A radiopharmaceutical solution containing device for providing reduced degradation of a component

Abstract

There is provided a device for holding a radioactive solution comprising a radioisotope. The device comprises a device body comprising an inner surface, an outer surface, and an interior chamber for receiving fluid, the interior chamber delimited at least in part by the inner surface. A solution is provided in the interior chamber. This solution comprises at least one stabilizer to prevent radiolytic degradation and a radioisotope binding species configured to bind to a radioisotope. The inner surface may have a combined surface concentration of SiOH and SiO-moieties of less than 2 nm-2.

Description

A RADIOPHARMACEUTICAL SOLUTION CONTAINING DEVICE FOR PROVIDING REDUCED DEGRADATION OF A COMPONENT CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application Serial No. 63 / 755,775, filed 7 February 2025, the entire contents of which are hereby incorporated by reference herein for any and all purposes.FIELD

[0002] There are provided devices for holding a radiopharmaceutical solution and use of such devices for reducing degradation when storing a radiopharmaceutical solution.BACKGROUND

[0003] Radioisotopes are increasingly used in various fields, for medical, industrial, and research applications. Radiopharmaceuticals, where radioisotopes are used to provide diagnostic imaging and therapeutic interventions, have provided major advances in diagnosing and treating cancer, brain diseases and cardiovascular diseases.

[0004] Radioisotopes (or “radionuclides”) used in radiopharmaceuticals solutions or compositions are often combined with a compound. For example, they can be used to label a compound. In many cases, the radioisotope is in combination with a chelator, which chelates the radioisotope. The chelator can then be connected to the compound, for example to a peptide portion, which can be suitable for binding to a receptor. The radioisotope may instead be covalently bonded to the compound, which may be an organic molecule, peptide, protein, or nanoparticle, either directly or through the use of a linker group.

[0005] However, there are many challenges in producing and storing radiopharmaceuticals, limiting their use and availability. One such challenge results from radiolysis of solutions comprising the radioisotopes. Radiolysis is molecular decomposition of molecules such as diluents, drug excipients, or reagents and precursor present in solutions with radioisotopes. In particular, radiation from radioactive decay (e.g. alpha, beta, gamma) interacts with these molecules and causes degradation, leading to radiolytic by-products. These by-products can significantly reduce the purity and effectiveness of the solutions.

[0006] In order to combat radiolysis, stabilizers are often used in solutions containing radioisotopes. Stabilizers are additives which can scavenge free radicals. As well as being capable of inhibiting decomposition attributable to free radicals, these compounds need to be safe for use in clinical formulations. The presence of stabilizers alongside a chelator, peptideand other excipients may lead to chemical degradation, separate to or in combination with radiolysis. There is therefore a balance between preventing radiolysis whilst also ensuring chemical stability and low toxicity.

[0007] There is a need in the art for improving the stability of stored radiopharmaceutical solutions without compromising on efficacy, safety or convenience.SUMMARY

[0008] In a first aspect, there is provided a device for holding a radioactive solution comprising a radioisotope, the device comprising a device body comprising an inner surface, an outer surface, and an interior chamber for receiving fluid, the interior chamber delimited at least in part by the inner surface. A solution is provided in the interior chamber. This solution comprises at least one stabilizer to prevent radiolytic degradation and a radioisotope binding species configured to bind to a radioisotope. The inner surface may have a combined surface concentration of SiOH and SiO" moi eties of less than 2 nm'2.

[0009] In a second aspect, a device for holding a radioactive solution comprising a radioisotope is provided. The device comprises a device body comprising an inner surface, an outer surface, and an interior chamber for receiving fluid, the interior chamber delimited at least in part by the inner surface. A solution is provided in the interior chamber. This solution comprises at least one stabilizer to prevent radiolytic degradation and a radioisotope binding species configured to bind to a radioisotope. The device body comprises an inner wall portion formed of material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass ceramic or an organic composition, the inner wall portion defining the inner surface.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The present disclosure will now be described in more detail with reference to the accompanying drawings, which are not intended to be limiting.

[0011] Fig. 1 provides a schematic view of the silicon-based groups at the surface of glass.

[0012] Figs. 2A and 2B provide schematic perspective views of a device according to the disclosure.

[0013] Figs. 3 A and 3B provide schematic perspective views of another device according to the disclosure.

[0014] Figs. 4A and 4B provide a schematic perspective view and a schematic plan view, respectively, of another device according to the disclosure.

[0015] Fig 5. provides a schematic perspective view of another device according to the disclosure.

[0016] Figs. 6A and 6B provide HPLC UV chromatograms relating to Example 1.

[0017] Fig. 7 provide HPLC UV chromatograms relating to Example 1.

[0018] Fig. 8 is a graph showing the stability of LuDOTATATE in a Lutathera solution, in the presence of borosilicate glass.

[0019] Fig. 9 is a graph showing the radiochemical purity of [177Lu]DOTATATE stored in different vials.

[0020] Fig. 10 is a graph showing the results of Example 9.DETAILED DESCRIPTION

[0021] There is a need in the art for improving the stability of stored radiopharmaceutical solutions without compromising on efficacy, safety or convenience. It has surprisingly been discovered that degradation of radioisotope binding species occurs in the presence of glass or glass-ceramics. This is a significant issue as glass containers, such as glass vials, are relied upon for holding and storing these radiopharmaceuticals solutions.

[0022] In a first aspect, a device for holding a radioactive solution comprising a radioisotope is provided. The device comprises a device body comprising an inner surface, an outer surface, and an interior chamber for receiving fluid, the interior chamber delimited at least in part by the inner surface. A solution is provided in the interior chamber, the solution comprising at least one stabilizer to prevent radiolytic degradation and a radioisotope binding species configured to bind to a radioisotope. The inner surface has a combined surface concentration of SiOH and SiO- moieties of less than 2 nm-2.

[0023] In a second aspect, a device for holding a radioactive solution comprising a radioisotope is provided. The device comprises a device body comprising an inner surface, an outer surface, and an interior chamber for receiving fluid, the interior chamber delimited at least in part by the inner surface. A solution is provided in the interior chamber. This solution comprises at least one stabilizer to prevent radiolytic degradation and a radioisotope binding species configured to bind to a radioisotope. The device body comprises an inner wall portion formed of material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass ceramic or an organic composition, the inner wall portion defining the inner surface.

[0024] Without being bound by theory, it is believed that silanol groups (Si-OH) on the surface of the glass can help catalyze reactions between stabilizers present in the solution and aradioisotope binding species, as well as with other substances found in the formulated drug product solution. These reactions may degrade the radiopharmaceutical and so reduce the efficacy of the treatment. Furthermore, the stabilizers involved in the reaction may no longer function to reduce radiolysis. Additionally, impurities may be formed as the product of the reaction. All of these issues contribute to the degradation of the radiopharmaceutical.

[0025] The devices in the first and second aspects, above, improve the stability of solutions comprising a radioisotope binding species and so increase the chemical and radiochemical purity by providing devices with inner surfaces which are substantially free or which are free of SiOH and SiO-. In the device of the first aspect, this is by virtue of the low SiOH and SiO-concentration and in the second aspect this is achieved through the use of non-glass-containing materials, which are inherently free of SiOH and SiO-. This can improve the effectiveness of the solutions, for example in treatments and imaging using radiopharmaceuticals. Improved stability also results in higher quality radiopharmaceuticals with more predictable and reliable pharmacokinetics, leading to more accurate diagnostic imaging and more effective therapeutic outcomes. It also improves the availability of radioisotope-containing solutions by prolonging the shelf-life of the solutions and increasing the concentration for a given isotope that can be stored and transported within a given time frame, as radiolytic degradation is typically accelerated at higher radioactivity concentrations.

[0026] The device disclosed herein can be used with existing radiopharmaceutical compositions, and achieve reduced chemical degradation, without the need to alter the composition itself. Given the strict regulatory requirements associated with radiopharmaceuticals, this means valuable improvements in purity of stored products can be achieved.

[0027] The way in which stability is increased in these devices can also provide significant benefits. It can improve the stability without reliance on existing methods, which themselves can have drawbacks, and in some cases can lead to the reduction or elimination of the use of existing methods for improving stability. For example, it can avoid the need to further alter the composition itself, for example through the inclusion of additives. Additives can complicate formulation, particularly for radiopharmaceuticals as they typically need a defined toxicity profile for use in injectable drug products. Accordingly, avoiding the need for these can be particularly advantageous for radiopharmaceuticals. For new compositions, it avoids having to conduct studies into possible interactions between the various components of the radiopharmaceutical compositions, reducing the complexity of development and subsequent regulatory approval. This also has advantages during synthesis of radiopharmaceuticals, whereadditives can be used but which then need to be removed, for example through filtration, solid phase extraction or chromatography.Degradation mechanism

[0028] As set out above, it has surprisingly been found that in the presence of silanol groups (SiOH), and their conjugate base (SiO-), as is found in most glasses, degradation of a radioisotope binding species can occur. Without being bound by theory, it is believed that silanol groups (SiOH), and their conjugate base (SiO-), on the surface of the glass can help catalyze reactions between stabilizers present in the solution and a radioisotope binding species. A potential mechanism by which the series of degradation pathways may proceed is discussed below, exemplified context of using ascorbic acid and gentisic acid as stabilizers and LuDOTATATE as the radioisotope binding species binding Lu-177 (i.e. forming LuDOTATATE).

[0029] Stabilizers, such as gentisic acid may react to form a reactive Michael acceptor. For example, in the case of gentisic acid (2,5-dioxobenzoic acid) (a benzoquinone derivative), upon oxidation, a reaction which can be catalysed by the silanol / siloxide functional groups present at the surface of standard glass (SiO2).

[0030] This reactive species, (e.g. 2,5-dioxobenzoic acid), may then dimerize (or polymerize) in a first reaction pathway. However, it is thought that the reactive species may then also react with a radioisotope binding species in a second reaction pathway, for example via a nucleophilic group. In the example of LuDOTATATE, this can be via the nucleophilic group present on the peptide portion, for instance via an amine or aryl-alcohol. This reaction may be further catalysed by SiOH / SiO-. This second pathway may therefore lead to the modification or loss of the radioisotope binding species, due to the reaction with the reactive species (e.g.2,5-dioxobenzoic acid).

[0031] The frequency with which the first pathway or second pathway occurs may depend on gentisic acid concentration and nucleophilicity of a part of the radioisotope binding species (e.g. the peptide, where present). It is also possible that radiolysis may form the benzoquinone derivative, which can then react in the same way - such that the pathway is not solely reliant on the presence of gentisic acid.

[0032] Linked to the second pathway, via a redox cycle, other stabilisers such as ascorbic acid may also degrade the radioisotope binding species. Ascorbic acid may be oxidised to form dehydroascorbic acid, or its isomers. This may occur as part of a redox cycle involving an oxidised form of another stabiliser, such as a gentisic acid derivative, for example formed asset out above due to SiOH / SiO- catalysis. Dehydroascorbic acid, or its isomers, can then react directly with the groups present in the radioisotope binding species (e.g. the amine group present in LuDOTATATE via glycation to form LuDOTATATE-gluconic acid). Alternatively, dehydroascorbic acid, or its isomers, may react further and the products of these reactions may then react with the radioisotope binding species (e.g. the amine group present in LuDOTATATE to form (Lys) N-conjugation products). In a similar manner, reaction with other nucleophilic groups, such as the aryl alcohol, present on the peptide portion, may also occur. Further potential nucleophilic sites include the carbon ortho to the hydroxy group on Tyrosine or the indole C3 carbon.

[0033] The result of these reactions is that the concentration of stabiliser and the chelating ligand have been reduced in the radiopharmaceutical solution, reducing the stability and effectiveness while potentially increasing toxicity and radiotoxicity. Additionally, the concentration of the radiopharmaceutical is reduced due to reaction with stabilizers or stabilizer degradation products.

[0034] While the stabilizers have been referred to in terms of their acid forms, it will be understood that essentially the same mechanism would apply for the conjugate bases, if these were present in solution. It will be understood that while the mechanism has been exemplified using ascorbic acid and gentisic acid as stabilizers and LuDOTATATE as the radioisotope binding species, binding Lu- 177, similar degradation mechanisms may apply to a variety of different stabilizers and radioisotope binding species.SiOH and SiO' moieties

[0035] SiOH moieties or functional groups, also called silanol groups, are often present at the surface of glass or glass-ceramics. These groups can also be deprotonated in solution to form SiO- moieties or functional groups, also known as siloxanes. The pKa of SiOH is around 4.5 and so it will be largely deprotonated at neutral pH. The surface concentration of SiOH and SiO- moieties or groups in untreated glass or glass-ceramics is typically above 4 nm-2. SiOH groups at the surface of glass have the potential to help form reactive oxygen species at the solid liquid interface, which can then oxidise other species and lead to degradation.

[0036] By combined surface concentration of SiOH and SiO" moieties or groups it is meant the average (mean) concentration of all SiOH moieties or groups and all SiO" moieties or groups on a surface. This average may be the mean concentration of all the inner surface which is in contact with the solution present in the inner chamber.

[0037] The surface concentration of SiOH / SiO- groups can be measured as known in the art. This may be measured using XPS (X-ray photoelectron spectroscopy) to measure the number of silanol or siloxide groups. Such a measurement method comprises irradiating a portion of the sample and fitting the curve of the resultant spectra in order to determine the presence of SiOH and SiO- groups. A typical O ls peak-fitting approach may be used to characterize the oxygen speciation or a stoichiometry-based algorithm via elemental composition may be used as described in Banerjee et al., Effect of heat treatment on the surface chemical structure of glass: Oxygen speciation from in situ XPS analysis, Journal of the American Ceramic Society, Volume 101, 2018, 644-656, DOI: 10.1111 / j ace.15245. SiOH quantification may be carried out after dehydration of the material, such as by heating to temperatures in excess of 175°C (e.g. where uncoated glass or glass-ceramic) or exposure to a desiccant.

[0038] Numerous areas of the inner surface material may be sampled, such two different areas or three different areas, in order to obtain a mean concentration of SiOH and SiO- groups, which is then taken as the concentration for the material in question. These areas may be of any suitable size, such as 100 pm x 100 pm. The areas should be spaced sufficiently far apart such that previous X-ray irradiation does not affect the result, such as being spaced 1 mm apart.

[0039] A “tag and count” approach can also be used, which consists of tagging surface silanols with Zn via atomic layer deposition followed by detection of the zinc by high sensitivity -low energy ion scattering (HS-LEIS), as set out in Tahereh G. Awal et Al. “A tag-and-count approach for quantifying surface silanol densities on fused silica based on atomic layer deposition and high-sensitivity low-energy ion scattering” Applied Surface Science, Volume 607, 2023, 154551, ISSN 0169-4332, https: / / doi.Org / 10.1016 / j.apsusc.2022.154551.

[0040] A suitable tag and count method involves:1) Dehydrating the sample (for instance by heating to 200°C (e.g. where uncoated glass or glass-ceramic) or exposure to a desiccant)2) Tagging surface silanols with Zn via atomic layer deposition (ALD), which consists of providing a single dose of trimethylaluminum (TMA), dimethylzinc (DMZ), or diethylzinc (DEZ), followed by a dose of water.3) Counting the Zinc atoms (and so surface silanols) using HS-LEIS.

[0041] Other methods may also or instead be used to determine the surface concentration of SiOH / SiO- groups as would be understood by the person skilled in the art.

[0042] The surface concentration of SiOH / SiO- on the inner surface may be measured prior to filling the device with the solution. Alternatively, the surface concentration of SiOH / SiO- on the inner surface may be measured after having contacted the inner surface with the solutionfor at least 1 minute, wherein the solution has then been removed to enable the measurement and without having further treated the surface.

[0043] It will be appreciated that this can also be assumed based on composition. For instance, a surface formed of a polymer which does not contain silica or SiOH / SiO' would necessarily have a surface concentration of SiOH / SiO' moieties which is free of SiOH and SiO' moieties and thus have a surface concentration of less than 2 nm'2.

[0044] Providing an inner surface which is substantially free of SiOH and SiO" can be achieved in a number of ways. The inner surface of the device body may be formed from a material which does not comprise SiOH or SiO" moieties on the surface. This may be that the device body or defining the inner surface is formed from or comprises an alternative material, i.e. one which does not comprise SiOH or SiO" moieties (e.g. has a concentration of less than 0.1 mol% SiOH, such as less than 0.05 mol% SiOH). Or this may be that a coating is provided on the device body (as an inner wall portion), which coating is formed from or comprises an alternative material, i.e. one which does not comprise SiOH or SiO" moieties. Alternatively or additionally, the inner surface (e.g. the inner wall portion defining the inner surface) may have been treated to remove SiOH and SiO" moieties. For instance, the inner surface may be made of a glass or glass ceramic which has been treated to remove SiOH and SiO" moieties.

[0045] To prevent unwanted degradation reactions, the inner surface may have a combined surface concentration of SiOH and SiO" moieties of less than 2 nm'2, or less than 1 nm'2, or less than 0.5 nm'2, or less than 0.1 nm'2, or the inner surface may be substantially free of SiOH and SiO' moieties. The inner surface may be substantially free or free of SiOH and SiO' moieties. The material which forms the inner surface may have fewer SiOH or SiO' moieties on the surface than standard glass, such as Type I borosilicate glass.

