug delivery will be discussed, along with examples of advancements and improvements in nanomedicine characterization.

Anticoagulants Influence the Performance of In Vitro Assays Intended for Characterization of Nanotechnology-Based Formulations.

The preclinical safety assessment of novel nanotechnology-based drug products frequently relies on in vitro assays, especially during the early stages of product development, due to the limited quantities of nanomaterials available for such studies. The majority of immunological tests require donor blood. To enable such tests one has to prevent the blood from coagulating, which is usually achieved by the addition of an anticoagulant into blood collection tubes. Heparin, ethylene diamine tetraacetic acid (EDTA), and citrate are the most commonly used anticoagulants. Novel anticoagulants such as hirudin are also available but are not broadly used. Despite the notion that certain anticoagulants may influence assay performance, a systematic comparison between traditional and novel anticoagulants in the in vitro assays intended for immunological characterization of nanotechnology-based formulations is currently not available. We compared hirudin-anticoagulated blood with its traditional counterparts in the standardized immunological assay cascade, and found that the type of anticoagulant did not influence the performance of the hemolysis assay. However, hirudin was more optimal for the complement activation and leukocyte proliferation assays, while traditional anticoagulants citrate and heparin were more appropriate for the coagulation and cytokine secretion assays. The results also suggest that traditional immunological controls such as lipopolysaccharide (LPS ) are not reliable for understanding the role of anticoagulant in the assay performance. We observed differences in the test results between hirudin and traditional anticoagulant-prepared blood for nanomaterials at the time when no such effects were seen with traditional controls. It is, therefore, important to recognize the advantages and limitations of each anticoagulant and consider individual nanoparticles on a case-by-case basis.

Zeta potential: a case study of cationic, anionic, and neutral liposomes.

Zeta potential is often used to approximate a nanoparticle's surface charge, i.e., cationic, anionic, or neutral character, and has become a standard characterization technique to evaluate nanoparticle surfaces. While useful, zeta potential values provide only very general conclusions about surface charge character. Without a thorough understanding of the measurement parameters and limitations of the technique, these values can become meaningless. This case study attempts to explore the sensitivity of zeta potential measurement using specifically formulated cationic, anionic, and neutral liposomes. This study examines zeta potential dependence on pH and ionic strength, resolving power, and highlights the sensitivity of zeta potential to charged liposomes. Liposomes were prepared with cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and varying amounts of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS). A strong linear relationship was noted between zeta potential values and the mole percentage of charged lipids within a liposome (e.g., cationic DOTAP or anionic DOPS). This finding could be used to formulate similar liposomes to a specific zeta potential, potentially of importance for systems sensitive to highly charged species. In addition, cationic and anionic liposomes were titrated with up to two mole percent of the neutral lipid 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (lipid-PEG; LP). Very small amounts of the lipid-PEG (<0.2 mol%) were found to impart stability to the DOTAP- and DOPS-containing liposomes without significantly affecting other physicochemical properties of the formulation, providing a simple approach to making stable liposomes with cationic and anionic surface charge.

Equivalence of complex drug products: advances in and challenges for current regulatory frameworks.

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified.

Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer- related deaths. PDAC remains one of the most difficult-to-treat cancers, owing to its unique pathobiological features: a nearly impenetrable desmoplastic stroma, and hypovascular and hypoperfused tumour vessels render most treatment options largely ineffective. Progress in understanding the pathobiology and signalling pathways involved in disease progression is helping researchers to develop novel ways to fight PDAC, including improved nanotechnology-based drug-delivery platforms that have the potential to overcome the biological barriers of the disease that underlie persistent drug resistance. So-called 'nanomedicine' strategies have the potential to enable targeting of the Hedgehog-signalling pathway, the autophagy pathway, and specific RAS-mutant phenotypes, among other pathological processes of the disease. These novel therapies, alone or in combination with agents designed to disrupt the pathobiological barriers of the disease, could result in superior treatments, with increased efficacy and reduced off-target toxicities compared with the current standard-of-care regimens. By overcoming drug-delivery challenges, advances can be made in the treatment of PDAC, a disease for which limited improvement in overall survival has been achieved over the past several decades. We discuss the approaches to nanomedicine that have been pursued to date and those that are the focus of ongoing research, and outline their potential, as well as the key challenges that must be overcome.