Method for purifying radiolabeled large particle aggregated human serum albumin

Abstract

The present invention relates to a method for purifying injectable radiolabeled macroaggregated human serum albumin (MAA) in a solution using a syringe filter, wherein the syringe filter used has the property of capturing and releasing the radiolabeled MAA while not retaining impurities from the bulk solution.

Description

Technical Field

[0001] The present invention relates to a simplified method for purifying radioactively metal-labeled (hereinafter more simply referred to as radiolabeled) macroaggregated human serum albumin (MAA). This simplification makes the synthesis of such radiotracers easier to automate. Background Art

[0002] Positron Emission Tomography

[0003] Positron emission tomography (PET) is a medical imaging method for obtaining quantitative molecular and biochemical information on physiological processes in the body. The most commonly used PET radiopharmaceutical today is [18F]-fluorodeoxyglucose ([18F]-FDG), a radiolabeled glucose molecule). PET imaging using [18F]-FDG allows visualization of glucose metabolism and has a wide range of clinical indications. Among the positron emitters, 18F is the most widely used in the current clinical setting. Due to increasing regulatory pressure, radiopharmaceuticals are typically prepared on disposable components assembled in ready-to-use cartridges today.

[0004] In addition to 18F, radioactively metals such as 64Cu, 89Zr, 67Ga, 68Ga, 86Y, 90Y, 177Lu, and 99mTc play a key role in nuclear medicine, as therapeutic agents and imaging agents for radiotherapy and for labeling biologically important low molecular weight molecules and macromolecules such as proteins, peptides, and antibodies.

[0005] Recently, a rapid increase in clinical and preclinical studies involving 68Ga-labeled radiopharmaceuticals has been noted (Velikyan I., Prospective of 68Ga-radiopharmaceutical development. Theranostics 2014;4:47-80; Banerjee SR, Pomper M.G. Clinical applications of Gallium-68. Appl. Radiat. Isot. 2013;76:2-13; Zimmerman BE Current status and future needs for standards of radionuclides used in positron emission tomography. Appl. Radiat. Isot. 2013;76:31-37; Smith DL, Breeman WAP, Sims-Mourtada J., The untapped potential of Gallium-68PET: The next wave of 68Ga-agents. Appl. Radiat. Isot. 2013;76:14-23). ​​This increase can be attributed to the favorable physical properties of 68Ga (Eβ-catenin) for imaging a variety of rapidly changing processes (proliferation, apoptosis, angiogenesis) and targets (growth hormone, myocardial and pulmonary perfusion, inflammation and infection). max 1.8 MeV, β+89%, T 1 / 2= 67.7 minutes (about 6 hours for 99mTc), and is attributable in part to newer, more reliable production and labeling methods. For example, gallium-68 labeled somatostatin analogs have shown their superiority over the existing agent 111In-DTPA-octreotide (Oberg K., Gallium-68 somatostatin receptor PET / CT: Is it time to replace 111Indium DTPA octrotide for patients with neuroendocrine tumors? [Gallium-68 somatostatin receptor PET / CT: Is it time to replace 111Indium DTPA octrotide for patients with neuroendocrine tumors?] Endocrine [Endocrine] 2012;42:3-4; Schreiter N.F., Brenner W., Nogami M., Buchert R., Huppertz A., Pape U.F., Prasad V., Hamm B., Maurer M.H., Cost comparison of 111In-DTPA-octrotide scintigraphy and 68Ga-DOTATOC PET / CT for staging enteropancreatic neuroendocrine tumours. [Cost comparison of 111In-DTPA-octrotide scintigraphy and 68Ga-DOTATOC PET / CT for staging enteropancreatic neuroendocrine tumours.] Eur.J.Nucl.Med.Mol.Imaging [European Journal of Nuclear Medicine and Molecular Imaging] 2012;39:72-82; Hofman M.S., Kong G., Neels O.C., Eu P., Hong E., Hicks R.J., High management impact of Ga-68 DOTATATE (GaTate) PET / CT for imaging neuro-endocrine and other somatostatin expressing tumours. [High management impact of Ga-68 DOTATATE (GaTate) PET / CT for imaging neuro-endocrine and other somatostatin expressing tumours.] J.Med.Imaging Radiat.Oncol. [Journal of Medical Imaging and Radiation Oncology] 2012;56-40-47).

