Use of cyclodextrin as radiation stabilizer
The radiopharmaceutical composition, comprising an 18F-labeled compound, ethanol, ascorbic acid, and cyclodextrin, addresses the challenge of radiolysis in conventional radiopharmaceuticals by enhancing stability and radiochemical purity, ensuring effective imaging over extended shelf life.
Patent Information
- Application Number
- JP2025016275
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2019-10-21
- Filing Date
- 2025-02-03
- Publication Date
- 2025-06-03
AI Technical Summary
Conventional radiopharmaceuticals face challenges in maintaining radiochemical purity due to radiolysis, especially at high radioactivity concentrations, leading to decreased stability and effectiveness over shelf life.
A radiopharmaceutical composition is developed that includes an 18F-labeled radiopharmaceutical compound, ethanol, ascorbic acid as a stabilizer, and cyclodextrin as a co-stabilizer, which collectively enhance the stability and radiochemical purity of the radiopharmaceutical.
The use of ascorbic acid and cyclodextrin significantly improves the radiation stability and radiochemical purity of the radiopharmaceutical, maintaining high stability even at high radioactivity concentrations, and extending the shelf life without significant degradation.
Smart Images
Figure 2025084755000007 
Figure 2025084755000008 
Figure 2025084755000001
Abstract
Description
[Technical field]
[0001] The present invention generally relates to a method for the preparation of a cyclohexyl ester (C-C-O) copolymer comprising the steps of: The present invention also relates to radiopharmaceutical compositions stabilized with rhodextrin. A method of imaging a subject using a radiopharmaceutical composition, said radiopharmaceutical composition Methods for preparing radiopharmaceutical compositions and kits for their preparation are also described. can be. [Background technology]
[0002] Stabilizers reduce the formation of radioactive impurities in radiopharmaceutical preparations during their shelf life. is needed to reduce
[0003] Conventional radiopharmaceuticals are preparations that contain a radiopharmaceutical, a gas, and solvents and stabilizers. Commonly used stabilizers include ethanol, ascorbic acid, among others. Sodium, ascorbic acid, maleic acid, gentisic acid and calcium chloride. can be.
[0004] Cyclodextrins have previously been used to increase the solubility of poorly water-soluble substances. Summary of the Invention
[0005] In one embodiment, the present invention comprises a composition comprising four components: 18 F-labeled radiopharmaceutical compounds or a pharma- ceutically acceptable salt thereof; (ii) ethanol; i) a stabilizer for radiolabeled compounds, said stabilizer comprising ascorbic acid; and (iv) a co-stabilizer for the radiolabeled compound, said co-stabilizer being Provided is a radiopharmaceutical composition comprising an auxiliary stabilizer of a radiolabeled compound, which is cyclodextrin. Provided.
[0006] The following subjects are provided in combination with the above aspects and the following additional aspects.
Mode for Carrying Out the Invention
[0007] The term radiopharmaceutical has its conventional meaning and refers to a radioactive compound suitable for in vivo administration to mammals for use in diagnosis or treatment. to mammals for use in diagnosis or treatment.
[0008] The radiopharmaceutical composition described herein may contain the components described in US Patent Application Publication No. 2013 / 129623. No. specification.
[0009] The radiolabeled compound 18 comprises an F-labeled radiopharmaceutical compound or a pharmaceutically acceptable salt thereof. Such 18 Examples of F-labeled radiopharmaceutical compounds include 18 1 8 18 18 18 18 18 18 18 18 18 18 18 18 18 18 1 8 F]T807, 2- 18 F]Fluoromethyl-L-phenylalanine, or combinations thereof are included. Preferably, the radiolabeled compound is 18 F]not FLT.
[0010] The radiolabeled compound can include a compound of formula (I):
[0011]
Chemical formula
[0012] The substituent A of formula (I) can be O. R 8 can be tert-butyl . G can be chloro
[0013] The compounds of formula (I) and methods for obtaining them can be found, for example, in International Publication No. 2005079391 pamphlet, the contents of which are incorporated herein by reference
[0014] The radiolabeled compound can contain flurupiridaz, which has the following structure:
[0015] [Chem.] has.