[0046] In an additional aspect, use of any aspects of the device disclosed herein may achieve reduced degradation of the radioisotope binding species. The reduced degradation may be reduced chemical degradation. Using the device may achieve a reduced rate of chemical degradation in comparison to a container which comprises a higher concentration of SiOH / SiO-moieties on the inner surface, such as a glass container, for instance a glass container made of Type I borosilicate glass.

[0047] The use of the device for storing a radiopharmaceutical and the subsequent reduced degradation results in improved higher quality radiopharmaceuticals with more predictable and reliable pharmacokinetics, leading to more effective therapeutic outcomes. It also improves the availability of radioisotope-containing compositions by prolonging the shelf-life of the compositions and increasing the concentration for a given isotope that can be stored andtransported within a given time frame. There is also a cost benefit, as less of the solution initially produced needs to be used in any one given dosage to achieve the same therapeutic effect. For example, a radiopharmaceutical with a radiochemical purity of 98% would contain 9% more active drug product than the same mCi quantity of radiopharmaceutical that has a radiochemical purity of 90%.

[0048] The various aspects of the device, including optional features, will now be described below.The device body

[0049] The device body comprises an inner surface, an outer surface, and an interior chamber for receiving fluid, the interior chamber delimited at least in part by the inner surface. The device body comprises an inner wall portion defining the inner surface. The device body may further comprise a wall portion defining the outer surface. The inner wall portion and wall portion together may be formed as a unitary part or, in other examples, the device body may comprise a first layer forming the wall portion and a second layer forming the inner wall portion. This may be a laminate structure, for example, and / or a coating may be provided on the wall portion so that the coating forms the inner wall portion and defines the inner surface. The inner wall portion and wall portion may accordingly be formed from the same or different materials.

[0050] The device may comprise a base and at least one sidewall extending from the base, wherein the interior chamber is delimited at least in part by the base and the at least one sidewall. Accordingly, the interior chamber may be delimited at least in part by the inner surface of at least one sidewall and, where present, the inner surface of the base. The inner wall portion may accordingly be a part of the base and sidewall. Similarly, the wall portion may be a part of the base and sidewall. In other words, the base and sidewall may each define a part of the inner wall portion and wall portion.

[0051] The device body, or container, described is suitable for storing a radiopharmaceutical solution and reduces degradation of the compounds used in the solution.

[0052] The device of the disclosure can be any container of any shape.

[0053] The device may be any device in which a solution comprising a radioisotope may be held or stored. For example, the device may be a vial or container for holding a solution comprising a radioisotope. Such a vial may further comprise an opening defined by the top of the sidewall(s) and a removeable cap to close the opening. Alternatively, the device may be or form a part of a separation apparatus, such as a filter or column, or other vessel used duringsynthesis or purification of radioisotope solutions. The device may also be a reaction vessel, such as a microreactor. Where a filter or a column, such as cylindrical column or vessel, the base may be a part of the cylindrical walls (the lowermost portion) and hence be integral with the sidewalls.Materials which form the device body

[0054] In the first aspect, the device body may comprise or be formed of (i.e. consist or consist essentially of) any material which provides no or very few SiOH or SiO- moieties (i.e. are free or substantially free of these), for example, a material selected from at least one of polymer, a metal (including a metal compound or allow, such as a metal oxide, which may exclude any silicon-containing oxides), a ceramic, silica-free glass, silica-free glass ceramic or an organic composition. In the second aspect, the device body is formed of (i.e. consist or consist essentially of) a material selected from at least one of polymer, a metal (including a metal compound or allow, such as a metal oxide, which may exclude any silicon-containing oxides), a ceramic, silica-free glass, silica-free glass ceramic or an organic composition. These materials can provide an inner surface which is substantially free or free of SiOH and SiO-moieties. For example, these may comprise or be formed of a polymer. Examples of suitable polymers include the polymeric materials may include one or more fluoropolymers (such as polyvinylidene fluoride (PVDF) or ethylene tetrafluoroethylene (ETFE)), polyolefins (such as high-density polyethylene (HDPE), cyclic olefin polymers or polytetrafluoroethylene (PTFE)) or others, such as butyl rubber. Examples of organic compositions include hydrocarbon coatings, such as C3 to C25 fatty acids chains.

[0055] By silica-free, it is meant a material which comprises less than 1 mol% silica (SiO2), or less than 0.1 mol% silica, or a material which is substantially free of silica, such that silica if present at all is only present as trace impurities.

[0056] Alternatively or additionally, the device body may comprise or be formed of any suitable material, for example, selected from at least one of a glass, a glass-ceramic, a ceramic, a polymer or a metal (including a metal compound or allow, such as a metal oxide) but be provided with a coating or treatment such that the external surfaces in contact with the solution (in the case of the insert array, this includes the internal surface) have no or very few SiOH or SiO- moieties (i.e. are free or substantially free of these). Accordingly, the device body may further comprise a coating, for example on its inner surface (i.e. the inner wall portion defining the inner surface and, hence, interior chamber), and / or the device walls (e.g. at least the inner surface) may be modified. The coating may be a polymeric and / or organic coating. Forexample, the coating may comprise or be formed of (i.e. consist or consist essentially of) one or more fluoropolymers (such as polyvinylidene fluoride (PVDF) or ethylene tetrafluoroethylene (ETFE)), polyolefins (such as high-density polyethylene (HDPE), cyclic olefin polymers or polytetrafluoroethylene (PTFE)) or others, such as butyl rubber. Examples of organic compositions include hydrocarbon coatings, such as C3 to C25 fatty acids chains (e.g. stearic acid).

[0057] By formed of or consist of it is meant that the item in question (such as the device body) comprises at least 99 wt% of the specified material, such as at least 99.5% or at least 99.9%, or that any other compounds present are only in trace amounts.

[0058] The device body may comprise less than 50 mol% silica, less than 40 mol% silica, less than 30 mol% silica, less than 20 mol% silica, less than 10 mol% silica, less than 5 mol% silica, or less than 1 mol% silica. The device body may be substantially free of silica. Silica is silicon dioxide (SiO2). Silica is the main component in many forms of glass and glass ceramics. Silica is mainly present in amorphous forms in glass and glass ceramics. When it is stated that the device body comprises less than X% silica, this includes amorphous silica.

[0059] The device body may comprise (e.g. be formed from) two or more materials. For example, this could include having a core material which forms the wall portion of the device body and a second material forming the coating.The inner surface

[0060] A surface is the outermost layer of a material or substance. In this instance, the inner surface is the outermost part of the device body which interacts, physically or chemically, with the liquid or gas which is contained in the inner chamber. The surface of a material may differ from the bulk of a material in its properties and solution. For instance, the bulk of a material may be non-reactive with a given compound whilst the surface is reactive. When interacting with a solution such as a solution as disclosed herein, the inner surface of glass may be involved in catalyzing chemical reactions. This can lead to unwanted degradation. SiOH and SiO" functional groups on the surface of glass can be involved in acid / base catalysis when in contact with a solution comprising a stabilizer or stabilizers and a radiopharmaceutical binding species.

[0061] A glass surface may include the top layer of siloxane, silanol and / or sil oxide functional groups as shown in Figure 1.

[0062] The surface layer may be taken as being 10 nm thick, or 5 nm thick, or 1 nm thick. The surface layer may be taken as 5 A thick, or 4 A thick, or 3 A thick. For context, the bond length of an Si-0 bond is around 1.65 A.

[0063] As set out above, providing an inner surface which is substantially free of SiOH and SiO" can be achieved in a number of ways: using a SiOH and SiO" moiety free material; a SiOH and SiO" moiety free coating; or through surface treatment.

[0064] For example, the device body (e.g. the inner surface) may have been treated to remove SiOH and SiO" moi eties from the inner surface. For instance, the inner surface may be made of a glass or glass ceramic treated to remove SiOH and SiO" moieties. This can be achieved using, for example, a plasma treatment, such as a hydrogen microwave plasma treatment of glass. This can be used, for example, to replace Si-0 bonds on the surface with Si-H bonds. The benefit of using glass treated in this way is that the beneficial properties associated with using glass as the bulk material are maintained whilst the issues with reactivity at the inner surface are mitigated. Alternatively or additionally, there may be a heat treatment. For example, a heat treatment involving heating a glass to at least 500°C (after forming the device) can reduce the number of silanol or siloxide groups on the surface.

[0065] The inner surface (e.g. the inner wall portion defining the inner surface) may comprise or be formed of (e.g. consist or consist essentially of) at least one of polymer, a metal (including a metal compound or alloy, such as a metal oxide, which may exclude any silicon-containing oxides), a ceramic, silica-free glass, silica-free glass ceramic or an organic composition. This may be a polymer. This polymer may be selected from fluoropolymers (such as polyvinylidene fluoride (PVDF) or ethylene tetrafluoroethylene (ETFE)), polyolefins (such as high-density polyethylene (HDPE), cyclic olefin polymers or polytetrafluoroethylene (PTFE)) or others, such as butyl rubber. These materials provide excellent strength, toughness, favourable optical properties, as well as aiding in reducing degradation.

[0066] The inner surface may be formed from a silica-free coating. This means that the body of the device can be made of any material and provided with a coating such that the inner surface is formed from a different material. The coating may be a polymeric and / or organic coating. For example, the coating may comprise or be formed of (i.e. consist or consist essentially of) one or more fluoropolymers (such as polyvinylidene fluoride (PVDF) or ethylene tetrafluoroethylene (ETFE)), polyolefins (such as high-density polyethylene (HDPE), cyclic olefin polymers or polytetrafluoroethylene (PTFE)) or others, such as butyl rubber. Examples of organic compositions include hydrocarbon coatings, such as C3 to C25 fatty acids chains (e.g. stearic acid).

[0067] Where present, the coating may have a thickness of from Inm to 1000 micrometers, for example from 100 nm to 1000 micrometers, for instance for instance from 1 micrometer to 100 micrometers, or 10 micrometers to 1 millimeter. Using a coating means that conventionalglassware can be used in the same way, but it can be easily and conveniently coated, as to minimize degradation.

[0068] The composition of the material forming the inner surface may be altered upon contact with the solution of the device. The inner surface should have a combined surface concentration of SiOH and SiO' moieties of less than 2 nm'2, less than 1 nm'2, less than 0.5 nm'2, less than 0.1 nm'2, or less than 0.01 nm'2as measured as set out above, and where the device body first contacts the solution for at least 5 minutes and the surface concentration is then measured. The inner surface may have substantially no SiOH or SiO' moieties as measured after contact with the solution.

[0069] The inner surface may be chemically inert in the presence of the solution in the interior chamber. For example, the inner surface may not act as a proton donor or acceptor or may not be capable of acting as a proton donor or acceptor.The interior chamber

[0070] The device body comprises an interior chamber for receiving and holding fluid. The interior chamber is delimited at least in part by the inner surface. The interior chamber may be fully delimited by the inner surface, aside from a portion for receiving fluid. By “delimit” or “define” a volume it is meant that the respective surface (or the wall defining the respective surface) at least partially encloses and separates the volume. This means that the surface or wall acts as a boundary or partition that creates a distinct area inside the device body. A volume can refer to a chamber, for instance the interior chamber of the device body.

[0071] The device body may be sealed. By “sealed” it is meant that the internal chamber is fully delimited, and so fully enclosed. This means that if the device body comprises an opening which can receive fluid, then this has been covered. The device may further comprise a lid or cap which seals the device body. The lid or cap may be removable. The lid or cap may have an inner surface which at least partly delimits the internal chamber.

[0072] The inner surface of the lid or cap may have a combined surface concentration of SiOH and SiO' moieties of less than 2 nm'2, or less than 1 nm'2, or less than 0.5 nm'2, or less than 0.1 nm'2, or the inner surface of the lid or cover may be substantially free of SiOH and SiO' moieties. The material which forms the lid may have fewer SiOH or SiO' moieties on the surface than standard glass, such as Type I borosilicate glass, such as a Type I, Class B glass according to ASTM Standard E438-92 (2011). The material which forms the lid or cap may have been treated to remove SiOH and SiO' moieties from the inner surface. For instance, the inner surface of the lid or cap may be made of a glass ceramic which has been treated to removeSiOH and SiO" moieties. The lid or cap may comprise or be formed of any of the materials set out for the device body.

[0073] The lid or cap may comprise less than 50 mol% silica, such as less than 40 mol% silica, less than 30 mol%, less than 20 mol%, less than 10 mol%, less than 5 mol%, or less than 1 mol% silica.

[0074] The inner surface of the lid or cap may be formed of or comprise a silica-free coating. This means that the lid or cap can be made of any material and then coated such that the inner surface is formed of the coating. The coating may be any of the coating materials set out for the device body. The coating may have a thickness of from Inm to 1000 micrometers, for example from 100 nm to 1000 micrometers, for instance from 1 micrometer to 100 micrometers, or 10 micrometers to 1 millimeter.

[0075] When the inner chamber is sealed, the solution present in the device body may also be degassed. By “degassed” it is meant that the gas dissolved in the solution is at least partially removed. In particular, the percentage of oxygen present be reduced from that present under atmospheric conditions. “Degassing” may be performed by bubbling an inert gas such as nitrogen through the solution. Degassing has the benefit of reducing the potential for oxidation reactions. In turn, this can reduce the degradation otherwise observed in the solution and so improve the purity.The solution

[0076] The devices as set out for any of the aspects disclosed herein comprises a solution comprising at least one stabilizer to prevent radiolytic degradation and a radioisotope binding species. At least a portion of the inner surface of each device body is in direct contact with the solution.

[0077] The solution may be an aqueous solution, such as an aqueous pharmaceutical solution. By pharmaceutical solution, it is meant that the solution can be used in combination with a radioisotope in therapeutic treatments or in diagnostic imaging.

[0078] The solution is designed to be suitable for producing a radiopharmaceutical, comprising a radioisotope present in the solution. This may be a solution comprising a radiopharmaceutical or a radiopharmaceutical solution. A radiopharmaceutical is a drug or composition which includes a radioisotope, such as a compound bound to a radioactive isotope. These are for use in medical applications, including diagnostic imaging and therapeutic treatments.

[0079] The solution may further comprise other excipients. For instance, the solution may comprise sodium ions, Na+. These ions may be aqueous. Other excipients comprising sodiumions may include sodium chloride, sodium acetate and / or sodium hydroxide. Other sodium salts may also or instead be present. Sodium ions may be present in amounts between 0.01 mol / L and 1 mol / L, such as between 0.05 mol / L and 0.5 mol / L, or between 0.1 mol / L and 0.2 mol / L.The at least one stabilizer

[0080] Stabilizers are used in radiopharmaceutical compositions in order to mitigate the effects of ionising radiation emitted from a radioisotope. They are often free radical scavengers and so prevent unwanted interactions of free radicals with other compounds. The stabilizers present may be capable of being oxidised, as is the case when accepting free radicals. When oxidised, it is possible that these stabilizers can react with other compounds present in the solution, such as the radioisotope binding species. While this would ideally be avoided, the presence of stabilizers is required in order to maintain the overall stability of the pharmaceutical compounds and so they often cannot simply be removed. The at least one stabilizer may be capable of being oxidised and then reacting with the radioisotope binding species.

[0081] Stabilizers which may be present include ascorbic acid and salts thereof, gentisic acid and salts thereof, methylenediphosphonic acid (MDP) and salts thereof, hydroxymethanediphosphonic acid (HMDP) and salts thereof, succinic acid and salts thereof, 4-aminobenzoic acid (pABA) and salts thereof, methionine, Se-methionine, ethanol, histidine, melatonine, phenyl N-tert-butylnitrone (PBN) and curcumin. Salts of acids may be sodium salts, or other metal salts. Salts of the acids may be formed using a buffer solution, such as sodium acetate. The at least one stabilizer may comprise ascorbic acid or a salt thereof, or a phenolic acid, or a slat thereof. The phenolic acid may be gentisic acid.

[0082] The solution may comprise at least two stabilizers and these stabilizers may be a phenolic acid or a salt thereof and ascorbic acid or a salt thereof. The phenolic acid may be gentisic acid. The presence of phenolic acid may serve a dual role of both preventing radiolytic degradation and preventing chemical degradation, when in the presence of a further stabilizer such as ascorbic acid as well as SiOH / SiO- groups. Accordingly, the solution may comprise ascorbic acid and gentisic acid.

[0083] The at least one stabilizer may be present at a concentration of between 0.000001 mol / L to 10 mol / L, such as between 0.001 mol / L and 1 mol / L, or between 0.01 mol / L and 0.05 mol / L. This may refer to the concentration of a single stabilizer if only one is present or the total concentration of stabilizer if more than one is present.The radioisotope binding species

[0084] The radioisotope binding species is configured to bind to a radioisotope. Being configured to bind a radioisotope means that it is suitable for chemically attaching to a radioisotope. For instance, the radioisotope binding species may comprise a chelating portion, which is configured to chelate a radioisotope, thus binding it. Alternatively, the radioisotope binding species may be configured to bind to a radioisotope via a covalent bond, or other form of chemical bond. For instance, the radioisotope binding species may comprise a linker and be configured to bind to a radioisotope via the linker (e.g. a PEG linker). When a radioisotope is present in the solution of the device, the radioisotope binding species may be bound to the radioisotope, in a manner as described above.