[0006] Another reason for the current enthusiasm for gallium-68 is that it can be produced on-site by a widely commercially available 68Ge / 68Ga generator. Such 68Ge / 68Ga generators are widely available in nuclear medicine facilities not equipped with an on-site cyclotron. The simplicity and relatively low capital cost of 68Ge / 68Ga generators make them more popular in nuclear medicine facilities with relatively low demand for 68Ga-labeled doses (Rosch F. Past, present and future of 68Ge / 68Ga generators. [68Ge / 68Ga generators' past, present and future] Appl. Radiat. Isot. [Applied Radiation and Isotopes] 2013;76:24-30).

[0007] Large particle aggregated human serum albumin (MAA) labeled with a radioactive metal

[0008] The use of macroaggregated human serum albumin (MAA) as a perfusate has been evaluated since 1965 (Furth ED, Okinaka AJ, Focht EF, Becker DV, The distribution, metabolic fate and radiation dosimetry of 131I labelled macroaggregated albumin. J. Nucl. Med. 1965; 6: 506-518). In 1974, an instant kit for the preparation of 99mTc-labeled MAA was evaluated for this purpose using single photon emission computed tomography SPECT (Charidra R., Shamoun J., Braunstein P., DuHov OL, Clinical evaluation of an instant kit for preparation of 99mTc MAA for lung scanning. J. Nucl. Med. 1974; 14-9: 702-705). This agent became the standard for lung perfusion studies and still dominates the market (Suga K., Kawakami Y., Zaki M., Yamashita T., Matsumoto T., Matsunaga N., Pulmonary perfusion assessment with respiratory gated Tc-99m macroaggregated albumin SPECT: preliminary results. Nucl. Med. Commun. 2004; 25: 183-193). Today, many FDA-approved MAA labeling kits for 99mTc are commercially available (e.g. (from CisBio), (from Covidien), (from Rotop), (from GE Healthcare (GE), etc.). All these kits are provided in the form of sterile, single-use vials containing approximately 2.0 mg of MAA particles, approximately 0.05 mg of SnCl2 (as a 99mTc reducing agent), and approximately 5.0 mg of free albumin.

[0009] 99Mo decays to form 99mTc and is used in approximately 600,000 medical imaging procedures globally each week. Against the backdrop of a global shortage of 99Mo, it is necessary to consider alternatives to avoid any lack of 99mTc. The 68Ge / 68Ga generator represents such an attractive alternative. In addition, the image resolution provided by PET / CT is significantly higher than that of SPECT. Therefore, 68Ga-labeled MAA for PET / CT perfusion imaging represents an attractive alternative to 99mTc-labeled MAA.