[0016] The term "stabilizer" particularly means a radiation stabilizer, which is a compound that inhibits decomposition reactions such as redox processes by capturing highly reactive free radicals such as free radicals containing oxygen generated from the radiolysis of water. The stabilizer of the present invention protects the radiolabeled compound from radiolysis, and thus reduces / prevents the decrease in the purity of the radiolabeled compound over its shelf life. The term "co-stabilizer" means a compound that enhances the desired effect of the stabilizer. radicals. is a compound that protects the radiolabeled compound from radiolysis and thus reduces / prevents the decrease in the purity of the radiolabeled compound over its shelf life. The term "co-stabilizer" means a compound that enhances the desired effect of the stabilizer.
[0017] Radiochemical purity (RCP) is determined using radioactive TLC or HPLC and can be defined as the ratio of the peak of the (radiolabeled) drug substance in the chromatogram to the total (radiolabeled) peak. When manufacturing radiopharmaceuticals with a high radioactivity concentration (RAC), radiolysis is more likely to occur than when the RAC is lower, so the decrease in RCP during storage is more likely to be high. High radioactivity results in the drug substance itself being destroyed (i.e., radiolysis). The most efficient stabilizers can be identified by preparing formulations of different radiopharmaceuticals at the same RAC and comparing the decrease in RCP over time, typically 8 - 10 hours, for 18 compound having the most effective stabilizer for that particular drug substance.
[0018] In some cases, ethanol can be considered a stabilizer. Further stabilizers include Ascorbic acid, aspartic acid, cysteine, maleic acid, gentisic acid, glutathione , glutamic acid, mannitol, nicotinamide, calcium chloride, N-t-butyl-α -phenylnitrone (PBN), tartaric acid and para-aminobenzoic acid (pABA), chloride ionic species or chloride salts, or combinations thereof. The stabilizer of the present invention contains as corbic acid. Ethanol can contain up to 10% (v / v) ethanol in an aqueous solution . Preferably, pharmaceutical grade materials are used.
[0019] Cyclodextrin can include α-cyclodextrin, β-cyclodextrin or γ -cyclodextrin, or pharmaceutically acceptable derivatives or combinations thereof . Cyclodextrin can contain β-cyclodextrin. Cyclo dextrin can contain hydroxypropyl-β-cyclodextrin (HPbCD) . In relation to the present invention, cyclodextrin is a co-stabilizer.
[0020] The radiopharmaceutical composition can contain a biocompatible carrier. The biocompatible carrier is a fluid , especially a liquid, in which the radiopharmaceutical is suspended or preferably dissolved so that the composition is physiologically tolerable, i.e., it can be administered to a mammalian body without toxicity or excessive discomfort. The biocompatible carrier is a liquid of an injectable able carrier, such as sterile pyrogen-free water for injection; aqueous solutions such as saline (it may be advantageous to be in equilibrium so that the final injectable product is isotonic); buffered aqueous solutions containing biocompatible buffers (e.g., phosphate buffer); one or more isotonic substances (e.g ). For example, an aqueous solution of a salt of a plasma cation and a biocompatible counter ion), sugar (e.g., glucose or sucrose), sugar alcohol (e.g., sorbitol or mannitol), glycol (e.g., glycerol), or other nonionic polyol materials (e.g., poly ethylene glycol and propylene glycol, etc.) are preferred. Preferably, the biocompatible carrier is pyrogen-free water for injection, isotonic saline or phosphate buffer.
[0021] The radiopharmaceutical composition can be in a form suitable for administration to a mammal. The expression "a form suitable for administration to a mammal" means a composition that is sterile, pyrogen-free, does not contain compounds that produce toxic or harmful effects, and is formulated at a biocompatible pH (for the agent of the present invention, approximately pH 4.0 to 10.5, preferably 4.5 to 9.5, more preferably 4.5 to 7.5) and a physiologically compatible weight osmolarity. Such a composition does not contain particles that may pose a risk of causing embolism in vivo, and is formulated so that no precipitation occurs upon contact with biological fluids (e.g., blood). Such a composition also contains only biologically compatible excipients and is preferably isotonic. Preferably, the mammal is an untreated mammal in vivo, more preferably a human subject. Preferably, the radiopharmaceutical can be administered to the mammal in a minimally invasive manner, i.e., a method that poses no substantial health risk to the mammal even when performed under the expertise of medicine. Such minimally invasive administration is preferably intravenous administration to a peripheral vein of the subject without the need for local or general anesthesia.