[0085] The radioisotope binding species may be formed of one part or portion, or at least two parts or portions. The radioisotope binding species may comprise a compound (or compound portion) selected from an organic molecule or compound (such as a small organic molecular compound), a peptide, a protein (such as an antibody or affibody), a microparticle or a nanoparticle. This compound may be a targeting or non-targeting chemical entity. The compound can be used to instigate binding to a particular receptor in vivo. For instance, the compound may be a peptide (or peptide portion).

[0086] The radioisotope binding species may further comprise a binding portion, for binding or attaching the compound portion of the radioisotope binding species to the radioisotope. This binding portion may be a linker such as a PEG linker or it may be a chelating portion. One example is a radioisotope binding species which comprises a peptide portion and a chelator portion.

[0087] The compound portion and binding portion (e.g. a chelator portion and peptide portion) may be linked. They may be directly linked (e.g. via a covalent bond or bonds) or linked via a linker or linking portion (e.g. to which each is covalently bonded), such as a PEG linker.

[0088] Where a PEG linker is used to link either different portions of the radioisotope binding species or to bind the radioisotope binding species to a radioisotope, the PEG linker may have an average molecular weight of 5 to 10000 Daltons, such as 200, 500, 1000 or 2000 Daltons.

[0089] Examples of suitable radioisotope binding species include DOTATATE which is made up of a chelating portion which binds the radionuclide: DOTA (1,4,7,10-Tetraazacyclododecane-l,4,7,10-tetraacetic acid) and a targeting chemical entity portion: TATE ((Tyr3)-octreotate). DOTATATE may be used in radiopharmaceuticals (e.g. 177Lu-DOTATATE) but it has been discovered that it is subject to chemical degradation when in the presence of SiOH / SiO- groups.

[0090] The radioisotope binding species may be present at a concentration of at least 0.1 nM or at least InM, or at least 1 pM. For instance, the radiopharmaceutical may be present in a range of 0.1 nM to ImM, or from 1 pM to 1 mM, or from 1 pM to 100 pM, or from 10 pM to 50 pM. This concentration includes the radioisotope binding species in its free and bound forms.

[0091] Where gentisic acid or salts thereof are present in the solution, this may be at a concentration between 0.001 mol / L and 0.5 mol / L, such as between 0.001 mol / L and 0.1 mol / L, or between 0.001 mol / L and 0.01 mol / L, or between 0.002 mol / L and 0.006 mol / L, or between 0.003 mol / L and 0.005 mol / L. Where ascorbic acid or salts thereof are present, this may be at a concentration between 0.005 mol / L and 0.5 mol / L, such as between 0.005 mol / L and 0.05 mol / L, or between 0.01 mol / L and 0.03 mol / L or between 0.01 mol / L and 0.02 mol / L. Gentisic acid or salts thereof and ascorbic acid or salts thereof may be used in combination, in the same concentrations as stated.A binding portion

[0092] As described above, the radioisotope binding species may comprise a binding portion which binds to the radioisotope. For instance, the radioisotope binding species may comprise a chelating portion as a binding portion, which is configured to chelate with a radioisotope. When chelated, the radioisotope is bound by the chelating portion of the radioisotope binding species and so can be transported in combination with it. “Chelating” or “chelation” is defined herein as forming numerous co-ordinate bonds between the chelator and an ion or atom, typically a metal ion or atom. When an atom or ion is chelated by the chelating portion it may be referred to as “complexed” and the resultant combination of the chelator portion and atom or ion as a “complex”.

[0093] The chelator portion may be a crown ether (such as 15 -Crown-5, 18-Crown-6, etc), nitrogen and / or oxygen containing macrocycles or open chains chelators.

[0094] The chelator portion of the radioisotope binding species may comprise 1,4,7,10-Tetraazacyclododecane-l,4,7,10-tetraacetic acid (DOTA), 2-[4,7,10-tris(2-amino-2-oxoethyl)- l,4,7,10-tetrazacyclododec-l-yl]acetamide (DOTAM aka TCMC), Diethylentriaminepentaacetic acid (DTPA), Nitrilotriacetic acid (NTA), Ethylenediaminetetraacetic acid (EDTA), l,4,7,10-Tetraazacyclododecane-l,4,7-triacetic acid (DO3A), 1,4,7-Triazacyclononane-l ,4,7-triacetic acid (NOTA), l,4,7-triazacyclononane-l,4-diacetic acid (NODA), l,4,7-triazacyclononane-l,7-diacetic acid (NO2A), 3,6,9,15-Tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9-triacetic acid (PCTA), Deferoxamine (DFO), DFO*, 2-(4,7-bis(carboxymethyl)-l,4,7-triazonan-l-yl)pentanedioicacid (NOD AGA), 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N",N"',N"",N -hexaacetic acid (HEHA), Macropa, Trizoxetan, Tetraxetan or mixtures thereof. The chelator portion may further comprise analogues and / or derivatives of these compounds.

[0095] The chelator portion of the radioisotope binding species may comprise 1,4,7,10-Tetraazacyclododecane-l,4,7,10-tetraacetic acid (DOTA). DOTA is particularly suitable for complexing lanthanide atoms and ions, including certain radioisotopes. DOTA may be suitable for use in various pharmaceutical applications, for instance in combination with the peptide portion (Tyr3)-octreotate (TATE).

[0096] The chelator portion may additionally refer to any related ligands termed “DOTA” in the art, regardless of whether these are literally 1,4,7, 10-Tetraazacy clododecane- 1,4, 7,10-tetraacetic acid.

[0097] For instance, the radioisotope binding species may be bound to the radioisotope via a covalent bond. For example, it may be directly bound or comprise a linker (i.e. be configured to bind to a radioisotope via the linker (e.g. a PEG linker) or the linker may link the radioisotope binding species to the radioisotope). Examples of radioisotopes to which radioisotope binding species may be covalently bound include 18F.A compound portion

[0098] The radioisotope binding species may comprise a compound portion or compound (or “active portion”) selected from an organic molecule (such as a small organic molecular compound), a peptide, a protein (such as an antibody or affibody), a microparticle or a nanoparticle. This compound may be a targeting or non-targeting chemical entity. This compound may represent the entire radioisotope binding species, or it may form a part of the radioisotope species in conjunction with another portion, such as a binding portion. As used herein, the term "organic molecule" or “small organic molecular compound” refers to small molecules, such as discrete, chemically synthesized compounds which have a weight of less than 1000 Daltons and which do not include a repeating subunit structure.

[0099] For instance, the radioisotope binding species may comprise a peptide or peptide portion. A peptide is a string of amino acids, joined via amide bonds through a condensation reaction. Where present, a peptide portion may comprise a chain of 2-50 amino acids, or 2-40 amino acids, or 2-30 amino acids, or 2-20 amino acids. A peptide portion may be referred to as a targeting vector, as it may function to target a specific receptor or other target in vivo. A peptide portion may be part of a protein, or the compound may be a protein. The protein may be an antibody or an affibody.

[0100] A peptide portion may comprise a nucleophilic functional group. This nucleophilic functional group can result in reactions occurring and so unwanted products are formed. The nucleophilic functional group may be an amine or an aryl-alcohol. The peptide portion may contain a Tyrosine (Tyr) amino acid residue, or a derivative thereof. Tyrosine comprises an aryl alcohol on its side chain which can act as a nucleophile.

[0101] As used herein, the term “aryl" refer to a polyunsaturated, aromatic hydrocarbyl group having a single ring or multiple aromatic rings fused together, each containing 6 to 10 ring atoms. The aromatic ring may optionally include one to two additional rings (cycloalkyl, heterocyclyl or heteroaryl as defined herein) fused thereto. Suitable aryl groups include phenyl, naphtyl and phenyl ring fused to a heterocyclyl, like benzopyranyl, benzodi oxolyl, benzodioxanyl and the like. Aryl groups can be unsubstituted or substituted with, for example, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy groups.

[0102] A peptide portion may comprise or be selected from (Tyr3)-octreotate (TATE), d-Phel-Tyr3 -octreotide (TOC), 1-Nal 3 -octreotide (NOC), or mixtures thereof. The peptide portion may comprise modified versions of these peptides. The peptide portion may comprise or be (Tyr3)-octreotate (TATE).

[0103] A peptide portion may be a somatostatin receptor (SSR) binding peptide. SSRs are found with high density in numerous tumours. SSR overexpression is present in several Neuroendocrine tumours (NETs). SSR binding peptides bind the transmembrane receptors of NETs with the highest activity and is transported into the cell. When further linked to a chelator portion which is chelating a radioisotope, this allows the radioisotope to be “trapped” in the tumour and so increases the probability of desired DNA breakage. Equally, the trapping of the radioisotope allows it to be used for diagnostics and imaging.

[0104] The device disclosed herein allows compounds which are part of the radioisotope binding species, such as peptide portions, which would otherwise be subject to degradation pathways to be used with reduced loss of the compound.A radioisotope

[0105] The solution may further comprise a radioisotope. The radioisotope binding species may be bound to the radioisotope covalently (e.g. via a linker or linker portion) or via the chelator portion.

[0106] The radioisotope may be selected from carbon-11, fluorine-18, gallium-67, gallium-68, zirconium-89, yttrium-90, terbium-152, iodine-123, iodine-131, lutetium-177, actinium-225,lead-212, bismuth-213, bismuth-212, radium-223, indium-ill, astatine-211, rubidium-82, technetium-99m, technetium-94m, promethium-151, thulium-172, tin-121, tin-117m, praseodymium- 142, praseodymium- 143, gold- 198, gold- 199, scandium -43, scandium-44, scandium-47 or copper-64. The radioisotope may be selected from radioisotope is lutetium-177, gallium-68, yttrium-90 or copper-64. The radioisotope may be lutetium-177.

[0107] Lutetium-177 can be used in combination with the chelating agent DOTATATE in order to treat cancers which express somatostatin receptors, and which may over express somatostatin receptors. It is a radiolabelled somatostatin analogue and treats tumours by emitting ionizing beta radiation. Provision of a device which reduces degradation of DOTATATE would therefore be advantageous. Alternatives to Lu- 177 LuDOTATATE include Y-90 YDOTATATE, which functions in a similar manner. Other uses of radionuclides include imaging and diagnostics. For instance, Ga-68 GaDOTATATE and Cu-64 CuDOTATATE are used when localizing tumours and to measure tumour density and distribution.

[0108] The solution may have a radioactive concentration of at least 0.01 mCi / mL (0.37 MBq), at least 0.1 mCi / mL (3.7 MBq), or at least ImCi / mL (37 MBq). This may be up to 1000 mCi / mL (37000 MBq).

[0109] Radiolysis is not linearly proportional to radioactivity concentration at higher concentrations, and increases significantly at a threshold concentration, where afterwards there is essentially an exponential increase. It has been found that the devices disclosed herein can increase this threshold concentration before. That is, the concentration threshold at which radiolysis increases significantly can be itself be increased. For example, by at least 50%. Accordingly, the devices allow for an increased radioactive concentration. Accordingly, the solution may have a radioactive concentration of at least 50 mCi / mL (1850 MBq) or at least 100 mCi / mL (3700 MBq). The solutions may be aqueous solutions.

[0110] The solution may have a concentration of radiopharmaceutical (comprising the radioisotope) radioisotope of at least 0.1 nM or at least InM, or at least 1 pM. For instance, the radiopharmaceutical may be present in a range of 0.1 nM to ImM, or from 1 pM to 1 mM, or from 1 pM to 100 pM, or from 10 pM to 50 pM.The pH of the solution

[0111] The pH of the solution can vary depending on the additives used. This in turn can affect the stability of the components of the solution, due to acid or alkali degradation pathways. Additionally, the pH of the solution needs to be physiologically tolerable if the solution is tobe directly injected into a patient. The pH of the solution can be between 0 and 8 or between 0 and 7.5, or between 1 and 7.5, or between 2 and 7.5, or between 3 and 7.5, or between 4 and 7.5, or between 4.5 and 7.5. The pH of the solution can be between 0 and 7, or between 1 and 7, or between 2 and 7, or between 3 and 7, or between 4 and 7, or between 4.5 and 7. The pH of the solution can be between 0 and 6.5, or between 1 and 6.5, or between 2 and 6.5, or between 3 and 6.5, or between 4 and 6.5, or between 4.5 and 6.5. The pH of the solution can be between 0 and 6, or between 1 and 6, or between 2 and 6, or between 3 and 6, or between 4 and 6, or between 4.5 and 6. The pH of the solution may be between 4.5 and 6. A pH between 4.5 and 6 is acceptable for use in injectable solutions whilst preventing degradation of components of the solution.Specific radiopharmaceutical solutions

[0112] Specific radiopharmaceutical compositions are already known in the art and are used for therapeutic and diagnostic purposes.

[0113] One example of a known composition is for [177Lu]LuDOTATATE (marketed under the name “Lutathera”). The composition of Lutathera is provided as formulation 1 :Formulation 1:Lu 177 DOTATATE 370 MBq / mL (10 mCi / mL)Ascorbic acid 2.8 mg / mLSodium acetate 0.66 mg / mLDTPA 0.05 mg / mLGentisic acid 0.63 mg / mLAcetic acid 0.48 mg / mLNaOH 0.65 mg / mLNaCl 6.85 mg / mLWater for injection ad 1 ml

[0114] The pH of the Lutathera composition is between 4.5 and 6.

[0115] The solution of the device may comprise ascorbic acid and gentisic acid. The solution of the device may further comprise sodium acetate. The solution of the device may further comprise any or all of DTPA, acetic acid, sodium hydroxide, sodium chloride and water. The solution of the device may comprise DOTATATE as the radioisotope binding species. Thesolution of the device may have a pH of between 4.5 and 6. The solution in the device may be formulation 1 (Lutathera).Radiolysis

[0116] Both chemical degradation and radiolytic degradation can affect a radiopharmaceutical solution. As such, the device disclosed herein may additionally be configured to reduce radiolysis.

[0117] The device configuration can provide a structural, geometric solution to reduce radiolysis in radioisotope solutions. By dividing the interior chamber into multiple subvolumes, the device limits the interaction between the emitted particles which cause radiolysis and the remainder of the solution, thereby reducing the formation of radiolytic by-products and improving the stability and purity of the solution. Further, such device configurations reduce the amount of radiolysis while avoiding many of the drawbacks which can occur with existing methods of reducing radiolysis and whilst maintaining the benefit of reduced chemical degradation.

[0118] Radiolysis may be reduced in the device through the use of inset arrays, particles, or both, as described in more detail below.Insert array

[0119] The devices of the first and second aspects may further comprise an insert array provided within the interior chamber of the device body, insert array provided within the interior chamber of the device body, the insert array comprising one or more insert walls. The one or more insert walls enclose at least one internal sub-volume so as to at least in part separate the internal sub-volume from the remainder of the interior chamber. At least one external subvolume may be formed within the interior chamber between the one or more insert walls and the at least one of the internal surface of the one or more device sidewalls (i.e. the inner surface of the device body). The device may comprise a plurality of the internal sub-volumes and / or a plurality of the external sub-volumes. The device may further comprise a composition comprising a radioisotope provided to each internal sub-volume and external sub-volume.

[0120] The insert array provides a structural, geometric solution to reduce radiolysis in radioisotope compositions. By dividing the interior chamber into multiple sub-volumes, the device limits the interaction between the emitted particles which cause radiolysis and the remainder of the composition and the insert array attenuates the high energy charged particles produced by the emissions to reduce attenuation in the composition, thereby reducing theformation of radiolytic by-products and improving the stability and purity of the composition. Further, such devices reduce the amount of radiolysis while avoiding many of the drawbacks which can occur with existing methods of reducing radiolysis.

[0121] Reduction of the radiolysis in the device is provided through the use of the insert array. By making geometric changes to / dividing up the interior chamber of the device via the use of the insert array, smaller sub-volumes of fluid are created. Radiolysis occurs through the depositing of emitted particles during decay of the radioisotope into the composition. The provision of smaller sub-volumes of the fluid means that a larger proportion of the emitted particles (such as a, P, y particles) are deposited outside of the composition, instead being deposited into the one or more walls of the insert array and the walls of the device. This reduces the interaction of the emitted particles with the other components of the composition, thereby reducing the ionization of these other components and, hence, radiolysis. Furthermore, the insert array structure further attenuates high energy charged particles produced by radioactive emissions to reduce attenuation in the composition.

[0122] The reduction of radiolysis generally has several significant benefits. It improves the stability of compositions comprising radioisotopes so that the chemical and radiochemical purity of the radiopharmaceutical, and effectiveness of the radiopharmaceutical when used for treatment or imaging is maintained. Generally speaking, this can improve the effectiveness of the compositions, for example in treatments and imaging using radio radiopharmaceuticals, improved stability also results in higher quality radiopharmaceuticals with more predictable and reliable pharmacokinetics, leading to more accurate diagnostic imaging and more effective therapeutic outcomes. It also improves the availability of radioisotope-containing compositions by prolonging the shelf-life of the compositions and increasing the concentration for a given isotope that can be stored and transported within a given time frame.