[0010] MAA was first successfully labeled with 68Ga in 1986 (Maziere B., Loc'h C., Steinling M., Comar D., Stable labeling of serum albumin microspheres with gallium-68. Int. J. Radiat. Appl. Instrum. Part A 1986; 37: 360-361) and 1989 (Even GA, Green MA, Gallium-68-labeled macroaggregated human serum albumin, 68Ga-MAA. Int. J. Radiat. Appl. Instr. 1989; 16: 319-321), but was never used at the time, probably due to the lack of reliability of existing 68Ge / 68Ga generators and the low availability of PET imaging cameras. Later, Mathias et al. (Mathias CJ, Green MA, A convenient route to [68Ga]Ga-MAA for use as a particulate PET perfusion tracer. Appl. Radiat. Isot. 2008; 66: 1910-1912) also successfully labeled MAA with 68Ga.Similar results have also been reported using commercially available 99mTc-MAA kit systems (Jain A., Subramanian S., Pandey U., Sarma H.D., Ram R., Dash A., In-house preparation of macroaggregated albumin (MAA) for 68Ga labelling and its comparison with commercially available MAA. [Internal preparation of macroaggregated albumin (MAA) for 68Ga labelling and its comparison with commercially available MAA] J. Radioanal. Nucl. Chem. [Journal of Radioanalytical and Nuclear Chemistry] 2016; 308: 817-824; Amor-Coarasa A., Milera A., Carvajal D., Gulec S., McGoron A.J., Lyophilized kit for the preparation of the PET perfusion agent [68Ga]-MAA. [Freeze-dried kit for the preparation of the PET perfusion agent [68Ga]-MAA] Int. J. Mol. Imaging [International Journal of Molecular Imaging] 2014: 1-7; Ament S.J., Maus S., Reber H., Buchholz H.G., Bausbacher N., Brochhausen C., Graf F., Miederer M., Schreckenberger M., PET lung ventilation / perfusion imaging using 68Ga aerosol (Galligas) and 68Ga-labeled macroaggregated albumin. [PET lung ventilation / perfusion imaging using 68Ga aerosol (Galligas) and 68Ga-labeled macroaggregated albumin] Recent Results Cancer Res. [Recent Results in Cancer Research] 2013; 194: 395-423). To remove unwanted components such as stannous chloride, which is commonly used as a reducing component, the lyophilized material of the MAA-kit system was resuspended and washed with 0.9% saline by centrifugation.In this process, pre-conjugation of MAA with the DOTA chelator (Kotzerke J., Andreeff M., Wunderlich G., Wiggermann P., Zphel K., Ventilation / Perfusion scans using Ga-68labeled tracers. [Ventilation / Perfusion scans using Ga-68-labeled tracers] Abstracts of invited lectures. [Abstracts of invited lectures] World J. Nucl. Med. [World Journal of Nuclear Medicine] 2011; 10: 26-59) is not required for efficient 68Ga labeling. After labeling, 68Ga-MAA was purified by centrifugation, which is very time-consuming, significantly reduces the final yield, and is not easily automated. The authors also showed that unlabeled and labeled MAA particles were morphologically indistinguishable. Maus et al. (Maus S., Buccholz H.G., Ament S., Brochhausen C., Bausbacher N., Schreckenberger M., Labelling of commercially available human serum albumin kits with 68Ga as surrogates for 99mTc-MAA microspheres. [Labeling of commercially available human serum albumin kits with 68Ga as surrogates for 99mTc-MAA microspheres] Appl. Radiat. Isot. [Applied Radiation and Isotopes] 2011; 69: 171-175) found similar results and studied the labeling efficiency using HEPES buffer with this method. The maximum labeling efficiency has been found to be 70%, and the radiochemical purity after the final solid-phase extraction (SPE) purification step (using a C18 SEP-Pack column) is higher than 95%. Nevertheless, it was shown that this final SPE purification significantly reduces the final 68Ga-MAA result (>30% of the labeled MAA still adheres to the SPE column). All these published reports on the radiolabeling of MAA disclose the direct use of the crude fraction of the 68Ge / 68Ga generator eluate. Due to the use of the crude fraction of the eluate, the 68Ge breakthrough of the generator cannot be separated from the final product during the labeling process. In addition, this method only uses a fraction of the elutable 68Ga activity.To overcome this drawback, Mueller et al. (Mueller D., Kulkarni H., Baum R.P., Odparlik A., Rapid synthesis of 68Ga-labeled macroaggregated human serum albumin (MAA) for routine application in perfusion imaging using PET / CT. 2017;122:72-77) recently provided a convenient preparation of 68Ga-MAA using cation pre-purification of the generator eluate. This method allows the use of most of the eluted 68Ga activity from the generator and does not require any purification steps of the reaction medium as 68Ge breakthrough is removed during cation pre-purification. Nevertheless, in the case of low-yield labeling without a final purification step, yields may be lost. The authors also showed that an MAA pre-washing step using centrifugation to remove stannous chloride was unnecessary to achieve efficient labeling yields.

[0011] Commercially available gallium-68 (68Ge / 68Ga) generators have been widely used. The parent isotope 68Ge has a half-life of 270.95 days and can be easily shipped to hospitals as a generator where it can serve as a source of Ga-68 for at least 1 year. The short-lived 68Ga can be easily eluted from the generator at any time at the point of application. The chromatographic 68Ga generator is a glass column with a modified TiO2-based adsorbent. The parent radionuclide 68Ge is immobilized on this adsorbent. The column is placed in a lead-shielded container and an eluate and an elution line are provided. 68Ga produced as a result of 68Ge decay is eluted from the column, for example, using a 0.1 M HCl solution. The activity of the parent isotope is, for example, between 10 mCi (370 MBq) and 100 mCi (3700 MBq). The 68Ge breakthrough is usually less than 0.005%.