[0022] Preferably, the mammal is an untreated mammal in vivo, more preferably a human subject. Preferably, the radiopharmaceutical can be administered to the mammal in a minimally invasive manner, i.e., a method that poses no substantial health risk to the mammal even when performed under the expertise of medicine. Such minimally invasive administration is preferably intravenous administration to a peripheral vein of the subject without the need for local or general anesthesia. That is, even when performed under the expertise of medicine, the radiopharmaceutical can be administered to the mammal in a method that poses no substantial health risk. Such minimally invasive administration is preferably intravenous administration to a peripheral vein of the subject without the need for local or general anesthesia.
[0023] In certain embodiments of the present invention, the stabilizer comprises ascorbic acid and ethanol, and cyclodextrin comprises hydroxypropyl-β-cyclodextrin (HPβCD), and the radiolabeled compound comprises flurpiridaz. Ascorbic acid can be in an amount of about 1 to about 100 mg / mL, ethanol can be in an amount of about 2 to about 10% (v / v), and HPβCD can be in an amount of about 1 to about 100 mg / mL.
[0024] In one embodiment of the present invention, ascorbic acid is present in an amount of 1 to about 100 mg / mL, such as about 30 to about 50 mg / mL.
[0025] In one embodiment of the present invention, HPβCD is present in an amount of about 1 to about 100 mg / mL, or about 40 to about 50 mg / mL, such as about 40 to about 47 mg / mL.
[0026] In one embodiment of the present invention, ethanol is present in an amount of about 2 to about 10% (v / v), or about 5 to about 10% (v / v), such as 7% (v / v).
[0027] In another aspect, the present invention provides the use of cyclodextrin as an auxiliary stabilizer in a radiopharmaceutical composition. The definitions of cyclodextrin and radiopharmaceutical composition for this aspect are the same as above.
[0028] The above radiopharmaceutical composition can comprise a radiolabeled compound, and the radiolabeled compound is 18 not [18F]FLT.
[0029] The present invention also provides a method of imaging a subject using the above radiopharmaceutical composition.
[0030] The present invention also provides the above-mentioned radiopharmaceutical composition for use in positron emission tomography (PET) imaging.
[0031] In another aspect, the present invention provides a method for preparing a radiopharmaceutical composition, comprising the step of combining the following four components: (i) 18 an F-labeled radiopharmaceutical compound or a radiolabeled compound comprising a pharmaceutically acceptable salt thereof, (ii) ethanol, (iii) a stabilizer for the radiolabeled compound, wherein the stabilizer comprises ascorbic acid, and (iv) a co-stabilizer for the radiolabeled compound, wherein the co-stabilizer is cyclodextrin. The present invention also provides a kit for preparing a radiopharmaceutical composition, comprising the following four components: (i)
[0032] a precursor compound for the production of an F-labeled radiopharmaceutical 18 compound or a radiolabeled compound comprising a pharmaceutically acceptable salt thereof, (ii) ethanol, (iii) a stabilizer for the radiolabeled compound, and (iv) cyclodextrin, which is a co-stabilizer for the radiolabeled compound. The "precursor compound" includes a non-radioactive derivative of a radiolabeled compound, which is designed such that a site-specific chemical reaction with a detectable label in a convenient chemical form occurs in vivo, can be carried out in a minimum number of steps (ideally a single step), requires no significant purification (ideally no further purification), and results in the desired in vivo imaging agent. Such precursor compounds are synthetic and can be readily obtained in good chemical purity.