[0123] The insert array does not interfere with the reduction of chemical degradation achieved by using a device as disclosed herein.

[0124] Instead of or as well as an insert array, a device disclosed herein may further comprise a plurality of particles provided within the interior chamber, wherein the particles are arranged as a stack and defining a plurality of fluidly connected sub-volumes between the plurality of particles within the interior chamber and wherein each particle has a maximum dimension of from 20 pm to 8 mm. A composition comprising a radioisotope may be provided in the fluidly connected sub-volumes.

[0125] By dividing the interior chamber into multiple sub-volumes using the particles (such as beads or balls), and, in particular, those having the size disclosed herein, the device limits theinteraction between emitted particles and the components of the composition. The particles can create small sub-volumes therebetween, of the order of 20 pm to 8 mm, since the size of these sub-volumes is defined in part by the size of the particles. As this is of the order of the average range of many particle emissions in water, this which volumes lead to a significant proportion of the emitting particles being deposited into the beads and the device sidewall. Further, even at the higher particle sizes, it has surprisingly been found that the amount of radiolysis is decreased significantly as compared to an empty device (without particles or an insert array) or existing compositions, but without significant impact on the useability of the device as compared to an empty device. This reduces the formation of radiolytic by-products and, therefore, improves the stability and purity of the radioisotope composition. Moreover, the use of the particles of the claimed size means that these will absorb a large proportion of the emitted particles. Accordingly, for the same reasons as the insert array disclosed herein, the particles provide the benefits associated with lower radiolysis, listed above, and in a similar manner.

[0126] An insert array may be provided within the interior chamber of the device body. This insert array may be provided in combination with any other aspect of the device.Insert array form

[0127] In the aspects comprising an insert array, the insert array is a provided within the interior chamber of the device body and comprises one or more insert walls.

[0128] The device may comprise a plurality of internal sub-volumes defined by the one or more insert walls. For example, the insert array may comprise a plurality of insert walls and the device may comprise a plurality of internal sub-volumes, wherein each of the plurality of internal sub-volumes is defined by a corresponding one of the plurality of insert walls. The insert array may comprise a plurality of discrete inserts, each insert comprising at least one of the plurality of insert walls. In other words, the insert array may be an arrangement of separate inserts within the device body, each comprising one of the insert walls. Alternatively, it may be an arrangement of discrete sub-assemblies where each sub-assembly comprises plural insert walls.

[0129] In configurations where there are discrete inserts or sub-assemblies, these may be spaced apart or in contact with one another. These may have a fixed relationship to one another (e.g. by bonding or fusing or through the use of connectors or spacers or other means) or may be moveable relative to one another within the confines of the device interior chamber. Where the inserts or sub-assemblies are moveable relative to one another, the size of the external sub-volumes may be changeable but the insert (e.g. the shape, size, spacing features) can ensure that external sub-volumes are defined between the respective inserts.

[0130] Where there are discrete inserts, each insert may comprise an insert body comprising the insert wall and the wall may have an internal surface and an external surface. The internal sub-volume is accordingly delimited at least in part by the corresponding insert body. The insert body may enclose, either partially or fully, the internal sub-volume, for example providing a wall or sidewall which extends around the internal sub-volume. The insert body may additionally comprise other walls, such as a base and a top, which may further delimit the internal sub-volume.

[0131] Where present, an insert (where there is a single insert) or each (where there are plural) insert may comprise an insert body comprising a respective insert wall and the insert wall and / or insert body may define a tubular structure. This tubular structure has a hollow providing the internal sub-volume. The tubular structure may have a hollow cylindrical shape or a hollow prism shape. The tubular structure may be an elongate tubular structure, such as an elongate hollow cylindrical shape or a hollow prism shape. The tubular structure may have at least one open end, for example to provide fluid communication with at least some of the other internal and external sub-volumes, or these may be closed (e.g. using a removable cap).

[0132] Where there is a plurality of inserts, each may be arranged within the interior chamber of the device in contact (i.e. with the insert body or insert wall in contact) with an adjacent insert of the plurality of inserts, with the shape of each insert body causing the respective insert to be spaced apart from at least one of the other inserts of the plurality of inserts so as to provide the a further sub-volume therebetween. This advantageously creates a further type of subvolume enclosed between the insert walls of the different inserts, which further creates regions with smaller dimensions in which radiolysis is reduced. For example, for discrete inserts, the insert body may comprise a tubular structure and the inserts may be an arranged within the interior chamber with the tubular structure in contact with the tubular structure of an adjacent insert causing the respective inserts to be spaced apart from at least one of the other inserts of the plurality of inserts so as to provide an inter-insert sub-volume therebetween.

[0133] Such arrangements and shapes advantageously provides the plurality of different subvolumes, including the using the shape of the insert walls and insert body and, therefore, in an efficient and straightforward manner. Moreover, reliance on the shape of the insert assemblies to create the external and inter-insert sub-volumes enables the provision of small diameter inter-insert and external sub-volumes and further sub-volumes with narrow sections where the insert walls and internal surfaces of the device body meet. This creates regions where there isa high proportion of emitted particles being deposited into the insert walls and outside of the device. For example, insert walls with an arcuate shape (e.g. cylindrical or spherical shapes) packed together create external sub-volumes by virtue of forming spaced-apart pockets where tight packing is not possible. These shapes also taper from very narrow dimensions where the arcuate walls meet creating small regions. Thes regions have low radiolysis rates, but still feed into the central part of the inter-insert and external sub-volumes, maintaining efficient fluid transfer between the sub-volumes. The same can also be true of other shapes, including prism and polyhedron shapes, where these are packed or arranged in such a way that these inter-insert and external sub-volumes are created therebetween. Reliance on the shape also helps to provide efficient packing and use, avoiding further attachments or spacers, and allowing for easier manufacture and assembly.

[0134] Where the insert array is a single unitary component comprising a plurality of insert walls, the insert walls may be connected as a unitary structure but each at least partially defining a separate internal sub-volume, for example such that there are a plurality of internal subvolumes. Each insert wall may enclose an internal sub-volume, for example providing a wall or sidewall which extends around the internal sub-volume to separate it from the volume of composition between the sidewalls of the device body and the internal sub-volume. There may additionally be other walls, such as a base and a top, which may further delimit the internal sub-volume(s). Provision of single unitary component can be easier to install than separate inserts or sub-assemblies and further in that the shapes of the external sub -volumes are more fixed. The unitary assembly may also provide improved structural integrity and stability within the device as compared to separate inserts.

[0135] Where the insert array comprises a plurality of sub-assemblies joined together, each subassembly may comprise a plurality of the insert walls. The insert walls in each sub-assembly may be connected as a unitary structure but each at least partially defining a separate internal sub-volume, for example such that there are a plurality of internal sub-volumes. The subassemblies may combine to define an internal sub-volume(s). Each insert array may comprise an array body comprising the plurality of insert walls. The internal sub-volume(s) are delimited at least in part by the internal surface of the respective array body. Each insert wall may enclose an internal sub-volume, for example providing a wall or sidewall which extends around the internal sub-volume. There may additionally be other walls, such as a base and a top, which may further delimit the internal sub-volume(s).

[0136] The insert array may define a plurality of internal sub -volumes and / or a plurality of external sub-volumes. For example, each insert wall may define its own internal sub-volumesuch that there are a plurality of internal sub-volumes. There may additionally or alternatively be a plurality of external sub-volumes defined by the insert walls. Plural internal and / or external sub-volumes configuration can reduce radiolysis by providing multiple compartments for the radioisotope composition separated by the insert walls.Insert wall structure

[0137] By “delimit” or “define” a sub-volume, it is meant that the respective surface (or the wall defining the respective surface) at least partially encloses and separates a volume from the other sub-volumes and the remainder of the interior chamber of the device body. This means that the surface or wall acts as a boundary or partition that creates a distinct area inside the device. This may be enclosing (which means to surround at least a majority of a portion of the interior chamber to form the sub-volume but still have an interconnection to allow for some fluid communication, e.g. through opening(s) through the insert wall) or fully enclosing the sub-volume so that it is completely separated (this may be a temporary arrangement, with a closeable aperture for fluid communication, for example). In some embodiments, each insert wall may enclose a separate internal sub-volume. Partially enclosing may include fully enclosing in at least one dimension while remaining open in another, such as in the form of a tubular structure open at least one end. Thus, the term “enclose” encompasses configurations in which a wall completely surrounds a volume in all dimensions and those in which the enclosure is directional or partial. The wall may not need to be a fluid impermeable barrier, but may in some cases.

[0138] By “at least partially delimiting” or “at least partially defining” it is meant that the insert wall defines a part of the enclosure either entirely or together with additional walls, such as other insert walls or the walls of the device (sidewall, base, etc.). That is, the insert wall may co-operate or connect (e.g. by being placed against) further walls or surfaces to provide the sub-volume in question. For example, combining with another internal or external surface to define the respective sub-volume. For example, the internal surface may combine with the internal surfaces of other insert walls to define the internal sub -volume or the external surface may combine with the external surface of another insert wall of the device body walls.

[0139] The one or more insert walls and device body wall(s) (e.g. sidewall) can be any shape for creating the sub-volumes within the device. The insert wall(s) may be planar (e.g. extending straight across a section of the interior chamber) or may be curved or be formed of varying parts across the surfaces. The internal and external surfaces of the insert wall(s) may be different shapes (i.e. the insert walls may be non-uniform across their thickness). The insertwall(s) may have an arcuate shape (e.g. cylindrical or spherical shapes) so that, when packed together, the insert walls create external sub -volumes by virtue of forming spaced-apart pockets caused by the arcuate shape. The use of arcuate insert walls, and particularly arcuate walls having a convex external surface, advantageously creates external sub -volumes with shapes which taper from very narrow dimensions where the arcuate walls meet (dependent on the arcuate shape) to larger central portions of the sub-volumes. This creates small regions with very low radiolysis rates, but which still feed into the central part of the external sub-volume, where fluid transfer is easier. The same is also true of other shapes, including prism and polyhedron shapes to extent where these are packed in such a way that these external sub-volumes are created therebetween. Similarly, the device body sidewall(s) may additionally or alternatively have an arcuate shape (e.g. cylindrical or spherical shapes).

[0140] The or each insert wall may delimit or define an insert chamber, the insert chamber delimiting or defining the internal sub-volume. In other words, where there are plural insert walls, each insert wall may define or enclose its own internal sub-volume such that the internal surface of the particular wall defines the internal sub-volume. The wall defining the internal surface may partially or fully enclose the sub-volume. The wall defining the chamber may provide a tubular structure having a hollow providing the internal sub-volume. The tubular structure may be an elongate tubular structure and may be a hollow cylindrical shape or a hollow prism shape, such as an elongate hollow cylindrical shape or a hollow prism shape. The tubular structure may have at least one open end, for example to provide fluid communication with at least some of the other sub-volumes, or these may be closed (e.g. using a removable cap). In such embodiments, the internal sub-volumes may be those fully enclosed by each insert wall and the external sub-volumes may be those defined in conjunction with other parts of the device, namely other insert walls and / or the device body.

[0141] The wall thickness of the or each of the insert walls may be at least 50 pm, such as at least 100 pm, such as at least 250 pm. This can be from 50 pm to 2mm, such as from 100 pm to 2mm or from 100 pm to 1mm. These thicknesses, particularly of materials such as glasses, plastics, metals and ceramics, will prevent transfer of a significant proportion, if not all, of the emitted particles from the respective sub-volume to related portions of the interior chamber, thereby reducing radiolysis.Internal, inter-insert and external sub-volumes

[0142] A cross-section dimension of the internal and / or inter-insert sub-volume(s) may be related to the range of the emitted particles (e.g. at least one of (i) the beta (beta(+) or beta(-)) range of the radioisotope or (ii) the alpha range of the radioisotope). It will be appreciated that the emitted particle type depends on the isotope in question, as does the path length. Table 1 provides examples of average (mean) and maximum ranges for the primary emitted particles from a number of radionuclides.

[0143] A cross-section dimension of the internal and / or inter-insert sub-volume(s) may be less than or equal to 3 x average (mean) range of an emitted particle. The range may be range within water, as set out in Table 1, below. Accordingly, for each isotope in Table 1, a device used forthat composition may have a cross-section dimension of the internal and / or inter-insert sub-volume(s) may be less than or equal to 3 x average (mean) range of an emitted particle as set out in Table 1. Although it will be appreciated that range may vary within different mediums, average range in water provides a good model and devices adhering to this will provide the increased attenuation and reduced probability of depositing of emissions, discussed above. This limitation may further be all cross-sectional dimensions in a single plane. For example, this may be a maximum cross-section dimension and it may be along a whole length of the insert or sub-volume, for example.

[0144] Alternatively, for each isotope in Table 1, a device used for that composition may have a cross-section dimension of the internal and / or inter-insert sub-volume(s) which is be less than or equal to the values set out in the column “Optional internal sub-volume, inter-insert subvolume and / or external sub-volume maximum dimensions (mm)”.

[0145] A cross-section dimension of the internal and / or inter-insert sub-volume(s) may be below at least one of (i) the beta (beta(+) or beta(-)) range of the radioisotope or (ii) the alpha range of the radioisotope. Additionally or alternatively, a cross-section dimension of the external sub-volume(s) may be below at least one of (i) the beta (beta(+) or beta(-)) range of the radioisotope or (ii) the alpha range of the radioisotope. This can further be all cross-sectional dimensions in a single plane, such that all dimensions in that plane are less than or equal to at least one of (i) the beta(+) or beta(-) range of the radioisotope or (ii) the alpha range of the radioisotope. This can be a maximum range or an average (mean) range, as set out in Table 1, below. The range can be the range of the emitted particles in water. References herein to a single plane can be, for example, where the insert wall provides an enclosure surrounding the internal sub-volume, such as a cylinder or a prism-shape, but may permit a longer dimension in other directions, such as perpendicular to the plane in question. Forexample, where the insert wall or the internal surface thereof has a cylindrical or prism shape, the cross-section dimensions may be in a plane perpendicular to the central elongate axis.

[0146] Cross-section dimensions as referred to herein refer to the distance between two surfaces defining the sub-volume. This may be a diameter, for example. The cross-section dimension may be a maximum cross-section dimension, such as the maximum diameter, in a particular plane. The plane may be perpendicular to the insert walls, which in the case of tubular bodies may be perpendicular to the central axis of the tubular bodies, which may be parallel to the base of the device body. This can further be all cross-sectional dimensions in a single plane. For example, where the dimension refers to the internal sub-volume, this can be measured between two opposing parts of the insert wall or the insert wall and another wall defining the internal sub-volume. Where the insert wall provides an enclosure surrounding the internal subvolume, such as a cylinder or a prism-shape, this may be between two opposing surfaces of the insert wall (i.e. an internal diameter). It will be appreciated that a cross-sectional dimension may permit a longer dimension in other directions, such as perpendicular to the plane in question. For example, where the insert wall or the internal surface thereof has a cylindrical or prism shape, the cross-section dimensions (e.g. diameter) may be in a plane perpendicular to the central elongate axis. Where the dimension refers to an external sub-volume, this similarly can be measured between two opposing parts of the insert wall, or the insert wall and another wall defining the external sub-volume.

[0147] The or each internal and / or inter-insert sub-volume (e.g. each insert chamber for the internal sub-volume) may have a maximum cross-sectional dimension, such as a diameter, of from 20 pm to 8 mm. This size ranges optimize the balance between reducing the volume between the walls (and hence radiation absorption), attenuation and the volume for composition containment. It has surprisingly found that significant radiolysis reduction can be obtained within this range without difficulties in handling caused by further reduction. For example, narrow sub-volumes can restrict fluid flow and often require specialist equipment to insert and remove composition therefrom. This can be problematic and increase complexity of handling. Without wishing to be bound by theory, it is thought that the dimensions disclosed herein also provide attenuation of the emitted particles which thereby reduces attenuation in the composition. This maximum cross-sectional dimension may be from 100 pm to 8 mm. For example, from 100 pm to 5 mm, from 500 pm to 5 mm, such as greater than 1 mm to 6 mm, or 1.5 mm to 6 mm, or 2 mm to 6 mm. These provide dimensions which are of the order of, but typically higher, than the average range of beta(+) emissions for many of the common radioisotopes used in radiopharmaceuticals. This provides a reduction in radiolysis but stillprovides a larger volume for provision of a useful volume of fluid and of openings to facilitate use.

[0148] It will be appreciated that the specific maximum cross-sectional dimension used may be selected based on factors such as the type and activity of radioisotope, desired composition volume, and radiolysis reduction goals. Table 1 lists exemplary radioisotopes. The internal sub-volumes, and / or inter-insert sub-volumes and / or external sub-volumes may have the maximum dimensions listed therein when used with a composition comprising the radioisotope listed therein.Table 1 (* includes alpha emitting daughter nuclides)

[0149] An external sub-volume is defined within the interior chamber between the external surface of the one or more insert walls and at least one internal surface of the device body (e.g. the internal wall of the sidewall) and may further be between insert walls. For example, between an external surface of an insert wall and an external surface of another insert wall. There may be plural external sub-volumes and, in such cases, there may be fluid communication between all of the external sub-volumes. The insert array - and the one or more insert walls - may therefore be arranged within the interior chamber so as to define a plurality of external sub-volumes within the interior chamber.