[0012] Problems to be solved

[0013] 99mTc-labeled MAA is a widely used and approved lung perfusion agent using SPECT. Due to the superiority of PET over SPECT and the impending shortage of 99Mo, 68Ga-labeled MAA for PET / CT perfusion imaging represents an attractive alternative to 99mTc-labeled MAA.

[0014] Although the labeling conditions of 68Ga with MAA have been clearly defined, there is a lack of an effective, easily automatable, single-use cassette-based system, as well as a lack of time / yield-efficient final purification of the labeled 68Ga-MAA particles from the bulk reaction medium, which would remove 68Ge breakthroughs and consistently ensure a high radiochemical purity, enabling safe patient injection without affecting the final synthesis yield.

[0015] Currently, such final purification is either performed using centrifugation (which requires additional equipment, is time-consuming, has a negative impact on the total synthesis yield (about 20% loss of activity), and is undesirable from a radiation protection perspective), or using SPE purification (which has a negative impact on the yield (activity loss > 30% due to the labeled particles sticking to the column)). A recent example used cation pre-purification of the generator eluate, which was time-consuming and did not have any final purification, which is not compliant from a regulatory perspective. Therefore, alternative synthetic methods with very effective final purification steps are highly desirable. The purification method chosen must be effective and reliable enough to ensure a high level of radiochemical purity.

[0016] Object of the Invention

[0017] The present invention aims to synthesize 68Ga-labeled MAA particles, which can be easily automated on a disposable consumable and includes effective final purification of the labeled particles. Summary of the Invention

[0018] The present invention relates to a method for synthesizing and purifying radioactively labeled macroaggregated human serum albumin (MAA) to form a bulk solution injectable into a patient, wherein the method comprises the following steps:

[0019] - providing a radioactive metal in the form of a generator eluate in a generator;

[0020] - optionally pre-purifying the generator eluate on a cation column and eluting the pre-purified generator eluate;

[0021] - synthesizing the radioactively labeled MAA in a reactor with MAA particles from a commercially available 99mTc labeling kit and the pre-purified or un-pre-purified generator eluate;

[0022] - passing the synthesized radioactively labeled MAA particles through a syringe filter membrane, selecting the membrane composition, diameter, and pore size to capture these radioactively labeled MAA particles while not retaining impurities from the bulk solution, the impurities consisting essentially of free radioactive metal isotopes, parent radioactive metal breakthroughs, and stannous chloride present in the MAA labeling kit of 99mTc;

[0023] - Release the captured radiolabeled MAA particles from the syringe filter using saline or buffer solution passing through the syringe filter in a direction opposite to the capture movement, and provide the final bulk solution injectable into a patient into a vial.

[0024] According to a preferred embodiment, the method further comprises one or a suitable combination of the following features:

[0025] - The radiolabeled MAA particles to be purified are MAA particles labeled with a detectable metal ion selected from the group consisting of: 99mTc, 94mTc, 48V, 52Fe, 55Co, 64Cu, 68Ga, 67Ga, 111In, 113In, 86Y, 89Zr, 203Pb, 212Bi, 82Rb, 186Re, and 81mKr;

[0026] - The radiolabeled MAA particles to be purified are MAA particles labeled with a detectable metal ion selected from the group consisting of: 99mTc, 68Ga, 86Y, 89Zr, and 64Cu;

[0027] - The radiolabeled MAA particles to be purified are MAA particles labeled with 99mTc or 68Ga;

[0028] - The pore size of the syringe filter membrane is in the range of 0.1 - 10.0 μm;

[0029] - The pore size of the syringe filter membrane is in the range of 0.1 - 5.0 μm;

[0030] - The pore size of the syringe filter membrane is in the range of 0.1 - 0.45 μm;

[0031] - The diameter of the syringe filter membrane is in the range of 10 - 33 mm;

[0032] - The diameter of the syringe filter membrane is in the range of 20 - 33 mm;