[0033] imaging agent. Such precursor compounds are synthetic and can be readily obtained in good chemical purity. The "precursor compound" includes a non-radioactive derivative of a radiolabeled compound, which is designed such that a site-specific chemical reaction with a detectable label in a convenient chemical form occurs in vivo, can be carried out in a minimum number of steps (ideally a single step), requires no significant purification (ideally no further purification), and results in the desired in vivo imaging agent. Such precursor compounds are synthetic and can be readily obtained in good chemical purity. imaging agent. Such precursor compounds are synthetic and can be readily obtained in good chemical purity. imaging agent. Such precursor compounds are synthetic and can be readily obtained in good chemical purity. It is possible. In one embodiment, the precursor compound contains a leaving group. 18 A non-radioactive derivative of an F-labeled radiopharmaceutical compound, wherein the leaving group is such that when the precursor compound 18 reacts with a suitable source of F-fluoride, it is replaced by F. 18
[0034] The term "leaving group" refers to an atom or group of atoms that is replaced as a stable species during a substitution or substitution-type radiofluorination reaction. Suitable leaving groups include halogens and leaving groups containing sulfonate. Specific examples of suitable leaving groups include iodide, bromide, chloride, mesylate, triflate, tosylate, nosylate, or 1,2-cyclic sulfate.
[0035] " 18 The term "suitable source of F-fluoride" refers to an F-8-fluoride in a chemical form suitable for obtaining an F-labeled radiopharmaceutical compound by substituting the leaving group in a nucleophilic substitution reaction. 18 18 F-fluoride is usually obtained as an aqueous solution from nuclear reaction 18 O(p,n) 18 F and made reactive by adding a cationic counterion and then removing water. Suitable cationic counterions should have sufficient solubility in an anhydrous reaction solvent to maintain the solubility of F. Suitable counterions include large but soft metal ions such as rubidium or cesium, potassium complexed with a cryptand such as Kryptofix (trademark) 222 (K222), or tetraalkylammonium salts. 18 is included. A suitable tetraalkylammonium salt is tetrabutylammonium hydrogen carbonate salt. A detailed description of well-known 18 F-labeling techniques can be found in Chapter 6 of "Handbook of Radiopharmaceuticals "(2003; John Wiley and Sons: M.J. Welch and C.S. Redvanly, Eds.). can be found.
[0036] 18 When the F-radiopharmaceutical 18 comprises F-fulurpidaz, the precursor compound is the following compound:
[0037] [Chemical formula] wherein LG is a leaving group as defined above herein. Obtaining this precursor compound, labeling it to obtain 18 F-fulurpidaz, and a more detailed description of the presentation of suitable kits can be found, for example, in International Publication No. WO 2019 / 185932 pamphlet and International Publication No. WO 2011 / 097649 pamphlet, the contents of which are incorporated herein by reference. and the contents thereof are incorporated herein by reference. The radiopharmaceutical composition can contain additional optional excipients. For example, such additional optional excipients include antibacterial preservatives, pH adjusters, fillers, solubilizers or
[0038] osmolality adjusters. such additional optional excipients include antibacterial preservatives, pH adjusters, fillers, solubilizers or osmolality adjusters.
[0039] The term "antibacterial preservative" means an agent that inhibits the growth of potentially harmful microorganisms such as bacteria, yeast or mold. Antibacterial preservatives can also, depending on the dosage used, inhibit the growth of potentially harmful microorganisms such as bacteria, yeast or mold. Antibacterial preservatives can also, depending on the dosage used, It may also exhibit bactericidal properties. The main role of the antibacterial preservative of the present invention is in the pharmaceutical composition is to inhibit the growth of any such microorganisms. However, antibacterial preservatives It can also optionally be used to inhibit the growth of potentially harmful microorganisms in one or more components of a kit used to prepare the composition prior to administration . Suitable antibacterial preservatives include parabens, namely methylparaben, ethylparaben, propylparaben or butylparaben or mixtures thereof, benzyl alcohol, ethanol, phenol, cresol, cetrimide and thimerosal. Preferred antibacterial preservatives are parabens or ethanol.
[0040] The term "pH adjuster" means a compound or mixture of compounds useful for ensuring that the pH of the composition is within limits acceptable for human or mammalian administration (for the agents of the present invention, approximately pH 4.0 to 10.5, preferably 4.5 to 9.5, more preferably 4.5 to 7.5). Such suitable pH adjusters include pharmaceutically acceptable buffers, such as tricine, phosphate buffer, acetate buffer or TRIS [i.e., tris (hydroxymethyl)aminomethane], etc., and pharmaceutically acceptable bases, such as sodium carbonate, sodium bicarbonate or mixtures thereof. When the composition is utilized in the form of a kit, the pH adjuster may optionally be provided in a separate vial or container so that the user of the kit can adjust the pH as part of a multi-step procedure . . .