[0150] The external sub-volume may have a maximum dimension (e.g. maximum cross-sectional dimension), for example a maximum diameter. This may be a cross-sectional dimension in one dimension, such as perpendicular to the insert wall or perpendicular to a central axis defined by the sidewall(s) of the device body. The distance may be between the insert wall (e.g. the external surface delimiting the external sub-volume) and the internal surface of the device body delimiting the external sub-volume (e.g. the sidewall) or, where another insert wall also defines the external sub-volume, this may be between the insert walls if this provides the maximum dimension. This may be less than or equal to the diameter of the interior chamber of at least one of the respective inserts. The external sub-volume may have a maximum cross-sectional dimension, such as a diameter, of from 20 pm to 8 mm. This may be from 100 pm to 8 mm. For example, from 100 pm to 5 mm or from 500 pm to 5 mm, such as greater than 1 mm to 6 mm, or 1.5 mm to 6 mm, or 2 mm to 6 mm. The external sub -volume may have a maximum dimension as measured between the external surface and the at least one sidewall of the device body and an external surface of one of the other of the plurality of insert walls of less than or equal to the diameter of the interior chamber of at least one of the respectiveinsert walls (e.g. the inserts, where discrete), for example the interior chamber defined by the insert wall at least partially forming the external sub-volume in question. The maximum crosssection dimension of the external sub-volume(s) may be related to the range of the emitted particles. For example, it may be less than or equal to 3 x average (mean) range of an emitted particle, as defined in Table 1.

[0151] The internal sub-volume(s) defined by the insert walls may (each) have a volume of at least 0.01m, such as at least O.lmL or at least ImL, for example from 0.01 mL to lOmL, such as from O.lmL to 8mL, 0.5mL to 8mL, from 0.1 mL to 5mL, from O.lmL to 2mL. The interinsert sub-volume(s) defined by the insert walls may (each) have a volume of at least 0.01m, such as at least 0. ImL or at least ImL, for example from 0.01 mL to lOmL, such as from 0. ImL to 8mL, 0.5mL to 8mL, from 0.1 mL to 5mL, from 0. ImL to 2mL. The external sub-volume(s) may (each) have a volume of at least 0. ImL, such as at least ImL, for example from 0.1 mL to lOmL, such as from O.lmL to 8mL, 0.5mL to 8mL, from 0.1 mL to 5mL, from O.lmL to 2mL. The volumes of the sub-volumes is defined by the walls which define the respective volume. Where there is a disconnect in the walls, such as an opening or a gap defined by a neck portion before opening up into a wider portion, the sub-volume is delimited by a straight-line between the walls defining the disconnect. For example, in the case of a tubular structure with openings at either end, the top of the sidewall(s) defining the tubular structure may delimit the top and the bottom of the volume.

[0152] At least one of the external sub-volumes may have a volume that is less than the volume of the internal sub-volume and / or a cross-sectional area of at least one external sub-volume may be smaller than that of the internal sub-volume. In this way, the external sub-volume may reduce radiolysis to a greater extent as compared to the internal sub-volume.

[0153] Each sub-volume may be in fluid communication with the other sub-volumes. For example, the internal, inter-insert and external sub-volumes may all be in fluid communication. This allows for easier solution handling, such as providing and removing the solution from the device, since removal from individual sub-volumes is not required. For example, this can allow for only one sub-volume to be large enough to receive a syringe for handling or injection into a patient (which sub-volume may have a higher radiolysis rate) and the remainder can be smaller volumes (which can then have reduced rates of radiolysis) but which are still in fluid communication with the larger volume sub -volume so as to permit straightforward removal. Where the discrete inserts are moveable relative to one another, in some cases it is sufficient that these can move to provide the fluid communication. In some cases, the fluid communication may be permanently in fluid communication after insertion of the insert array.Particles

[0154] The devices of the third and fourth aspects include a plurality of particles provided within the interior chamber, wherein the particles are arranged as a stack (or “arrangement”) and define a plurality of fluidly connected sub-volumes between the plurality of particles within the interior chamber. Each particle has a maximum dimension of from 20 pm to 8 mm. The particles disclosed herein may also further be present in the devices of the other aspects, including the first and second aspects, in combination with the insert array.Particle geometryParticle size

[0155] Each particle has a maximum dimension (e.g. a maximum diameter) of from 20 pm to 8 mm. As discussed above, this size range provides optimal sub-volume size as well as shielding through the presence of the particles themselves. This also balances reducing radiolysis and the volume of the solution within the device. It has been found that difficulties in handling small volumes increase and lead to a falloff in useability. For example, narrow sub-volumes can restrict fluid flow and often require specialist equipment to insert and remove solution therefrom. This can be problematic and increase complexity of handling. Surprisingly, these sizes still provide an effective reduction in radiolysis. This maximum dimension may be from 100 pm to 8 mm. For example, from 100 pm to 5 mm, from 500 pm to 5 mm or from 1 mm to 6 mm (such as greater than 1 mm to 6 mm, or 1.5 mm to 6 mm, or 2 mm to 6 mm). These provide sub-volume dimensions which are of the order of, but typically higher, than the average range of beta(+) emissions for many of the common radioisotopes used in radiopharmaceuticals. This provides a reduction in radiolysis but still provides a larger volume for provision of a useful volume of fluid and of openings to facilitate use. It will be appreciated that this does not preclude particles of a larger diameter being present in the device provided there are a plurality within the stack as set out herein.

[0156] The particles may have a maximum dimension which is related to the range of the emitted particles, given that the diameter will in part define the size of the voids between the particles and, further, because the thickness of the particles will prevent through passage of emitted particles. For example, a maximum dimension may be less than or equal to 3 x average (mean) range of an emitted particle (but greater than the lower limit of 20 pm). The range may be range within water, as set out in Table 1, below. Accordingly, for each isotope in Table 1, a device used for that solution may have a maximum dimension of less than or equal to 3 xaverage (mean) range of an emitted particle as set out in Table 1. Additionally or alternatively, the particles may be sized and shaped so that the average (mean) of the average (mean) cross-sectional dimension of the sub-volumes defined therebetween is less than or equal to 3 x average (mean) range of an emitted particle, as defined in Table 1. This may be determined and further defined in line with the internal or inter-insert sub-volume definitions as set out for the insert array.

[0157] The maximum dimension refers to the largest dimension of (e.g. across) the particle. For spherical particles, this would be the diameter. For non-spherical particles, the maximum dimension may be measured as the longest dimension across the particle. The maximum dimension may be determined using techniques such as optical microscopy, electron microscopy, or particle size analysers. For irregularly shaped particles, multiple measurements can be taken to determine the maximum dimension.

[0158] The particles of the stack may have an average particle size, for example a mean particle size, of from 20 pm to 6 mm, such as from 100 pm to 5 mm or from 500 pm to 5 mm (such as greater than 1 mm to 6 mm, or 1.5 mm to 6 mm, or 2 mm to 6 mm). Mean particle size may be measured as the mean diameter of a representative sample of particles. The particle size distribution can be determined using techniques such as dynamic light scattering, laser diffraction, or image analysis of microscopy data. The arithmetic mean of the measured diameters may then be calculated to determine the average particle size. A more uniform spread of particle sizes may lead to a more uniform reduction in radiolysis between devices and regions of solution.Particle form

[0159] The particles may be of any shape and the stack (or “arrangement”) may comprise particles of different shapes. The particles may be spheres, polyhedrons, rods, hollow cylinders, or discs, for example. The particles may each comprise at least one rounded or arcuate surface. Particles with rounded or arcuate surfaces (e.g. cylindrical or spherical shapes) have been found to pack together to create sub-volumes having desirable shapes. These shapes of the sub-volumes formed taper from very narrow dimensions where the arcuate walls meet, particularly where the arcuate walls diverge and taper away from one another, creating small regions with small dimensions and diameters. This create regions with low radiolysis rates, but which still feed into the central part of each sub-volume, where fluid transfer is easier. These can also avoid close packing of the beads to ensure that there are ample sub-volumes. Each particle of the stack may have a shape selected from substantially spherical, substantially spheroidal, substantially ellipsoidal, substantially ovoidal, substantially toroidal, orsubstantially cylindrical. This can be spherical, spheroidal, ellipsoidal, ovoidal, toroidal, or cylindrical.Stack

[0160] By “stack” or “arrangement”, it is meant an arrangement of a plurality of particles, where the particles are each in contact with other particles within the stack or arrangement. The stack can include particles arranged randomly, for example as a pile, or in a predefined structure. The particles may be interconnected so as to prevent relative movement or may be moveable relative to one another.

[0161] The particles in the stack form a plurality of fluidly connected sub-volumes therebetween. These can be considered to be equivalent to the inter-insert sub-volumes discussed in respect of the insert array and have the same benefits as these and the internal subvolumes. The particles in the stack may further define sub-volumes equivalent to the external sub-volumes between either a particle and the device body (i.e. an internal surface thereof, such as the sidewall of the device body) or plural particles and the device body.

[0162] The stack includes a plurality of particles, such as at least 5 particles, at least 10 particles or at least 20 particles, at least 100 particles. These can be discrete particles or may be connected, such as fused or bonded. This can be, for example, after insertion into the device.

[0163] The use of particles creates a network of small sub-volumes, effectively limiting the interaction between radiation and the solution while maintaining fluid connectivity. The subvolumes may each have a maximum cross-sectional dimension, for example a maximum diameter, as measured between the external surface of the particle delimiting the sub-volume and the internal surface of the part of the device body (e.g. sidewall) and / or an external surface of one of the other particles of from 20 pm to 8 mm. This maximum cross-sectional dimension may be from 100 pm to 8 mm. For example, from 100 pm to 5 mm or from 500 pm to 5 mm, such as greater than 1 mm to 6 mm, or 1.5 mm to 6 mm, or 2 mm to 6 mm. The sub-volumes may each have a maximum dimension as set out above of less than or equal to the diameter of the particle(s) delimiting or defining the sub-volume. In some cases, the cross-section dimension of the internal sub-volumes formed by the beads may be less than or equal to below at least one of (i) the beta(+) or beta(-) range of the radioisotope or (ii) the alpha range of the radioisotope. This configuration can help to ensure that the emitted particles deposit in the walls of the beads or the device, not the solution, thereby reducing radiolysis.

[0164] The sub-volume(s) defined by the particles may (each) have a volume of at least O.OlmL, such as at least 0. ImL, for example from 0.1 mL to lOmL, such as from 0. ImL to 8mL, 0.5mLto 8mL, from 0.1 mL to 5mL, from O.lmL to 2mL. The external sub-volume(s) may (each) have a volume of at least 0. ImL, such as at least ImL, for example from 0.1 mL to lOmL, such as from 0. ImL to 8mL, 0.5mL to 8mL, from 0.1 mL to 5mL, from 0. ImL to 2mL. The volumes of the sub-volumes is defined by the walls which define the respective volume. Where there is a disconnect in the walls, such as an opening or a gap, the sub -volume is delimited by a straight-line between the walls defining the disconnect at the disconnection. For example, in the case of a tubular structure with openings at either end, the top of the sidewall(s) defining the tubular structure may delimit the top and the bottom of the volume.

[0165] A plurality of the sub-volumes are in fluid communication. It is conceivable that some sub-volumes will be fluidly isolated at least in some configurations, but in some cases all of the sub-volumes are either in fluid communication or can be manipulated or moved into fluid communication. By “delimit” or “define” a sub-volume, it is meant that the respective surface of the particles surrounding the volume at least partially encloses and separate a volume from the other sub-volumes and the remainder of the interior chamber of the device body. This means that the surface or wall acts as a boundary or partition that creates a distinct area inside the device. This may be enclosing (which allows for some fluid communication through opening(s)).

[0166] At least one of the plurality of particles is movable relative to another of the plurality of particles. Each of the particles within the stack may be relative moveable to the other particles. This can be advantageous as it provides for easy access to the sub-volumes, for example through manipulation of the particles.Insert array / particle materials

[0167] Although the presence of the insert array and / or particles will reduce radiolysis, the additional surface area in contact with the solution could increase the degradation reactions discussed herein. Accordingly, the insert array and / or particles may be formed of materials which are selected or modified so that there are no or very few SiOH or SiO- moieties (i.e. are free or substantially free of these) in contact with the solution.

[0168] For example, the insert array and / or particles may comprise or be formed of at least one of polymer, a metal (including a metal compound or allow, such as a metal oxide, which may exclude any silicon-containing oxides), a ceramic, silica-free glass, silica-free glass ceramic or an organic composition. These materials can provide an inner surface which is substantially free or free of SiOH and SiO- moieties. For example, these may comprise or be formed of a polymer. Examples of suitable polymers include the polymeric materials may include one or more fluoropolymers (such as polyvinylidene fluoride (PVDF) or ethylene tetrafluoroethylene (ETFE)), polyolefins (such as high-density polyethylene (HDPE), cyclic olefin polymers or polytetrafluoroethylene (PTFE)) or others, such as butyl rubber. Examples of organic compositions include hydrocarbon coatings, such as C3 to C25 fatty acids chains.

[0169] Alternatively or additionally, the insert array and / or particles may comprise or be formed of any suitable material, for example, selected from at least one of a glass, a glass-ceramic, a ceramic, a polymer or a metal (including a metal compound or allow, such as a metal oxide) but be provided with a coating or treatment such that the external surfaces in contact with the solution (in the case of the insert array, this includes the internal surface) have no or very few SiOH or SiO- moieties (i.e. are free or substantially free of these). For example, the insert array may be provided with a coating covering the insert walls and / or the particles may be provided with an outer coating surrounding each particle. The coating may be a polymeric and / or organic coating. For example, the coating may comprise or be formed of (i.e. consist or consist essentially of ) one or more fluoropolymers (such as polyvinylidene fluoride (PVDF) or ethylene tetrafluoroethylene (ETFE)), polyolefins (such as high-density polyethylene (HDPE), cyclic olefin polymers or polytetrafluoroethylene (PTFE)) or others, such as butyl rubber. Examples of organic compositions include hydrocarbon coatings, such as C3 to C25 fatty acids chains (e.g. stearic acid).

[0170] The internal surface and / or the external surface of the insert array and / or the external surface of the particles may have a combined surface concentration of SiOH and SiO- moieties of less than 2 nm -2, less than 1 nm-2, less than 0.5 nm-2, less than 0.1 nm-2, or less than 0.01 nm-2, or the internal surface may be substantially free from SiOH and SiO- moieties.Specific implementations

[0171] Fig. 2A and 2B provide a schematic depiction of a device 100 in the form of a vial for receiving a solution 105, the device 100 comprising a vial body 110 and a solution 105 provided in the vial body 110. The vial body 110 has a cylindrical shape with a circular base 118 and a cylindrical sidewall 115 extending upwards from the base 118 around the perimeter of the base 118. The sidewall 115 and base 118 enclose an interior chamber 120 for receiving the solution 105. An opening 116 is provided at the top of the device 100 and is defined by the top of the sidewall 115. The solution 105 can be provided to and removed from the interior chamber 120 of the device 100 through the opening 116. A cap or lid (not shown) can be used to close the opening 116 and thereby seal the interior chamber 120 of the device 100.

[0172] Fig. 2B provides the same view as Fig. 2A but with a magnified view of a part of the sidewall 115 in a cut-out. Here it can be seen that the sidewall 115 comprises an inner surface 130 and an outer surface 140, wherein the inner surface 130 delimits the interior chamber 120. A portion of the inner surface 130 is in contact with the solution. In the device 100 of Fig. 2, the inner surface 130 is formed of the same material as the bulk of the sidewall 115. In other words, the vial body 110 is formed from a single material. This material is one which does not contain SiOH or SiO- moieties such that the inner surface 130 is inert to the degradation mechanisms described herein.

[0173] The solution 105 contained in the interior chamber 120 of the vial body 100 comprises two stabilisers in the form of gentisic acid and ascorbic acid to prevent radiolytic degradation; and a radioisotope binding species.

[0174] In the device 100, the lack of silanol groups (SiOH), and their conjugate base (SiO-), on the inner surface 130 of the device 100 avoids or reduces reactions between stabilizers present in the solution and radioisotope binding species. As set out in detail above, stabilisers such as gentisic acid can react form a reactive Michael acceptor, in the case of gentisic acid 2,5-Dioxobenzoic acid (a benzoquinone derivative), upon oxidation, a reaction which can be catalysed by the silanol / siloxide functional groups present at the surface of standard glass (SiO2). This reactive species can then react with pepite-containing chelating agents via a nucleophilic group present on the peptide portion, specifically via an amine or aryl -alcohol. This reaction may be further catalysed by SiOH / SiO-. The second pathway discussed above may therefore lead to the chelating agent being degraded. Ascorbic acid can also degrade chelating agents in a related reaction pathway. Ascorbic acid may be oxidised to form dehydroascorbic acid, or its isomers. This may occur as part of a redox cycle involving anoxidised form of a gentisic acid derivative, formed due to SiOH / SiO- catalysis. Dehydroascorbic acid, or its isomers, can then react directly with the amine group present in certain chelating agents. Alternatively, dehydroascorbic acid, or its isomers, may react further, as shown, and the products of these reactions may then react with the amine group present in certain chelating agents. The result of these reactions is that the concentration of stabiliser and the chelating ligand have been reduced in the radiopharmaceutical solution, reducing the stability and effectiveness while increasing toxicity and radiotoxicity.