[0033] - The syringe filter membrane is a low protein binding hydrophilic membrane selected from the group consisting of: PVDF, PES, CA, hydrophilic PTFE, nylon, glass fiber, RC, CE, CN, and PP;

[0034] - The syringe filter is a disposable filter cartridge that may have a Luer lock fitting;

[0035] - The syringe filter is attached to a disposable cartridge during an automated process;

[0036] - Before the step of capturing the generator eluate on the syringe filter, the generator eluate is maintained at room temperature for 2 to 30 minutes, or heated at 40°C - 80°C for 2 to 20 minutes;

[0037] - The reactor for synthesizing radioactively metal-labeled MAA is an automatic synthesizer. Description of the Drawings

[0038] Figure 1 Schematically shows the steps of radioactively metal-labeled MAA capture (left side, particles are captured on the filter while impurities pass through the filter to the waste liquid) and release (right side, the solution flow releases the particles). Detailed Description of the Invention

[0039] The method of the present invention allows for the purification of 68Ga-labeled MAA particles, which are prepared directly using the entire generator eluate or alternatively with cation pre-purification of the generator eluate. In addition, the method is compatible with any commercially available 99mTc MAA labeling kit.

[0040] This effective purification is achieved by using a syringe filter. A syringe filter is a disposable filter cartridge. Syringe filters may have Luer lock fittings, but this is not universal. For manual purification, it is attached to the end of a syringe for use. For an automated process, the syringe filter can be fixed to a disposable cartridge. The use of a needle is optional; if needed, a needle can be mounted to the end of the syringe filter. Syringe filters typically consist of a plastic housing and a membrane that serves as the filter. Cleaning can be performed by drawing the fluid to be purified through the filter. Syringe filter membranes are characterized by their composition (material and pore size) and their diameter. Common available pore sizes are 0.1, 0.2, 0.22, 0.45, 5, and 10 μm, but medium pore sizes are also readily available. Membrane diameters of 10, 13, 25, 33 mm are also common. The syringe filter body can be made of materials such as polypropylene and nylon. The filter membrane can be made of polytetrafluoroethylene (PTFE), nylon, cellulose acetate (CA), polyvinylidene fluoride (PVDF), cellulose ester (CE), polyethersulfone (PES), polypropylene (PP), glass fiber (GF), regenerated cellulose (RC), cellulose nitrate (CN), etc.

[0041] When the reaction medium passes through the syringe filter membrane, the labeled and unlabeled MAA particles are retained on the filter due to size exclusion, while the 68Ge penetrates and the remaining free 68Ga3+ pass through the syringe filter membrane to the waste liquid ( Figure 1 , left side).

[0042] To release the particles from the syringe filter, the solution passes through the syringe filter membrane in the opposite (or relative) direction of the capture movement, reaching the final product vial ( Figure 1, on the right). The release is due to the flow of the release solution. The aforementioned release solution is injectable (e.g., a suitable phosphate buffer solution or physiological saline, i.e., 0.154 mol / L or 9 g / L NaCl), and the resulting tracer solution is easily injectable into the patient.

[0043] It brings several advantages: shortening the duration of preparation, thus increasing the overall yield; simplifying the automated equipment required for synthesizing radiopharmaceuticals; a purification method compatible with any radiolabeled MAA particles, and thus not limited to 68Ga or Tc99m; ensuring a high level of radiochemical purity even in the case of low-yield labeling.

[0044] According to the present invention, the purification process is carried out by passing the bulk of the synthesis of radiolabeled MAA particles through a syringe filter, which can be placed on a ready-to-use cassette for automation. Such a syringe filter has the property of retaining the labeled (and unlabeled) MAA product, but not retaining free unlabeled radioisotopes (i.e., 68Ga3+ in the case of 68Ga-MAA labeling, and also 68Ge penetrants) to ensure a high level of radiochemical purity, and also not retaining stannous chloride from the original MAA labeling kit.

[0045] In some embodiments of the present invention, the radiolabeled MAA particles to be purified are MAA particles labeled with detectable metal ions (such as 99mTc, 94mTc, 48V, 52Fe, 55Co, 64Cu, 68Ga, 67Ga, 111In, 113In, 86Y, 89Zr, 203Pb, 212Bi, 82Rb, 186Re, 81mKr).