[0041] The term "filler" facilitates the handling of materials during manufacture and lyophilization refers to a pharmaceutically acceptable bulking agent that can be formed. Suitable fillers include inorganic salts such as sodium chloride, and water-soluble sugars or sugar alcohols such as sucrose, maltose, mannitol or trehalose.
[0042] The term "solubilizer" means an additive present in the composition that increases the solubility of the radiopharmaceutical in the solvent. A preferred such solvent is an aqueous medium, and thus the solubilizer preferably increases solubility in water. Such suitable solubilizers include C alcohol, glycerin, polyethylene glycol (PEG), propylene glycol, polyoxy 1~4 ethylene sorbitan monooleate, sorbitan monooleate, polysorbate (e.g. Tween (trademark)), poly(oxyethylene) poly(oxypropylene) poly(oxy ethylene) block copolymer (Pluronics (trademark)), cyclodextrin e.g. α, β or γ cyclodextrin, hydroxypropyl-β-cyclodextrin trin or hydroxypropyl-γ-cyclodextrin) and lecithin are included. trin or hydroxypropyl-γ-cyclodextrin) and lecithin are included. trin or hydroxypropyl-γ-cyclodextrin) and lecithin are included. are included.
[0043] Preferred solubilizers are cyclodextrin, C 1~4 alcohol, polysorbate and also Pluronics (trademark), more preferably cyclodextrin and C 2~4 al cohol. When the solubilizer is alcohol, preferably ethanol or propanol ol, more preferably ethanol. Ethanol can also function as a biocompatible carrier, a radiation protection agent or an antibacterial preservative, and thus potentially has multiple roles. When the solubilizing agent is cyclodextrin, it is preferably γ-cyclodextrin, more preferably hydroxypropyl-β-cyclodextrin (HPbCD). The concentration of cyclodextrin is about 0.1 to about 50 mg / ml, preferably about 5 to about 50 mg / ml, more preferably 25 to 50 mg / ml, and most preferably about 40 to about 50 mg / ml. It can be in this range.
[0044] The inventors have found that when cyclodextrin is used as a co-stabilizer, the stability of radiopharmaceuticals is improved compared to the case of using conventional stabilizers. By adding cyclodextrin to radiopharmaceutical formulations, a more radiochemically stable product, and an additional value of a physically more stable product that is more compatible with plastic contact materials (tubes, sterilizing filters, syringes, etc.) can be obtained. When the active substance is poorly water-soluble, this is even more beneficial.
[0045] Calcium disodium edetate can also be used as an additional optional additive.
Brief Description of Drawings
[0046]
Figure 1
Figure 2
[0047] As shown in Figure 1, the RCP is more stable over 10 hours when HPbCD is present in the ascorbic acid formulation than when HPbCD is not present.
[0048] 18 F] The radiation stability of furupiridaz is equivalent to or higher than that when prepared using 30 mg / mL of ascorbic acid and 40 mg / mL of HPbCD, compared to when prepared without using HPbCD with 50 mg / mL of ascorbic acid. HPbCD also improves the water solubility of furupiridaz and reduces the risk of incompatibility with consumables (e.g., tubes, sterilizing filters , syringes, etc.).
[0049] As shown in Figure 2, 18 F] when furupiridaz is formulated with or without 40 - 47 mg / mL of HPbCD using 30 - 50 mg / mL of ascorbic acid (approx. pH 6), a decrease in RCP is observed over 4 - 10 hours. All samples contain approximately 7% (v / v) ethanol and are held under 0 - 21% (v / v) oxygen headspace gas.
[0050] The present invention will be described with reference to the following non - limiting examples.