[0175] Fig 3A provides a schematic view of another device 200 in the form of a vial for receiving a solution 205, the device 200 comprising a vial body 210 and a solution 205 provided in the vial body 210.

[0176] The vial body 210 has a cylindrical shape with a circular base 218 and a cylindrical sidewall 215 extending upwards from the base 218 around the perimeter of the base 218. The sidewall 215 and base 218 enclose an interior chamber 220 for receiving the solution 205. An opening 216 is provided at the top of the device 200 and is defined by the top of the sidewall 215. The solution 205 can be provided to and removed from the interior chamber 220 of the device 200 through the opening 216. A cap or lid (not shown) can be used to close the opening 216 and seal the interior chamber 220 of the device 200.

[0177] Fig. 3B provides the same view as Fig. 3A but with a magnified view of a part of the sidewall 215 in a cut-out and, separately, a magnified part of the base 218 in a cut-out. Here it can be seen that the vial body 210 is a multi-layered structure comprising an inner wall portion 235, which defines the inner surface 230 across both the sidewall 215 and the base 218, and an outer wall portion 236 forming outer surfaces 240 of the vial body 210. Accordingly, the inner wall portion 235 delimits the interior chamber 220 and provides the surface that the solution 205 will be in contact with. The inner wall portion 235 and outer wall portion 236 are laminated to one another to form the laminated vial body 210. This structure advantageously allows for the inner surface 230 to have different properties than the outer structure.

[0178] This laminated structure of the vial body 210 may be formed by having a first layer of a first material (one formed of a polymer, a metal, a ceramic, silica-free glass, silica-free glass ceramic or an organic composition - such that it does not contain SiOH or SiO- moieties) providing the inner wall portion 235 and a second layer of a second material (which may be any of the materials above, but may also be a glass or glass-ceramic, including those comprising SiOH or SiO- moieties, providing the outer wall portion). The first layer may be a coating provided on the outer wall portion 236 so that the coating forms the inner wall portion 235 and defines the inner surface 230.

[0179] The solution 105 contained in the interior chamber 120 of the vial body 100 comprises a stabiliser and a radioisotope binding species.

[0180] Although in the device 200 of Fig. 3 A, the inner wall portion 235 is a distinct layer of material forming the device body 210, this could instead be a treated region of the device body 210. In other words, the device body 210 may be formed of a first material across the entire wall thickness (at the sidewall 215 and base 218), but the inner surface 215 may then be treated or modified to form an inner wall portion 235 with a different chemical composition to the outer wall portion 236. This treatment may remove any SiOH or SiO- moieties on the inner surface 230 forming the inner wall portion 235.

[0181] While Figs. 2A to 3B exemplify the device in the form of a cylindrical vial, it should be noted that the device can be any container and take any shape. For instance, the device may be or form a part of a separation apparatus, such as a filter or column, or other vessel used during synthesis or purification of radioisotope compositions. The device may also be a reaction vessel, such as a microreactor. Where a filter or a column, such as cylindrical column or vessel, the base may be a part of the cylindrical walls (the lowermost portion) and hence be integral with the sidewalls.

[0182] Figs. 4A and 4B provide a schematic depiction of a device 300 in the form of a vial for receiving a solution 305 comprising a radioisotope, two stabilisers in the form of gentisic acid and ascorbic acid to prevent radiolytic degradation; and a radioisotope binding species. The device 300 comprises a device body 310 and an insert array 350 and a solution 305 provided in the device body 310.

[0183] The device body 310 has a cylindrical shape with a circular base 318 and a cylindrical sidewall 315 extending upwards from the base 318 around the perimeter of the base 318. The sidewall 315 and base 318 enclose an interior chamber 320 for receiving the solution 305. An opening 316 is provided at the top of the device 300 and is defined by the top of the sidewall 315. The solution 305 can be provided to and removed from the interior chamber 320 of the device 300 through the opening 316. A cap (not shown) can be used to close the opening 316 and thereby seal the interior chamber 320 of the device 300.

[0184] The insert array 350 is provided within the interior chamber 320 of the device body 310. The insert array 350 comprises a plurality of discrete inserts 360 in the form of identical hollow elongate cylindrical inserts 360, with the cylindrical wall of the inserts 360 forming the insert wall 365 of each insert 360. The hollow cylindrical shape is open at both end faces, providing a top opening 361 and a bottom opening (not depicted) at either end and providing fluid communication (allowing fluid flow) between the interior hollow portion of each insert 360and the interior chamber 320 of the device body 310. The inserts 360 are each arranged upright within the device body 310 and extend along the majority of the height of the device 300. The inserts 360 are arranged parallel to (i.e. coaxial with) one another and the sidewall 315 of the device body 310 and in contact (i.e. abutting) neighbouring inserts 360. The inserts located adjacent to the edge of the device body 310 also contact the sidewall 315 of the device body 310.

[0185] As most clearly visible in the top-down view of Fig. 4B, this arrangement creates a series of internal sub-volumes 370, inter-insert sub-volumes 372 and external sub-volumes 375 within the interior chamber 320. The hollow void within the cylindrical inserts 360 and surrounded around its circumference in the plane parallel to the base 318 by the internal surface of the insert wall 365 provides an enclosed internal sub-volume 370 within each insert 360. As noted above, the inserts 360 are each open at the top and bottom ends so as to provide fluid communication between the internal sub-volumes 370 and the rest of the device 300.

[0186] The shape of each insert 360 and their arrangement within the device body 310 further defines a plurality of inter-insert sub-volumes 372 located between the inserts 360 and a plurality of external sub-volumes 375 further located between the inserts 360 and the sidewall 315 of the device body 310. These external volumes 375 and inter-insert sub-volumes 372 are delimited at each end by the top of the insert wall 365 at one end and the bottom of the insert wall 365 and the base 318 of the device, such that they extend in this device 300 from the base 318 of the device body 310 to the top of the inserts 360. Specifically, the shape of each insert 360 causes the insert 360 to be spaced apart from at least one of the other inserts 360 and, further, from the device sidewall 315. The inter-insert sub-volumes 372 and external subvolumes 375 are each in fluid communication with the rest of interior chamber 320 and internal sub-volumes 370 through the upper portion of the device body 310 and through movement of the inserts 360.

[0187] Accordingly, there are three main types of sub-volume: internal sub-volumes 370, interinsert sub-volumes 372, and external sub-volumes 375. Those between the external surfaces 166 of the insert walls 365 of the inserts 360 within the interior chamber 320 are inter-insert sub-volumes 372 and those between the insert walls 365 of the inserts 360 and the sidewall 315 of the device body 310 are external sub-volumes 375. The inter-insert sub-volumes 372 are defined between the external surfaces 366 of the insert walls 365, have a maximum dimension across the width (i.e. as measured along the axis parallel to that defined by the insert wall 365 and the cylindrical shape, from the top-down view of the Fig. 4B) equal to the maximum internal dimension of the internal sub-volume 370, but the shape formed by virtue of the convexshape of the outer surfaces of the insert wall 365 means that a significant portion of these interinsert sub-volumes 372 has a cross-sectional dimension significantly lower than maximum. As can be seen from Fig. 4B, the cross-sectional shape is that of a three- or four-pointed star, with regions tapering to a point. In these regions, the dimensions are significantly smaller creating narrow regions in which a significant portion of emitted particles will be deposited outside of the solution 305, such as in the insert walls 365, the sidewall 315 of the device body 310 or outside of the device 300, thereby significantly reducing radiolysis. Further, despite at least some these particular inter-insert sub-volumes 372 having a smaller total volume than the internal sub-volumes 370, the presence of these inter-insert sub-volumes 372 across the device 300 overall provides a significant increase in the total volume of solution 305 within regions where the distance of any particular emitted particle to a wall, such as an insert wall 365 or sidewall 315, is reduced as compared to just utilising the internal sub-volumes 375. This significantly increases the utility and usability of the devices 300.

[0188] The external sub-volumes 375 are located between the insert walls 365 of the inserts 360 and the sidewall 315 of the device body 310. In this device 300, by virtue of convex shape of the inserts 360, these have similar narrow regions between the inserts 360 to the inter-insert sub-volumes 372, where the radiolysis rate will be very low, in addition to the central regions where the volume is high. Further, by virtue of the curvature of the sidewall 315 of the device body 310, the maximum dimension across the width of these external sub-volumes 375 is less than the dimension in the same plane for the internal sub-volumes 370 creating smaller subvolumes.

[0189] Compared to use of the device 300 alone for storage of solutions comprising radioisotopes, the provision of the internal sub-volumes 370, inter-insert sub-volumes 372 and external sub-volumes 375 provides the advantages discussed above. The configuration of the insert array 350 within the interior chamber 320 allows for the distribution of the solution 305 across multiple smaller volumes, improving the stability of radioisotope solutions stored or processed in the device 300. The fluid communication between the internal sub-volumes 370, inter-insert sub-volumes 372 and the external sub-volumes 375 allows for the distribution of the solution 305 across multiple small volumes without significantly impeding handling or requiring specialist equipment to use the device 300. The solution 305 can flow into the internal sub-volumes 370 within the inserts 360, the inter-insert sub-volumes 372 and the external sub-volumes between the inserts 360 and between the inserts 360 and the sidewall 315 of the device body 310.

[0190] The insert array 350 in this embodiment is formed of a material substantially free or free of SiOH and SiO- moieties so that the surfaces of the insert walls 365 do not provide further surfaces for catalysing the reaction pathways leading to degradation of the radioisotope binding species and stabilisers. For example, these may comprise or be formed of a polymer.

[0191] In use, solution 305 can be provided to the interior chamber 320 via the opening 361. The fluid communication between the various parts within the interior chamber 320 means that no specialist equipment is required to provide fluid to the internal sub-volumes 370, inter-insert sub-volumes 372 and external sub-volumes 375 and, instead, this can simply be achieved by filling the interior chamber 320 to the desired height. Further, as the inserts 360 are moveable relative to the device body 310 and one another, if manipulation is required to fill a particular region, this can be done either through individual movement of inserts 360 or through inverting of the device 300 when closed, for example - i.e. in a straightforward manner. Removal of the solution 305 is similarly straightforward, and the structure permits removal using, for example, a syringe with a needle inserted into just one of the sub-volumes 370, 375 or a part of the interior chamber 320 and reliance on the fluid communication to allow for removal of the solution 305.

[0192] The device 300 of Figs. 4A and 4B is provided as an example of an implementation of the devices disclosed herein. It will be appreciated that modifications can be made, in addition to those discussed in detail above. For example, with respect to the inserts 360, these could have numerous sizes and shapes. Further, not all inserts 360 within the device need to be identical and the device 300 may comprise inserts 360 of different sizes and / or shapes. To increase fluid handling useability, the inserts 360 may be raised from the base 318 so as to permit fluid flow through the bottom opening of the inserts 360 and / or there may be additional openings through the hollow cylindrical insert wall 365 to permit further fluid communication between the internal sub-volumes 370, inter-insert sub-volumes 372 and the external subvolumes 375.

[0193] The dimensions of the device body 310 and the inserts 360 can be selected for the particular solutions and radioisotopes that they are to be used for, including the diameter of the inserts 360 (e.g. as measured across the circular cross-section shown in Fig. 4B) and the wall thicknesses of the insert wall 365, the sidewall 315 and the base 318. In some cases, the insert array 350 may be designed such that at least some of the internal sub-volumes 370, inter-insert sub-volumes 372 and the external sub-volumes 375 are of similar size (maximum diameter and / or volume). This can help to ensure a uniform distribution of the solution 305 within the device 300. In other cases, these may be different sizes, for example, the insert array 350 maybe designed such that the internal sub-volumes 370 are larger than the inter-insert sub-volumes 372 and external sub-volumes 375, or such that the external sub-volumes 375 and inter-insert sub-volumes 372 are larger than the internal sub-volumes 370.

[0194] Although in the device 300 of Figs. 4A and 4B the insert array 350 are formed of a single material, alternatively, the insert array 350 may be formed of a first core material and may be coated with a coating surrounding all surfaces of the insert walls 365 such that the surfaces have no or very few SiOH or SiO- moieties or may be treated so as to remove SiOH or SiO-moieties or reduce these.

[0195] Similarly, although the insert array 350 comprises separate inserts 360, the insert array 350 may alternatively be provided as a single unitary body comprising multiple insert walls, each insert wall having an internal surface which delimits an internal sub-volume (a hollow void defined by each cylindrical insert wall provides an enclosed internal sub-volume) and an external surface which in part delimits an external sub-volume. In other words, the insert walls would effectively define hollow cylinders in a manner similar to the insert array 350 of device 300 of Figs. 4A and 4B with an opening at the top end and an opening at the bottom end (not depicted) for fluid communication between the internal sub-volumes and the remainder of the interior chamber. However, the main difference is that the insert walls are connected (e.g. bonded or fused) along their length to the adjacent insert walls so as to form a single, unitary insert array. In this way, this particular insert array 350 can be thought of a plurality of inserts fused together.

[0196] FIG. 5 depicts a device 400 in the form of a vial for receiving a solution 405 comprising a radioisotope. The device 400 includes a device body 410 having a cylindrical shape with a base 418 and a cylindrical sidewall 415 extending upwards from the base 418. The sidewall 415 and base 418 enclose an interior chamber 620 for receiving the solution 405. An opening 416 is provided at the top of the device through which the solution 405 can be provided to and removed from the interior chamber 420 of the device 400. A cap (not shown) can be used to close the opening 416 and thereby seal the interior chamber 420 of the device 400.

[0197] The device 400 also comprises a plurality of beads 482, each bead 482 having a substantially spherical shape. The beads 482 are arranged as a stack 480 provided on the base 418, with the beads 482 stacked on top of each and moveable relative to one another and relative to the device body 410 so that they can move within the interior chamber 420, as required.

[0198] The geometric (size and shape) of the beads 482 means that as they stack, the beads 482 define multiple fluidly connected sub-volumes 470, 475 within the interior chamber 420. Thesolution 405 containing the radioisotope is provided in these fluidly connected sub-volumes 470, 475. Specifically, the shape of each bead 482 causes the bead 482 to be spaced apart from the adjacent beads 482 in the stack and, further, from the device sidewall 415, creating regions or sub-volumes 470 between the beads 482 in the stack 480 (which can be referred to as “interparticle” sub-volumes 470). As will be appreciated, this creates a series of fluid pathways formed by interconnected sub-volumes 470 through stack 480 running between the beads 482. As solution 405 is added to the device body 410, it will flow down through the pathways and fill the sub-volumes 470 between beads 482.

[0199] In addition, the spacing of the beads 482 away from the internal surface of the sidewall 415 of the device body 410, creates further sub-volumes 475, which can be referred to as “external” sub-volumes 475. These external sub-volumes 475 are in fluid communication with the rest of interior chamber 420 and internal sub-volumes 470.

[0200] Each bead 482 has a maximum dimension of from 20 pm to 8 mm. In the particular depicted example, the beads 482 each have the same maximum dimension. By virtue of the shape (substantially spherical) of the beads 482 and the regular stacking within stack 480, this creates internal sub-volumes 470 having a maximum dimension equal to that of the beads 482. However, it will of course be appreciated that beads 582 could have different sizes and shapes in other embodiments.

[0201] The beads 482 in the stack 480 are movable relative to one another. This allows for flexibility in the arrangement of the beads 482 and the resulting sub-volumes 470 and external sub-volumes 475, but also improved handling. In use, solution 405 can be provided to the interior chamber 420 via the opening. The fluid communication between the various subvolumes within the interior chamber 420 means that no specialist equipment is required to provide the solution 405. Filling can simply be achieved by pouring solution into the interior chamber 420 to the desired height. Further, as the beads 482 are moveable relative to the device body 410 and one another, if manipulation is required to fill a particular region, this can be done either through individual movement of beads 482 directly or through tipping (e.g. inverting) of the device 400. Removal of the solution 405 is similarly straightforward, and the structure permits removal using, for example, using a syringe with a needle inserted into stack of beads 482 - reliance on the fluid communication will cause fluid to be drawn out from all of the internal sub-volumes 470 and external sub-volumes 475.

[0202] The beads 482 in are formed of a material substantially free or free of SiOH and SiO-moieties so that the surfaces of the beads 482 do not provide further surfaces for catalysing the reaction pathways leading to degradation of the radioisotope binding species and stabilisers.For example, these may comprise or be formed of a polymer. Alternatively or additionally, the beads 482 may be formed of a first core material and may be coated with a coating surrounding all surfaces of the beads 482 such that the surfaces have no or very few SiOH or SiO- moieties or may be treated so as to remove SiOH or SiO- moieties or reduce these.