[0046] In some preferred embodiments of the present invention, the radiolabeled MAA particles to be purified are MAA particles labeled with 99mTc, 68Ga, 86Y, 89Zr or 64Cu.

[0047] In some preferred embodiments of the present invention, the radiolabeled MAA particles to be purified are MAA particles labeled with 99mTc or 68Ga.

[0048] In some embodiments, the pore size of the syringe filter membrane is in the range of 0.1 - 10.0 μm.

[0049] In some preferred embodiments, the pore size of the syringe filter membrane is in the range of 0.1 - 5.0 μm.

[0050] In some preferred embodiments, the pore size of the syringe filter membrane is in the range of 0.1 - 0.45 μm.

[0051] In some embodiments, the diameter of the syringe filter membrane ranges from 10 to 33 mm.

[0052] In some embodiments, the diameter of the syringe filter membrane ranges from 20 to 33 mm.

[0053] In some embodiments, the syringe filter membrane is selected from the group of low protein-binding hydrophilic membranes (PVDF, PES, CA, hydrophilic PTFE, nylon, glass fiber, RC, CE, CN, PP).

[0054] Example

[0055] Example 1

[0056] This example shows the efficiency of using a syringe filter to purify the bulk of 68Ga-MAA. On an automated synthesizer, 68Ga-MAA was synthesized using cation pre-purification of the generator eluate (eluting an Eckert & Ziegler 68Ge / 68Ga generator with 5 mL of 0.1 M HCl). The generator eluate was captured on a PS-H+ cation column that retained the eluted 68Ga3+. Then the activity was eluted into the reactor using acidified concentrated NaCl solution. MAA dissolved in acetate buffer from the labeling kit was added to the reactor. After heating at 60 °C for 6 minutes, the reaction medium was transferred to the final product vial and formulated with phosphate buffer to give a final pH of 7.0 (final volume 10 mL). The radiochemical yield without decay correction (n.d.c.) was 75% (111.4 MBq) and the radiochemical purity was 80%. The final product solution (111.4 MBq) was manually passed through a 25 mm, 5 µm pore size PVDF syringe filter membrane (Millipore reference number SLSV025LS). The entire labeled 68Ga-MAA particles were retained on the filter (activity on the filter: 88.6 MBq), while the free 68Ga3+ passed through the filter (activity in the filtrate: 22.8 MBq). After capture, 10 mL of normal saline was passed through the syringe filter in the opposite direction to the capture movement to release the labeled particles. An effective release of 98.2% was achieved (2 MBq remaining on the filter). Thin layer chromatography (TLC) analysis showed a radiochemical purity of 98.9% for the released 68Ga-MAA particles.

[0057] Example 2

[0058] This example shows the efficiency of using a syringe filter to capture and release the bulk of 99mTc-MAA. Using a commercially available labeling kit, 99mTc-MAA was synthesized according to a conventional procedure: the Tc-generator was eluted directly into Into the labeling kit. After gently mixing at room temperature for 15 minutes, the 99mTc-labeled MAA bulk solution was manually passed through a syringe filter (25 mm in diameter, 5 μm pore size, PVDF membrane, Millipore reference number SLSV025LS). The labeled particles were retained on the filter (activity on the filter: 44163 cps / 10 s). After capture, 10 mL of normal saline was passed through the filter in the direction opposite to the capture movement. The release efficiency was 91% (activity remaining on the filter: 4523 cps / 10 s).

[0059] Examples 3 - 11

[0060] The following examples show the efficiency of purifying the bulk of 68Ga-MAA using a syringe filter. 68Ga-MAA was synthesized on an automated synthesizer without pre-purification of the generator eluate (i.e., using the entire generator eluate), but with final purification on a syringe filter placed on a disposable cassette. The Eckert & Ziegler 68Ge / 68Ga generator was directly eluted with 5 mL of 0.1 M HCl into a reactor containing MAA particles from the labeling kit dissolved in 2 mL of 0.35 M acetic acid solution. After heating at 60 °C for 6 minutes, the reaction medium was passed through a syringe filter that retained the labeled particles, while free 68Ga3+ and 68Ge penetrates passed through the filter to the waste liquid. Then 10 mL of normal saline was used to release the labeled particles into the final product vial. The synthesis time after generator elution was 12 minutes. The experiment was repeated by changing the filter syringe type (Examples 3 - 11). Table 1 shows the decay-corrected (n.d.c.) radiochemical yield (RCY), radiochemical purity (RCP), and 68Ge content (when measured) in the final product vials for Examples 3 - 11.