Examples
[0051] [Example 1] Using SPE purification 18 F] Radiosynthesis of furupiridaz 18 F] Fluoride (approx. 200 GBq) was produced by the O](p,n) 18 1 8 F] nuclear reaction using a GE Medical Systems PETtrace cyclotron with a silver target. A total target volume of 3.2 - 4.8 mL was used. The radioactive flu oride was pre - conditioned with carbonate ions using a Waters QMA cartridge ) was trapped, and the fluoride was eluted with a solution of tetrabutylammonium hydrogen carbonate (22 mg) in water (100 μL) and acetonitrile (400 μL). Using nitrogen, the solution was transferred from the QMA cartridge to the reaction vessel. The [F] fluoride was dried at 110 - 120 °C for about 15 minutes under a constant nitrogen flow and reduced pressure. The precursor (10.2 mg) in MeCN (1.7 mL) was added to the dried [F] fluoride, and the reaction mixture was heated at 110 °C for 3 minutes. Then, the crude product was hydrolyzed with a solution of NaOH (2 M, 2.3 mL). Next, the hydrolyzed crude product was loaded onto a tC18 SPE cartridge (Waters, product number WAT036800) and purified using the following method. 18 The SPE cartridge was washed with ascorbic acid (21 mL) to wash away acetonitrile, NaOH, and hydrophilic and radiochemical impurities. Then, the SPE cartridge was washed with a 40% aqueous acetonitrile solution (11.9 mL) to remove hydroxy impurities. After that, the first SPE cartridge was connected in series to a second SPE cartridge (Waters, product number WAT036800), and the two were continuously washed with a 40% aqueous acetonitrile solution (22.2 mL), followed by a nitrogen flow to transfer the [F] fluoropyridazoles to the second cartridge and trap more lipophilic chemical and radiochemical impurities in the first SPE cartridge. 18 The second SPE cartridge was washed with a 40% aqueous acetonitrile solution (5.1 mL), followed by washing with ascorbic acid (21 mL) to remove acetonitrile. Then, the product was eluted from the second SPE cartridge with a 45% ethanol solution. The [F] fluoride was eluted with a solution of tetrabutylammonium hydrogen carbonate (22 mg) in water (100 μL) and acetonitrile (400 μL). Using nitrogen, the solution was transferred from the QMA cartridge to the reaction vessel. The [F] fluoride was dried at 110 - 120 °C for about 15 minutes under a constant nitrogen flow and reduced pressure. The precursor (10.2 mg) in MeCN (1.7 mL) was added to the dried [F] fluoride, and the reaction mixture was heated at 110 °C for 3 minutes.
[0052] The SPE cartridge was washed with ascorbic acid (21 mL) to wash away acetonitrile, NaOH, and hydrophilic and radiochemical impurities. Then, the SPE cartridge was washed with a 40% aqueous acetonitrile solution (11.9 mL) to remove hydroxy impurities. After that, the first SPE cartridge was connected in series to a second SPE cartridge (Waters, product number WAT036800), and the two were continuously washed with a 40% aqueous acetonitrile solution (22.2 mL), followed by a nitrogen flow to transfer the [F] fluoropyridazoles to the second cartridge and trap more lipophilic chemical and radiochemical impurities in the first SPE cartridge. The second SPE cartridge was washed with a 40% aqueous acetonitrile solution (5.1 mL), followed by washing with ascorbic acid (21 mL) to remove acetonitrile. Then, the product was eluted from the second SPE cartridge with a 45% ethanol solution. The [F] fluoride was eluted with a solution of tetrabutylammonium hydrogen carbonate (22 mg) in water (100 μL) and acetonitrile (400 μL). Using nitrogen, the solution was transferred from the QMA cartridge to the reaction vessel. 18 The [F] fluoride was dried at 110 - 120 °C for about 15 minutes under a constant nitrogen flow and reduced pressure. The precursor (10.2 mg) in MeCN (1.7 mL) was added to the dried [F] fluoride, and the reaction mixture was heated at 110 °C for 3 minutes. Then, the crude product was hydrolyzed with a solution of NaOH (2 M, 2.3 mL). Next, the hydrolyzed crude product was loaded onto a tC18 SPE cartridge (Waters, product number WAT036800) and purified using the following method. The SPE cartridge was washed with ascorbic acid (21 mL) to wash away acetonitrile, NaOH, and hydrophilic and radiochemical impurities. Then, the SPE cartridge was washed with a 40% aqueous acetonitrile solution (11.9 mL) to remove hydroxy impurities. After that, the first SPE cartridge was connected in series to a second SPE cartridge (Waters, product number WAT036800), and the two were continuously washed with a 40% aqueous acetonitrile solution (22.2 mL), followed by a nitrogen flow to transfer the [F] fluoropyridazoles to the second cartridge and trap more lipophilic chemical and radiochemical impurities in the first SPE cartridge. Elute with (9 mL, first 2 mL not recovered), 18 F] Fulurpidaz was eluted into the product vial in the alcohol.