[0203] Although the devices 100-400 of Figs. 2A to 5 have been depicted in the upright orientation, it will be appreciated that these devices 100-400 could represent a device operated in a horizontal orientation, such as a separation device (e.g. a column) or a part of a reactor, such as portion of a fluid conduit within a reactor. In such a configuration, the bases 118-418 would instead be a part of the wall labelled as sidewall 115-415 - i.e. the portion on which it rests in the horizontal position. In this arrangement, the part labelled as base 118-415 may be an open end or have an opening therein to permit fluid flow therethrough, such that solution can pass from one end of the device to the other.Examples

[0204] Various examples are provided below to demonstrate how the devices disclosed herein have been tested and evidence reduced degradation issues for solutions contained therein.Example 1

[0205] The stability of DOTATATE was measured under different conditions, without the presence of a radioisotope. The percentage loss of LuDOTATATE per day was recorded after storage over time (in the dark under aluminum foil). To determine the loss of LuDOTATATE, HPLC UV data was recorded prior to and after storage and the peak area analyzed in order to determine total loss of LuDOTATATE. The results are shown in Table 2 below.

[0206] The first sample comprised Lutathera formulation (as above) using non-radioactive LuDOTATATE - stored for 12 days. The second sample comprised the same formulation stored in a plastic vial for 12 days. The third sample was the same Lutathera formulation and stored for 12 days. All samples were analyzed after 5 days and after 12 days. The loss was calculated as the concentration of intact LuDOTATATE at 12 days minus intact LuDOTATATE at 5 days, divided by 7 days.

[0207] Where a glass vial was used, this was a glass HPLC vial with insert, clear insert, 300 uL, fused insert, product ID: Microsolv, 9532S-0CV. Where a plastic vial was used, this was a Waters HPLC vial, SKU: 186009186, QuanRecovery with MaxPeak HPS 12 x 32 mm Screw Neck Vial, 300 pL. The HLPC used a Thermo Scientific column (Acclaim 120, C18, 3um,120A, 3x150 mm, Product No. 063691) with a flow rate of 0.6 mL / min, column temperature of 30 °C and Gradients: A: H2O + 0.1% TFA, B: MeCN + 0.1% TFA.Table 2Lutathera formulation = acetic acid (0.48 mg / mL), sodium acetate (0.66 mg / mL), gentisic acid (0.63 mg / mL), sodium hydroxide (0.65 mg / mL), ascorbic acid (2.8 mg / mL), diethylene triamine pentaacetic acid (0.05 mg / mL), sodium chloride (6.85 mg / mL), and Water for Injection (ad 1 mL).

[0208] The results show that an increased percentage loss per day is seen with a glass vial compared to plastic. Furthermore, this appears to be related to at least one of the components of the Lutathera solution. Based on these results, it is evident that an interaction between the glass and a compound or compounds in the Lutathera formulation can lead to degradation of LuDOTATAE. This must be a chemical degradation as no radioisotope was present. Figs. 6A and 6B show the UV spectra of the radioactive Lutathera sample and the non-radioactive precursor sample, both held in glass vials. Similar degradation patterns for the radioactive and non-radioactive samples can be seen, suggesting that the radioactivity is not key to the degradation. Fig. 7 further shows the same analysis carried out on the Lutathera formulation held in a plastic vial. The amount of degradation products seen between 2.1 and 2.8 minutes is significantly reduced in comparison to the same formulation in a glass vial. This evidences the reduced chemical degradation seen when using a vial made of material other than glass, which has SiOH / SiO- groups present on the inner surface.Example 2

[0209] The stability of non-radioactive Lutathera was measured in different conditions (set out in Table 3, below). The samples were stored in the dark (wrapped in aluminum foil) and at room temperature. HPLC data were recorded before and after storage for 7 days and measured by HPLC, as to determine the % loss of LuDOTATATE per day and the % loss of gentisate, by dividing the total loss between day 0 and day 7 by 7. The results are shown in Table 4 below. The vials used were as per Example 1, as was the HPLC method.Table 3Table 4

[0210] As evident from Table 4, when comparing sample VI and V2, using a device body made of plastic (and so without SiOH / SiO- groups on the inner surface), leads to a decrease in degradation of LuDOTATATE. It appears from sample V3 that this degradation is at least partially related to the presence of ascorbate. It is also evident that increased LuDOTATATE loss appears correlated with increased gentisic acid loss. Without wishing to be bound by theory, it is thought that an increased gentisic acid concentration can help prevent the second pathway discussed above, given the increased likelihood of polymerization and so an increased concentration of gentisic acid can offer a protective effect against LuDOTATATE degradation.

[0211] Furthermore, gentisate appears to have a protective role, such that when ascorbate / ascorbic acid is present, gentisic acid / gentisate mitigates its effects. Despite this protective effect, the presence of gentisate in combination with glass still causes increased degradation when compared to a plastic vial, even when ascorbate is not present (see V6). Without gentisate but with the presence of ascorbate, degradation of LuDOTATATE is increased (see V5). As such, it is clear that degradation pathways exist when glass is present regardless of whether both stabilizers are present.Example 3

[0212] Both glass and plastic vials containing samples of Lutathera solutions were analyzed for LuDOTATATE loss either when the solution had been degassed or when it had not. The vials are as per Example 1, except for the plastic saline vial which is made of polypropylene copolymer (Product ID: Hospira #0409-4888-02). The method for determining loss is as per Example 2.

[0213] The results are shown in Table 5 below.Table 5

[0214] Degassing the solution prevents oxidation reactions occurring, as dissolved oxygen has been removed from the solution. Degradation of LuDOTATATE is therefore reduced. The combination of degassing and using a plastic vial ensures essentially no LuDOTATATE degradation is observed. However, even when degassing is carried out, this does not necessarily fully prevent oxidation reactions when in combination with the glass surface, as seen with the degassed sample in a glass vial. Using a device in combination with a degassed solution therefore allows optimal preservation of the solution.Example 4

[0215] The stability of a Lutathera solution was tested in the presence of borosilicate glass. The glass was present either as part of the container holding the solution or as 2mm beads, or both. A 1 ml sample of Lutathera solution was held in a plastic vial without beads, a glass vial without beads, plastic vial with 2mm glass beads, and three different glass vials with varying amounts of 2mm beads (providing the surface area shown in Fig. 8), such that the overall ratio of surface area of glass to mL of solution was varied.

[0216] The amount of LuDOTATATE lost was recorded and Fig. 8 (% loss per day vs cm2 borosilicate glass / mL liquid) shows the percentage of LuDOTATATE lost per day on average (as a mean), where the results for plastic vial without beads (590), a glass vial without beads (592), plastic vial with 2 g of 2 mm glass beads (594) and a glass vial with 1 g, 2 g and 4 g of 2 mm glass beads (596) are plotted. The recorded surface area was only the surface area which was in contact with the solution. As can be seen from the graph, an increased surface area of glass to mL of liquid ratio led to increased loss of LuDOTATATE. The effect of glass beads is the same as that of the glass container. The borosilicate glass used is typical of that commercially available for storing drug products including radiopharmaceuticals. The glass beads used were 2 mm diameter, borosilicate glass beads (Z273627-1EA, PCode 1003472521, Source 3110). The plastic vials used were the saline vials described in Example 3.Example 5

[0217] The effects of using PTFE beads on chemical degradation within different containers was investigated using a radioactive Lutathera solution (19.6 mCi / mL at EOS), containing DOTATATE and gentisic acid (GA). A plastic HLPC vial (as per Example 1, used as a control), and one made of Valor glass, containing PTFE beads (5.3g of 3 / 32” PTFE beads, Item 91512, "United States Plastic Corp."), were analysed to see the average change in LuDOTATATE. The results are shown in Table 6 below.Table 6*Corrected for evaporation

[0218] It does not appear that PTFE beads themselves induce chemical degradation of LuDOTATATE. When the sample which had been kept in the glass vial was analyzed using HPLC UV, the signals eluting at 1.8, 2.2 and 2.8 minutes were larger than in the plastic controlsample. This is indicative of some degradation products, either of ascorbic acid or a conjugation of ascorbic acid degradation products with LuDOTATATE. It was additionally noted that the beads are hydrophobic and so despite themselves being plastic, they cause a larger effective glass surface area in the vial and so increased degradation.Example 6

[0219] The radiochemical stability of [177Lu]LuDOTATATE in a radioactive Lutathera solution (19.6 mCi / mL at EOS) was measured in different vials over time. Samples were taken from a plastic HPLC vial with a plastic insert-style design (690), a plastic HPLC vial with a glass insert (692) and a 10 mL glass vial (694) (vials as per Example 5). The radiochemical purity (RCP) of the samples was measured as a percentage of the original sample after 3 days, 6 days, 10 days and 13 days.

[0220] Fig. 9 shows the radiochemical purity of the samples which have been stored in the various different conditions at the various times they were measured. After 6, 10, and 13 days, the plastic HPLC vial showed the highest purity. Including a glass insert in this vial lowered the purity, presumably due to interactions with the glass of the insert. The glass vial consistently showed a lower purity than the HPLC vial with a plastic insert and the HPLC vial containing an insert of glass. It should be noted that the initial RCP was the same for all the samples, and the RCP for the plastic HPLC vial with a plastic insert-style design (690) and the plastic HPLC vial with a glass insert (692) was very similar at day 3, such that the data points overlap on Fig.9.Examples 7-9

[0221] Various further examples are provided below to demonstrate how the insert arrays and particles disclosed herein have been tested for improvements in reducing radiolysis.Example 7

[0222] 10 mL and 5mL glass vials (HPLC vials) were used in this example to determine reduction of radiolysis using insert arrays. Three of the lOmL vials were filled with insert arrays comprised of separate inserts as set out in Table 7, below. Vials 1 and 5 are comparative and do not contain any insert arrays (i.e. they are empty). Vials 2 to 4 contain insert arrays and are inventive. Specifically, each of vials 2 to 4 were filled with discrete cylindrical tubes of different sizes, as set out in Table 6. The cylindrical tubes are each of constant diameter and are open at both ends, in a similar manner to that of the insert array of Fig. 3. Photographs ofthe tubes are provided in Figs. 13A-E. The vials were each filled with a solution comprising 200 pL of Img / mL N,N-diethyl-2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3 -acetamide (“DPA714”) (DPA714 Reference, 200328-03, DPA-714, 1 mg, Pharmasynth) together with 95-97 mCi / mL of [18F]F-. Where the vials contained insert arrays (i.e. Vials 2 to 4), the vials were filled with the inserts in situ. The same volume of solution was provided to each vial. It is known that emitted particles from [18F]F- causes DPA714 to degrade and, therefore, radiolysis can be tracked by tracking the degradation of DPA714 in solution. This is reported as “percentage degradation (%)” in Table 2, below.

[0223] The vials were left overnight (23 hours after time of mixing [ 18F]F- withDPA714). The contents of each vial was analyzed by reverse phase HPLC using a LunaCl 8(2) HPLC column 5 pm, 4.6 mm x 250 mm with an isocratic mobile phase (50% MeCN in aqueous 100 mM ammonium formate, pH 4.5). The HPLC column was heated to 30°C. Injection volume was 10 pL and UV detection was performed using a PDA detector. 254 nm was used for quantification of intact DPA714. The calculation of %degradation was made by dividing the area under the peak with the area under the peak for a reference sample comprising DPA714 only, below. Table 7* NMR tubes 3mm OD, borosilicate glass, via Sigma Aldrich (WIMWG3000750-50EA), #WG-3000-7-50A, Lot 3110, Wilmad NMR tubes 3mm diam, Type 1 Class A, high throughput** NMR tubes 5mm OD, borosilicate glass, via Sigma Aldrich, Z271987-1PAK Lot# 3110, Wilmad NMR tubes 5mm diam., precision, frequency 100 MHz, L 7 in. Pcode 1003143122

[0224] It can be seen that the empty vials Vial 1 and Vial 5 have the greatest percentage (%) rate of degradation of DPA714 and, hence, the highest levels of radiolysis. Each of Vials 2 to 4, which contain the inserts, decreases radiolysis significantly. Compared to Vial 1, Vials 2 and 3 decreased radiolysis by over 60% (Vial 2 a 63% reduction and Vial 3 a 65% reduction compared to Vial 1). The larger diameter insert array of Vial 4 was still effective, decreasing radiolysis compared to Vial 1 by around 45%. Despite the presence of the insert arrays, the solution was readily introduced and removed from Vials 2 to 4 and no reduction in volume of solution was necessary.Example 8

[0225] 10 mL glass vials (HPLC vials) were used in this example to determine reduction of radiolysis using beads. The radiochemical stability of a 85 mCi / mL solution of [18F]-radiolabeled phenoxyanilide ([18F]FEPPA) was monitored over time, with a measurement at 5 hours after the solution was provided to each vial. A first 10 mL glass vial was used as a comparative example (herein “Vial 7”) and did not comprise any inserts or beads. A second 10 mL glass vial was filled with glass beads (Sigma Aldrich, Solid Glass Beads, Z273627-1EA, diameter 2 mm, borosilicate glass) (herein “Vial 8”). The same volume of the [18F]FEPPA was added to each and the stability monitored and reported as a percentage of radiochemical purity. This was determined by reverse phase HPLC with an in-line UV and gamma detector. LunaC18(2) HPLC column 5pm, 4.6 mm x 250 mm using isocratic mobile phase conditions 45% 100 mM aqueous ammonium formate in 55% acetonitrile, 1 ml / min, column at ambient temperature. 1.3 uL injection volumes at approximately 5 hours after the solution was provided to each vial. The radiochemical purity was measured by integrating the signals from the gamma detector and compared to the purity at the start.

[0226] At time 0, both of the solutions in Vials 7 and 8 had a radiochemical purity of 99.65%. After 5 hours, the radiochemical purity of the solution in Vial 7 was reduced to 83.81%, whereas the radiochemical purity of the solution in Vial 8 with the beads, after 5 hours, remained at 98.61%. Accordingly, the presence of the beads in Vial 8 significantly reduced the degradation of the compounds therein and vastly improved the radiochemical purity of the solution compared to the use of a vial alone.Example 9

[0227] Example 10 further explored reduction of radiolysis. 10 mL glass vials (HPLC vials) were used in this example to determine reduction of radiolysis using beads. A first 10 mL glass vial was used as a comparative example (herein “Vial 9”) and was empty (i.e. did not comprise an insert array or beads). A second 10 mL glass vial (inventive, herein “Vial 10”) was filled with glass beads having a diameter of 2 mm and a substantially spherical shape. A third 10 mL glass vial (inventive, herein “Vial 11”) was filled with glass beads having a diameter of 4 mm and a substantially spherical shape.

[0228] Vials 9 to 11 were each filled with a solution comprising a N,N-diethyl-2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-acetamide (“DPA714”) together with varying radioactivity concentrations of [18F]F-, as set out in Table 8, below. Where the vials contained beads (i.e. Vials 10 and 11), the vials were filled with the beads in situ. The same volume of solution was provided to each vial. The amount of radiolysis which had occurred in each of the vials was determined using HPLC (as set out for Example 8, above) after approximately 24 hours, for each solution concentration.Table 8

[0229] As can be seen from Table 8 and Fig. 10, radiolysis was significantly reduced in the vials comprising beads (i.e. Vials 10 and 11), even though these beads have diameters which are significantly above the average path length for positrons emitted during 18F decay. It can also be seen that the 2 mm beads of Vial 10 provided this to a greater extent than the 4 mm beads of Vial 11. Moreover, it is also apparent that the use of beads allows for the use of solutions with higher radioactivity concentrations before the inflection point at which radiolysis significantly increased occurs. In other words, whereas for the solution, the inflection point of radioactivity concentration beyond which radiolysis significantly increases with increased radioactivity concentration was reduced. Vials 10 and 11 accordingly enabled much more concentrated solutions to be stable compared to Vial 9 without beads. It can also be seen that the 2 mm beads of Vial 10 provided this to a greater extent than the 4 mm beads of Vial 11.

[0230] In Examples 1-6, the following materials were used: Cytiva, HyPure WFI, Quality Water, 1000 mL, Cat No, SH30221.10; IM sodium hydroxide; Sodium acetate, Anhydrous USP, Spectrum, S0104; 0.9% Sodium chloride injection, USP, Hospira, NDC 0409-6138-22; Ascorbic acid, Spectrum, L- Ascorbic acid, USP, product number AS102, 100g; DOTA-TATE acetate, 1 mg per vial, ABX, Product number: 9770.0001; Lu-DOTA-TATE (pichem); DTP A, Akzo Nobel; Gentisic acid, Spectrum, Product Number D2156, 100 g; HC1, 0.1M, Eckert&Ziegler; and Glacial acetic acid 500 mL, Spectrum Chemical MFG Company, AC110.Clauses

[0231] Further examples will now be set out as clauses.

[0232] Clause 1. A device for holding a radiopharmaceutical solution , the device comprising: a device body comprising an inner surface, an outer surface, and an interior chamber for receiving fluid, the interior chamber delimited at least in part by the inner surface, wherein the inner surface has a combined surface concentration of SiOH and SiO- moieties of less than 2 nm-2; and a solution provided in the interior chamber, the solution comprising: (A) at least one stabilizer to prevent radiolytic degradation; and (B) a radioisotope binding species configured to bind to a radioisotope.

[0233] Clause 2. The device of clause 1, wherein the inner surface has a combined surface concentration of SiOH and SiO- moieties of less than 1 nm-2

[0234] Clause 3. The device of clause 1 or clause 2, wherein the inner surface is substantially free from SiOH and SiO- moieties

[0235] Clause 4. The device of any of clauses 1 to 3, wherein the device body comprises an inner wall portion formed of a material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass-ceramic, or an organic composition, the inner wall portion defining the inner surface.

[0236] Clause 5. The device of clause 4, wherein the inner wall portion is formed of a polymer, optionally one or more fluoropolymers, polyolefins, silicone or butyl rubber.

[0237] Clause 6. The device of any clause 4 or clause 5, wherein the device body comprises a wall portion defining the outer surface and further comprises a coating provided on the wall portion so as to form the inner wall portion and define the inner surface.

[0238] Clause 7. The device of any of clauses 1 to 5, wherein the device body is formed from a material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glassceramic, or an organic composition.

[0239] Clause 8. The device of any preceding clause, wherein the radioisotope binding species comprises an organic molecule, a peptide, a protein, a microparticle or a nanoparticle.

[0240] Clause 9. The device of clause 8, wherein the radioisotope binding species comprises a peptide comprising an aryl-alcohol.

[0241] Clause 10. The device of any preceding clause, wherein the radioisotope binding species comprises a somatostatin receptor binding peptide.

[0242] Clause 11. The device of any preceding clause, wherein the radioisotope binding species comprises (Tyr3)-octreotate (TATE), d-Phel-Tyr3 -octreotide (TOC), 1-Nal 3 -octreotide (NOC), or mixtures thereof.

[0243] Clause 12. The device of any preceding clause, wherein the radioisotope binding species comprises a chelator portion.

[0244] Clause 13. The device of clause 12, wherein the chelator portion comprises 1,4,7,10-Tetraazacyclododecane-l,4,7,10-tetraacetic acid (DOTA), 2-[4,7,10-tris(2-amino-2-oxoethyl)-l,4,7,10-tetrazacyclododec-l-yl]acetamide (DOTAM aka TCMC), Diethylentriaminepentaacetic acid (DTPA), Nitrilotriacetic acid (NTA), Ethylenediaminetetraacetic acid (EDTA), l,4,7,10-Tetraazacyclododecane-l,4,7-triacetic acid (DO3A), 1,4,7-Triazacyclononane-l ,4,7-triacetic acid (NOTA), l,4,7-triazacyclononane-l,4-diacetic acid (NODA), N02A , 3,6,9,15-Tetraazabicyclo[9.3.1]pentadeca-l(15),ll,13-triene-3,6,9-triacetic acid (PCTA), Deferoxamine (DFO), DFO*, 2-(4, 7-bis(carboxymethyl)- 1,4,7-triazonan-l-yl)pentanedioic acid (NOD AGA), 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N",N"',N"",N -hexaacetic acid (HEHA), Macropa, Trizoxetan, Tetraxetan or mixtures thereof.

[0245] Clause 14. The device of any preceding clause, wherein the at least one stabilizer comprises an antioxidant.

[0246] Clause 15. The device of any preceding clause, wherein the at least one stabilizer comprises a phenolic acid or salt thereof and / or (ii) ascorbic acid or a salt thereof.

[0247] Clause 16. The device of clause 15, wherein the phenolic acid is gentisic acid.

[0248] Clause 17. The device of any preceding clause, wherein the device is a vial.

[0249] Clause 18. The device of any preceding clause, wherein the pH of the solution is between 4.5 and 6.

[0250] Clause 19. The device of any preceding clause, wherein the solution further comprises (C) a radioisotope.

[0251] Clause 20. The device of clause 19, wherein the radioisotope is carbon-11, fluorine-18, gallium-67, gallium-68, zirconium-89, yttrium-90, terbium-152, iodine-123, iodine-131, lutetium-177, actinium-225, lead-212, bismuth-213, bismuth-212, radium-223, indium-ill, astatine-211, rubidium-82, technetium-99m, technetium-94m, promethium-151, thulium-172, tin-121, tin-117m, praseodymium- 142, praseodymium- 143, gold-198, gold-199, scandium-43, scandium-44, scandium-47 or copper-64.

[0252] Clause 21. The device according to any preceding clause, further comprising: an insert array provided within the interior chamber of the device body, the insert array comprising one or more insert walls, wherein the one or more insert walls enclose at least one internal subvolume so as to at least in part separate the internal sub -volume from the remainder of the interior chamber; wherein at least one external sub-volume is formed within the interior chamber between the one or more insert walls and the inner surface of the device body; and wherein the device comprises a plurality of the internal sub-volumes and / or a plurality of the external sub-volume.

[0253] Clause 22. The device according to clause 21, wherein the internal surface and external surface of the insert array each have a combined surface concentration of SiOH and SiO-moi eties of less than 2 nm-2.

[0254] Clause 23. The device according to clause 21 or clause 22, wherein the insert array is formed of a material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass-ceramic, or an organic composition.

[0255] Clause 24. The device according to any preceding clause, further comprising: a plurality of particles provided within the interior chamber, wherein the particles are arranged as a stackand defining a plurality of fluidly connected sub-volumes between the plurality of particles within the interior chamber and wherein each particle has a maximum dimension of from 20 pm to 8 mm; and optionally a solution comprising a radioisotope provided in the fluidly connected sub-volumes.

[0256] Clause 25. The device according to clause 24, wherein particles each have an outer surface in contact with the solution, wherein the outer surface of each particle has a combined surface concentration of SiOH and SiO- moi eties of less than 2 nm-2.

[0257] Clause 26. The device according to clause 24 or clause 25, wherein the particles are formed of a material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass-ceramic, or an organic composition.

[0258] Clause 27. A device for holding a radiopharmaceutical solution comprising a radioisotope, the device comprising: a device body comprising an inner surface, an outer surface, and an interior chamber for receiving fluid, the interior chamber delimited at least in part by the inner surface, wherein the device body comprises an inner wall portion formed of material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass ceramic or an organic composition, the inner wall portion defining the inner surface; and wherein the device further comprises: a solution provided in the interior chamber, the solution comprising: (A) at least one stabilizer to prevent radiolytic degradation; and (B) a radioisotope binding species configured to bind to a radioisotope.

[0259] Clause 28. The device of clause 27, wherein the inner wall portion is formed of a polymer, optionally one or more fluoropolymers, polyolefins, silicone or butyl rubber.

[0260] Clause 29. The device of clauses 27 or 28, wherein the device body comprises a wall portion defining the outer surface and further comprises a coating provided on the wall portion so as to form the inner wall portion and define the inner surface.

[0261] Clause 30. The device of any of clauses 27 to 29, wherein the device body is formed from a material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glassceramic, or an organic composition.

[0262] Clause 31. The device of any of clauses 27 to 30, wherein the inner surface has a combined surface concentration of SiOH and SiO- moi eties of less than 2 nm-2

[0263] Clause 32. The device of clause 31, wherein the inner surface has a combined surface concentration of SiOH and SiO- moieties of less than 1 nm-2

[0264] Clause 33. The device of any of clauses 27 to 32, wherein the inner surface is substantially free from SiOH and SiO- moieties.

[0265] Clause 34. The device of any of clauses 27 to 33, wherein the radioisotope binding species comprises an organic molecule, a peptide, a protein, a microparticle or a nanoparticle.

[0266] Clause 35. The device of clause 34, wherein the radioisotope binding species comprises a peptide comprising an aryl-alcohol.

[0267] Clause 36. The device of any of clauses 27 to 35, wherein the radioisotope binding species comprises a somatostatin receptor binding peptide.

[0268] Clause 37. The device of any of clauses 27 to 36, wherein the radioisotope binding species comprises (Tyr3)-octreotate (TATE), d-Phel-Tyr3 -octreotide (TOC), 1-Nal3-octreotide (NOC), or mixtures thereof.

[0269] Clause 38. The device of clauses 27 to 37, wherein the radioisotope binding species comprises a chelator portion.

[0270] Clause 39. The device of clause 38, wherein the chelator portion comprises 1,4,7,10-Tetraazacyclododecane-l,4,7,10-tetraacetic acid (DOTA), 2-[4,7,10-tris(2-amino-2-oxoethyl)-l,4,7,10-tetrazacyclododec-l-yl]acetamide (DOTAM aka TCMC), Diethylentriaminepentaacetic acid (DTPA), Nitrilotriacetic acid (NTA), Ethylenediaminetetraacetic acid (EDTA), l,4,7,10-Tetraazacyclododecane-l,4,7-triacetic acid (D03A), 1,4,7-Triazacyclononane-l ,4,7-triacetic acid (NOTA), l,4,7-triazacyclononane-l,4-diacetic acid (NODA), N02A , 3,6,9,15-Tetraazabicyclo[9.3.1]pentadeca-l(15),ll,13-triene-3,6,9-triacetic acid (PCTA), Deferoxamine (DFO), DFO*, 2-(4, 7-bis(carboxymethyl)- 1,4,7-triazonan-l-yl)pentanedioic acid (NOD AGA), 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N",N"',N"",N -hexaacetic acid (HEHA), Macropa, Trizoxetan, Tetraxetan or mixtures thereof.

[0271] Clause 40. The device of any of clauses 27 to 39, wherein the at least one stabilizer comprises an antioxidant.

[0272] Clause 41. The device of any of clauses 27 to 40, wherein the at least one stabilizer comprises a phenolic acid or salt thereof and / or (ii) ascorbic acid or a salt thereof.

[0273] Clause 42. The device of clause 41, wherein the phenolic acid is gentisic acid.

[0274] Clause 43. The device of any of clauses 27 to 42, wherein the solution further comprises Na+.

[0275] Clause 44. The device of any of clauses 27 to 43, wherein the device is a vial.

[0276] Clause 45. The device of any of clauses 27 to 44, wherein the pH of the solution is between 4.5 and 6.

[0277] Clause 46. The device of any of clauses 27 to 45, wherein the solution further comprises: (C) a radioisotope.

[0278] Clause 47. The device of clause 46, wherein the radioisotope is carbon-11, fluorine-18, gallium-67, gallium-68, zirconium-89, yttrium-90, terbium-152, iodine-123, iodine-131, lutetium-177, actinium-225, lead-212, bismuth-213, bismuth-212, radium-223, indium-ill, astatine-211, rubidium-82, technetium-99m, technetium-94m, promethium-151, thulium-172, tin-121, tin-117m, praseodymium- 142, praseodymium- 143, gold-198, gold-199, scandium-43, scandium-44, scandium-47 or copper-64.

[0279] Clause 48. The device according to any of clauses 27 to 47, , further comprising: an insert array provided within the interior chamber of the device body, the insert array comprising one or more insert walls, wherein the one or more insert walls enclose at least one internal subvolume so as to at least in part separate the internal sub-volume from the remainder of the interior chamber; wherein at least one external sub-volume is formed within the interior chamber between the one or more insert walls and the inner surface of the device body; and wherein the device comprises a plurality of the internal sub-volumes and / or a plurality of the external sub-volumes.

[0280] Clause 49. The device according to clause 48, wherein the internal surface and external surface of the insert array each have a combined surface concentration of SiOH and SiO-moi eties of less than 2 nm-2.

[0281] Clause 50. The device according to clause 48 or clause 49, wherein the insert array is formed of a material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass-ceramic, or an organic composition.

[0282] Clause 51. The device according to any of clauses 27 to 50, further comprising: a plurality of particles provided within the interior chamber, wherein the particles are arranged as a stack and defining a plurality of fluidly connected sub-volumes between the plurality of particles within the interior chamber and wherein each particle has a maximum dimension of from 20 pm to 8 mm; and optionally a composition comprising a radioisotope provided in the fluidly connected sub-volumes.

[0283] Clause 52. The device according to clause 51, wherein the particles each have an outer surface in contact with the solution, wherein the outer surface of each particle has a combined surface concentration of SiOH and SiO- moi eties of less than 2 nm-2.

[0284] Clause 53. The device according to clause 51 or clause 52, wherein the particles are formed of a material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass-ceramic, or an organic composition.

[0285] Clause 54. Use of a device according to any of clauses 1-53 to achieve reduced degradation of a component of a radiopharmaceutical solution.

[0286] Clause 55. Use of a device according to clause 54, wherein the component of the radiopharmaceutical solution is a radioisotope binding species.

[0287] Clause 56. A method of treating cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a radiopharmaceutical solution, wherein the radiopharmaceutical solution is stored in a device according to clauses 1-53.

[0288] Clause 57. A method of imaging tumours in a subject, the method comprising administering to the subject a suitable amount of a radiopharmaceutical, wherein the radiopharmaceutical solution is stored in a device according to clauses 1-53.

[0289] Clause 58. A radiopharmaceutical solution for use in the treatment of patient with cancer, wherein the radiopharmaceutical solution is stored in a device according to any of clauses 1 to 53.

[0290] Clause 59. A radiopharmaceutical solution for use in imaging tumours, wherein the radiopharmaceutical solution is stored in a device according to any of clauses 1 to 53.

Claims

CLAIMS1. A device for holding a radiopharmaceutical solution comprising a radioisotope, the device comprising:a device body comprising an inner surface, an outer surface, and an interior chamber for receiving fluid, the interior chamber delimited at least in part by the inner surface, wherein the inner surface has a combined surface concentration of SiOH and SiO" moieties of less than 2 nm'2; anda solution provided in the interior chamber, the solution comprising:(A) at least one stabilizer to prevent radiolytic degradation; and (B) a radioisotope binding species configured to bind to a radioisotope.

2. The device of claim 1, wherein the radioisotope binding species comprises a chelator portion.

3. The device of any preceding claim, wherein the radioisotope binding species comprises an organic molecule, a peptide, a protein, a microparticle or a nanoparticle.

4. The device of any preceding claim, wherein the device body comprises an inner wall portion formed of a material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass-ceramic, or an organic composition, the inner wall portion defining the inner surface.

5. The device of any preceding claim, wherein the device body is formed from a material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass-ceramic, or an organic composition.

6. The device of any preceding claim, wherein the at least one stabilizer comprises a phenolic acid or salt thereof and / or (ii) ascorbic acid or a salt thereof.

7. The device of any preceding claim, wherein the solution further comprises (C) a radioisotope.

8. The device of any preceding claim, further comprising:an insert array provided within the interior chamber of the device body, the insert array comprising one or more insert walls,wherein the one or more insert walls enclose at least one internal sub-volume so as to at least in part separate the internal sub-volume from the remainder of the interior chamber; wherein at least one external sub-volume is formed within the interior chamber between the one or more insert walls and the inner surface of the device body; andwherein the device comprises a plurality of the internal sub-volumes and / or a plurality of the external sub-volumes.

9. The device of any preceding claim, further comprising a plurality of particles provided within the interior chamber, wherein the particles are arranged as a stack and defining a plurality of fluidly connected sub-volumes between the plurality of particles within the interior chamber and wherein each particle has a maximum dimension of from 20 pm to 8 mm.

10. A device for holding a radiopharmaceutical solution comprising a radioisotope, the device comprising:a device body comprising an inner surface, an outer surface, and an interior chamber for receiving fluid, the interior chamber delimited at least in part by the inner surface, wherein the device body comprises an inner wall portion formed of material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glass ceramic or an organic composition, the inner wall portion defining the inner surface; andwherein the device further comprises:a solution provided in the interior chamber, the solution comprising:(A) at least one stabilizer to prevent radiolytic degradation; and (B) a radioisotope binding species configured to bind to a radioisotope.

11. The device of claim 10, wherein the radioisotope binding species comprises a chelator portion.

12. The device of claim 10 or 11, wherein the radioisotope binding species comprises an organic molecule, a peptide, a protein, a microparticle or a nanoparticle.

13. The device of any one of claims 10-12, wherein the inner wall portion is formed of a polymer, optionally one or more fluoropolymers, polyolefins, silicone or butyl rubber.

14. The device of any one of claims 10-13, wherein the device body is formed from a material selected from a polymer, a metal, a ceramic, silica-free glass, silica-free glassceramic, or an organic composition.

15. The device of any one of claims 10-14, wherein the at least one stabilizer comprises a phenolic acid or salt thereof and / or (ii) ascorbic acid or a salt thereof.

16. The device of any one of claims 10-15, wherein the solution further comprises: (C) a radioisotope.

17. The device of any one of claims 10-16, further comprising:an insert array provided within the interior chamber of the device body, the insert array comprising one or more insert walls,wherein the one or more insert walls enclose at least one internal sub-volume so as to at least in part separate the internal sub-volume from the remainder of the interior chamber; wherein at least one external sub-volume is formed within the interior chamber between the one or more insert walls and the inner surface of the device body; andwherein the device comprises a plurality of the internal sub-volumes and / or a plurality of the external sub-volumes.

18. The device of any one of claims 10-17, further comprising a plurality of particles provided within the interior chamber, wherein the particles are arranged as a stack and defining a plurality of fluidly connected sub-volumes between the plurality of particles within the interior chamber and wherein each particle has a maximum dimension of from 20 pm to 8 mm.

19. The device of any one of claims 10-18, wherein the particles each have an outer surface in contact with the solution, wherein the outer surface of each particle has a combined surface concentration of SiOH and SiO" moi eties of less than 2 nm'2.

20. Use of a device according to claim 1 or claim 10 to achieve reduced degradation of a component of a radiopharmaceutical solution.

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