[0061]

[0062] (*) Measured after complete decay of 68Ga3+. The limit for patient injection is 0.001% of the initial activity.

[0063] Table 1 - Results of Examples 3 - 11

[0064] Table 1 shows the high efficiency of purifying radiolabeled MAA using a syringe filter. Even in cases of low labeling yield and low release yield, a high level of radiochemical yield is almost always achieved. The procedure is also time-saving as the synthesis time (including final purification and dispensing into the final product vial) is 12 minutes after generator elution.

Claims

1. A method for synthesizing and purifying radiolabeled macroaggregated human serum albumin (MAA) to form an injectable bulk solution for a patient, wherein the method comprises the following steps: - Providing a radioactive metal in the form of a generator eluate in a generator; - Optionally pre-purifying the generator eluate on a cation column and eluting the pre-purified generator eluate; - Synthesizing the radiolabeled MAA in a reactor with MAA particles from a commercially available 99mTc labeling kit and the pre-purified or unpurified generator eluate; - Passing the synthesized radiolabeled MAA particles through a syringe filter membrane, selecting the membrane composition, diameter, and pore size to capture these radiolabeled MAA particles while not retaining impurities from the bulk solution, the impurities consisting of free radioactive metal isotopes, parent radioactive metal penetrants, and stannous chloride present in the MAA labeling kit of 99mTc; - Releasing the captured radiolabeled MAA particles from the syringe filter using a saline or buffer solution passing through the syringe filter in a direction opposite to the capture movement and providing the injectable bulk solution for the patient into a vial.

2. The method according to claim 1, wherein the radiolabeled MAA particles to be purified are MAA particles labeled with a detectable metal ion selected from the group consisting of: 99mTc, 94mTc, 48V, 52Fe, 55Co, 64Cu, 68Ga, 67Ga, 111In, 113In, 86Y, 89Zr, 203Pb, 212Bi, 82Rb, 186Re, and 81mKr.

3. The method according to claim 1, wherein the radiolabeled MAA particles to be purified are MAA particles labeled with a detectable metal ion selected from the group consisting of: 99mTc, 68Ga, 86Y, 89Zr, and 64Cu.

4. The method according to claim 1, wherein the radiolabeled MAA particles to be purified are MAA particles labeled with 99mTc or 68Ga.

5. The method according to any one of claims 1 to 4, wherein the pore size of the syringe filter membrane is in the range of 0.1 - 10.0 μm.

6. The method according to claim 5, wherein the pore size of the syringe filter membrane is in the range of 0.1 - 5.0 μm.

7. The method according to claim 6, wherein the pore size of the syringe filter membrane is in the range of 0.1 - 0.45 μm.

8. The method according to claim 5, wherein the diameter of the syringe filter membrane is in the range of 10 - 33 mm.

9. The method according to claim 8, wherein the diameter of the syringe filter membrane is in the range of 20 - 33 mm.

10. The method according to claim 8, wherein the syringe filter membrane is a low protein binding hydrophilic membrane selected from the group consisting of: PVDF, PES, CA, hydrophilic PTFE, nylon, glass fiber, RC, CE, CN, and PP.

11. The method according to claim 1, wherein the syringe filter is a disposable filter element with a Luer lock fitting.

12. The method according to claim 1, wherein the syringe filter is attached to a disposable cartridge during an automated process.

13. The method according to claim 1, wherein the generator eluate is maintained at room temperature for 2 to 30 minutes or heated at 40°C - 80°C for 2 to 20 minutes prior to the step of capturing the generator eluate on the syringe filter.

14. The method according to claim 1, wherein the reactor for synthesizing the radiolabeled MAA is an automated synthesizer.

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