[0053] The first 45 mL product vial consisted of water (42 mL), ethanol (3 mL), calcium disodium edetate (0.25 mg / mL), ascorbic acid (50 mg / mL) and sodium hydroxide (7.5 mg / mL). The second 45 mL product vial consisted of water (42 mL), ethanol (3 mL), calcium disodium edetate (0.25 mg / mL), ascorbic acid (50 mg / mL), hydroxypropyl-β -cyclodextrin (45 mg / mL; HPbCD) and sodium hydroxide (7.5 mg / mL).
[0054] The non-decay corrected recovery rate was 41 - 44%, and a product with an RAC of approximately 1800 MBq / mL was obtained (Table 1). The RCP of the final product was 96 - 98%.
[0055] After 2 hours, the RCP decreased by 0.8 - 1.4% in the formulation vial without HPbCD or by 0.3 - 0.4% in the formulation vial containing HPbCD (Table 1). After 4 hours, the RCP decreased by 1.1 - 1.7% in the formulation vial without HPbCD or by 0.6% in the formulation vial containing HPbCD. The RCP specification was 95% at the end of the storage period (8 - 10 hours), so if HPbCD was excluded from the formulation the batch was rejected.
[0056] Furthermore, when HPbCD was used in the formulation, the starting activity increased to 350 GBq and the production The RAC of the substance can be made about 2500 MBq / mL. The RCP is 96 - 98%, and there is a decrease in RCP of about 0.5 - 1.3% in 8 - 10 hours.
[0057]
Table 1
[0058] As described above, the inventors have found that when cyclodextrin is used as a co - stabilizer, compared with conventional radiation stabilizers, such as ascorbic acid alone, or radiation stabilization systems, such as ascorbic acid and ethanol, the radiation stability of the radiopharmaceutical composition is improved.
Claims
1. It consists of four components: (i) １８ Radiolabels including F-labeled radiopharmaceutical compounds or pharma- ceutically acceptable salts thereof compound, (ii) ethanol, (iii) a stabilizer for said radiolabeled compound, said stabilizer comprising ascorbic acid. , a stabilizer for the radiolabeled compound, and (iv) a co-stabilizer for the radiolabeled compound, the co-stabilizer being a cyclodextrin. Phosphorus, a costabilizer for radiolabeled compounds 1. A radiopharmaceutical composition comprising:
2. The radiolabeled compound is １８ F]FDG, [ １８ F]FMAU,[ １８ F]FMIS O[ １８ F]FHBG[ １８ F]AV-45[ １８ F]V-19[ １８ F]A V-1, １８ F]Flutemetamol, １８ F] Fururupiridazu, [ １８ F]K5, [ １ ８ F]HX4[ １８ F]W372[ １８ F]VM4-037[ １８ F]CP18、 [ １８ F]ML-10, １８ F] T808, [ １８ F] T807, 2-[ １８ F] Full 2. The release agent of claim 1, comprising oromethyl-L-phenylalanine, or a combination thereof. Injectable pharmaceutical composition.
3. The radiolabeled compound comprises a compound of formula (I): 【Chemistry 1】 In the formula, A is N(R ７ ), S, O, C(=O), C(=O)O, NHCH ２ CH ２ O. A bond, or C(=O)N(R ７ ) are selected from B, when present, is hydrogen, alkoxyalkyl, alkyloxy, aryl, optionally C optionally substituted with an imaging moiety １ ~C ６ Alkyl, heteroaryl, and and an imaging moiety, C, when present, is hydrogen, alkoxyalkyl, alkyloxy, aryl, optionally C optionally substituted with an imaging moiety １ ~C ６ Alkyl, heteroaryl, and and an imaging moiety, D is hydrogen, alkoxyalkyl, alkyloxy, aryl, optionally image C substituted with a zing moiety １ ~C ６ Alkyl, Heteroaryl, and Imaging Selected from the part, or C and D together with the atoms to which they are attached form a 3- or 4-membered carbocyclic ring; G is halo or haloalkyl; n is 0, 1, 2 or 3; R １ , R ２ , R ３ , R ４ , R ５ , R ６ and R ７ are independently hydrogen, optionally C substituted with an imaging moiety １ ~C ６ alkyl, and imaging moieties. Selected, R ８ is optionally substituted with an imaging moiety; １ ~C ６ It is an alkyl , and E is selected from a bond, carbon and oxygen, provided that when E is a bond, B and C are is absent, D is selected from aryl and heteroaryl, and E is oxygen; then B and C is absent; D is hydrogen, alkoxyalkyl, aryl, optionally an image C substituted with a sizing moiety １ ~C ６ alkyl, and heteroaryl. 、 With the proviso that at least one imaging moiety is present in formula (I): A radiopharmaceutical composition according to claim 1 or 2.
4. The radiolabeled compound is flurpiridaz: 【Chemistry 2】 4. The radiopharmaceutical composition according to any one of claims 1 to 3, comprising:
5. The radiolabeled compound is １８ F]FLT is not a cytochrome P450 inhibitor according to any one of claims 1 to 4. Radiopharmaceutical compositions.
6. 6. The method according to claim 1, wherein the stabilizer comprises ascorbic acid and ethanol. The radiopharmaceutical composition described above.
7. 10. The method according to claim 1, wherein the ethanol comprises up to 10% (v / v) ethanol in an aqueous solution.
7. The radiopharmaceutical composition according to any one of claims 1 to 6.
8. The cyclodextrin is α-cyclodextrin, β-cyclodextrin or gamma-cyclodextrin, or a pharma- ceutically acceptable derivative or combination thereof.
8. The radiopharmaceutical composition of claim 1 , comprising:
9. 9. The method according to claim 1, wherein the cyclodextrin comprises β-cyclodextrin.
2. The radiopharmaceutical composition according to claim 1 .
10. The cyclodextrin is hydroxypropyl-β-cyclodextrin (HPbC 10. The radiopharmaceutical composition of claim 1 comprising:
11. 11. A radiopharmaceutical composition according to any preceding claim, comprising a biocompatible carrier.
12. 12. A radiopharmaceutical according to any one of claims 1 to 11, in a form suitable for mammalian administration. composition.
13. The stabilizer comprises ascorbic acid and ethanol, and the cyclodextrin is and wherein the radiolabeled compound comprises hydroxypropyl-β-cyclodextrin (HPbCD).
13. A radiopharmaceutical composition according to any one of claims 1 to 12, comprising flurpiridaz.
14. The ascorbic acid is in an amount of about 1 to about 100 mg / mL, and the ethanol is in an amount of about 2 to about 100 mg / mL. about 10% (v / v) and said HPbCD is in an amount of about 1 to about 100 mg / mL 14. The radiopharmaceutical composition of claim 13.
15. Use of cyclodextrins as co-stabilizers in radiopharmaceutical compositions.
16. The radiopharmaceutical composition comprises a radiolabeled compound, the radiolabeled compound being １８ F]FL The use according to claim 15, wherein said compound is not T.
17. Imaging a subject using a radiopharmaceutical composition according to any one of claims 1 to 15 How to do it.
18. 16. The method of claim 1 for use in Positron Emission Tomography (PET) imaging. A radiopharmaceutical composition according to any one of the preceding claims.
19. It consists of four components: (i) a radiolabeled compound according to any one of claims 1 to 14, (ii) ethanol, (iii) a stabilizer for a radiolabeled compound according to any one of claims 1 to 14, and (iv) a cyclodextrin according to any one of claims 1 to 14.
23. A method for preparing a radiopharmaceutical composition comprising the step of combining
20. It consists of four components: (i) A precursor compound for the production of a radiolabeled compound according to any one of claims 1 to 14. thing, (ii) ethanol, (iii) a stabilizer for a radiolabeled compound according to any one of claims 1 to 14, and (iv) a cyclodextrin according to any one of claims 1 to 14.
23. A kit for the preparation of a radiopharmaceutical composition comprising: