JP2010106041A - Stabilization of radiopharmaceutical labeled with 18f - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an<SP>18</SP>F isotope-labeled FDG ([<SP>18</SP>F]2-Fluoro-2-Deoxy-D-glucose (hereinafter FDG)), radiopharmaceutical which is stable and safety to human body. <P>SOLUTION: The<SP>18</SP>F isotope-labeled FDG radiopharmaceutical is stabilized against degradation in radiochemical purity due to radiolysis using selected amounts of ethyl alcohol that depend on the activity concentration of the<SP>18</SP>F, considering the limits set by various pharmacopoeia standards. Any of the well-known production methods for the FDG may be used and ethyl alcohol maybe added at several stages, preferably as part of the standard hydrolysis step. The particular radiopharmaceutical is used extensively in diagnostic imaging by the Positron Emission Tomography technique. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

This invention relates to the stabilization of glucose compounds containing ¹⁸ F radioisotopes against radiolysis. Stabilized compounds are used for diagnostic imaging by positron emission tomography.

¹⁸ F isotope-labeled glucose [ ¹⁸ F] 2-fluoro-2-deoxy-D-glucose (FDG) is a nuclear medicine for diagnostic studies using positron emission tomography (PET) human body scanning systems. Widely used in the field. ^{Since the 18} F isotope has a short half-life (109 min), this product must be produced in relatively large quantities to allow for decay during delivery from the manufacturing plant to the patient. Therefore, shift work begins with manufacturing for long-distance hospitals (even if using a car) in the middle of the night and manufacturing for short-distance hospitals early in the morning. Typical delivery times range from 5 to 8 hours. An additional 4 hours may elapse between arrival and use by the final patient. That is, 8 to 12 hours may elapse between the time of manufacture and the time of administration to the patient. This corresponds to a half-life of 4.4 to 6.6 times and requires preparation with an initial radioactivity concentration 20 to 100 times that actually required at the time of administration.
When prepared at relatively high concentrations, eg, 3.7 GBq / ml (100 mCi / ml) or higher, radiation-induced degradation of FDG occurs. This process is called radiolysis. It is mainly caused by oxidation by free radicals generated by the interaction of ionizing radiation from ¹⁸ F isotopes with solvent water and possibly air. These processes can then cause FDG degradation, which can be quantified in the form of reduced radiochemical purity (RCP). RCP is generally expressed as% radioactivity as FDG relative to the total radioactivity present in the sample.
Typically, upon completion of manufacture, FDG has an RCP of 98-100%. Result of radiolysis, partially exploded of FDG molecules, other than FDG radioactive substances (mainly free ¹⁸ F ^- ions) and a. This may reduce the RCP to less than 90% over a period of less than 12 hours, as demonstrated by the experiments described below. The quality standard established by the United States Pharmacopeia (USP) for FDG is “RCP not less than 90%”. Of course, to achieve the best PET image quality, it is desirable to keep the RCP as high as possible for as long as possible.

The production of FDG involves the synthesis of ¹⁸ F-labeled compound followed by purification. The synthesis includes an ¹⁸ F fluorination step that will form an acetylated derivative of FDG (intermediate product), followed by a hydrolysis step in which the protected acetyl group is removed to yield the final product. . Although the hydrolysis step is only about 10 minutes, the concentration of radioactive material is about 5 times the concentration of radioactive material in the final product, and its significant degradation occurs during the production of the FDG intermediate product. Since accumulated radioactive impurities are removed in the purification step, decomposition of the intermediate product does not directly affect the RCP of the final product. However, it is important to recognize that any degradation will result in a low radiochemical yield. Therefore, it is very useful to reduce or control radiolysis in the hydrolysis step not only for the final product but also for the intermediate product.
A 12 hour storage capacity is a practical requirement for delivery and use. Therefore, RCP after 12 hours or more is a useful indicator of the stabilizing effect.
In short, increasing the stability of FDG and increasing the RCP at the time of administration are important goals for FDG production. Controlling radiolysis in the FDG manufacturing process is also important to increase the radiochemical yield of the product.

The production of ¹⁸ F-labeled FDG is now known. Information 1) Fowler et al., “2-Deoxy-2- [18F] Fluoro-D-Glucose for Metabolic Studies: Current Status,” Applied Radiation and Isotopes, vol.37, no.8, 1986, 663-668 2) Hamacher et al., “Efficient Stereospecific Synthesis of No-Carrier-Added 2- [18F] -Fluoro-2-Deoxy-D-Glucose Using Aminopolyether Surpported Nucleophilic Substitution,” Journal of Nuclear Medicine, vol. 27, 1986. , 235-238, 3) Coenen et al., "Recommendation for Practical Production of [2-18F] Fluoro-2-Deoxy-D-Glucose," Applied Radiation and Isotopes, vol.38, no.8, 1987, 605 -610 (good review), 4) Knust et al., "Synthesis of 18F-2-deoxy-2-fluoro-d-glucose and 18F-3-deoxy-3-fluoro-D-glucose with no-carrier added 18F- fluoride, "Journal of Radioanalytic Nuclear Chemistry, vol.132, no.1, 1989, 85+, 5) Hamacher et al." Computer-aided Synthesis (CAS) of No-carrier-added 2- [18F] Fluoro- 2-Deoxy-D-Glucose: An Efficient Automated System for the Aminopolyether-supported Nucleophilic Fluorination, "Applied Radiation and Isotopes, vol.41, no.1, 1990, 49-55 and 6) European Patent No. 0 798 307 A1 (NKK Plant Engineering Corp. et al.) October 1, 1997, "Fluoro-deoxyglucose See "synthesizer using columns."

Regarding the stabilization of radiopharmaceuticals, EP 0 462 787 describes, for example, a freeze / thaw technique for storing radiopharmaceuticals ethylenediamine-tetraethylenephosphonic acid (EDTMP) labeled with ¹⁵³ Sm. Disclosure. Radioactivity degradation over time is compared using a solution containing 0.9% benzyl alcohol, a solution containing 5.0% ethanol, and a no preservation control. Benzyl alcohol solution delays the onset of decomposition, and after that, the rate is slow. On the other hand, even at concentrations as high as 5.0%, ethanol only slightly delayed degradation, and after initiation, degradation proceeds faster than control. Other additives for stabilizing various radiopharmaceuticals are described in Patent Document 2 (US Pat. No. 5,384,113, Deutsch et al. January 24, 1995), Patent Document 3 (US Pat. No. 6,027,710, Higashi et al. February 2000). ), Patent Document 4 (No. 6,066,309, Zamara et al., May 23, 2000), and Patent Document 5 (No. 6,261,536, Zamara et al., July 17, 2001).
Because the PET method requires injection of an FDG solution, there is a United States Pharmacopeia for limiting potentially toxic ingredients to appropriate limits. The allowable dose of ethanol mentioned above, currently established by the European Pharmacopoeia and the US Pharmacopoeia, is 0.5% (1/10 of the concentration used for EDTMP). Also, conformity requires verification by one or more effective limit tests. From a practical point of view, it is highly desirable to limit the concentration of potentially toxic components to half the limit, ie 0.25% or less. Considering measurement uncertainty and safety, using more than about half of the limit value requires more testing to prove confidently.

European Patent 0 462 787 Specification U.S. Pat.No. 5,384,113 U.S. Patent No. 6,027,710 U.S. Patent 6,066,309 US Patent 6,261,536

  Accordingly, it is an object of this invention to increase the stability of FDG and thereby increase the RCP of the product in use. Yet another object is to increase manufacturing efficiency by controlling radiolysis in the manufacturing process of FDG. These must be achieved at the same time as keeping potentially toxic additives within a practically safe range.

Surprisingly, the concentration in the final product, practical (practical) pharmacopoeias in the following limits, the object is achieved in ¹⁸ F- labeled FDG containing ethanol in the range of minimum effective stabilizing amount obtain. The effective minimum concentration is the concentration that maintains 90% RCP for over 12 hours. Experiments have shown that when the radioactive concentration of ¹⁸ F is about 10 GBq / ml, the minimum effective ethanol concentration is about 0.1% (v / v). In light of these experimental results, a linear approximation of the minimum effective ethanol concentration to the practical radioactivity concentration is approximately 0.01% (v / v) / GBq / ml of the radioactivity concentration of ¹⁸ F. It was theoretically shown.
The upper limit of ethanol concentration is set by the pharmacopoeia of each country. Currently, the upper limit of ethanol concentration in FDG solution is 0.5% (v / v). However, in order to ensure compliance with regulations, it is realistic to lower the upper limit to about 0.25% (v / v). is there. If the radioactive concentration of at least ¹⁸ F is about 10 GBq / ml or less, an ethanol concentration of about 0.1% to 0.25% is an effective and safe FDG solution stabilizer.
When FDG is synthesized by a nucleophilic ¹⁸ F fluorination step followed by a hydrolysis step described later, ethanol is added to NaOH hydrolysis reagent solution, dilution water, collection bottle, NaCl solution injected into the collection bottle, Or they may be added to these combinations. If added to the NaOH solution, a stabilizing effect is achieved as early as possible in the manufacturing process. It is preferable to adjust the amount of ethanol so that the concentration in the final product described above can be obtained at any point.

  The FDG manufacturing process described here is based on an automatic FDG synthesizer system manufactured by Nuclear Interface GmbH (Münster, Germany). The description of the system and radiochemical synthesis is only an example. There are various apparatuses and methods suitable for the synthesis of FDG, which have been known in the past. The synthesis of FDG itself is not considered part of this invention, and only a description of the basic process is included here.

  The synthesizer system includes a synthesis module control unit, a chemical process control unit, and a computer. The control unit is disposed within the lead shielded space and includes a number of reagent tubes, bottles, valves; reaction vessels, product collection vessels; and connections for purification columns and cartridges.

The usual synthesis of FDG is a two-step process consisting of two chemical reactions: nucleophilic ¹⁸ F fluorination followed by hydrolysis.
In the fluorination step, the organic precursor 1,3,4,6-tetra-O-acetyl-2-O-trifluoro-methanesulfonyl-β-D-mannopyranose (mannose triflate) is incorporated with ¹⁸ F label. The substitution reaction is accomplished by combining a phase transfer catalyst with ¹⁸ F fluoride extracted from the irradiated target material. The mixture is dried in a stream of inert gas. This dried mixture is added to a solution of mannose triflate in acetonitrile and the solution is heated and dried in a stream of inert gas.
Hydrolysis steps such as base-catalyzed hydrolysis of acetyl protecting groups generate free hydroxyl groups in the final formulation. A predetermined amount of NaOH aqueous solution is added to the dried fluorinated mannose triflate as a hydrolysis reagent, and the resulting solution is heated to achieve complete removal of the acetyl groups.
In order to purify the resulting mixture to obtain an aqueous FDG solution, it is diluted with a predetermined amount of water and filtered through a purification cartridge.
The present invention is not dependent on the details of the above steps, but applies to any process that utilizes a nucleophilic fluorination step followed by a hydrolysis step.

Four examples:
In order to investigate the effect of the addition of ethyl alcohol on the stability of an aqueous FDG solution, it was prepared as described above. Each sample was prepared such that the FDG in 9 ml of water was 82 to 106 Bq (2.3 to 2.8 Ci). Therefore, the initial radioactivity concentration immediately after production was about 8 to 11 GBq / ml (263 to 320 mCi / ml).
In all experiments, RCP was measured by a standard thin layer chromatography (TLC) method using a 10 cm silica coated glass plate from Alltech (Deerfield, IL). A 95: 5 mixture of acetonitrile and water was used as the mobile phase and the radioactivity distribution on the plates was measured using a TLC plate scanner from Bioscan (Washington, DC). In most cases, the sample size was less than 1 ml.
The ethanol concentration was measured by gas chromatograph (GC) analysis using a HP 5890 gas chromatograph equipped with a DB WAX type 50m capillary column from Alltech and a standard HP flame ionization detector (FID). The carrier gas was 4-10 ml / min helium. The FID injector was heated at 200 ° C. with a split ratio of 1:50. The column temperature was 50 to 200 ° C. while increasing the temperature at 20 ° C./min. The response of the FID detector was calibrated using an external standard.
RCP was measured after storage for 14-21 hours. However, it should be noted that radiolysis occurs during the first 3 to 6 hours, as the radioactivity concentration decreases exponentially with a half-life of 1.82 hours. After 6 hours, only about 10% of the radioactivity remains and will not be sufficient to cause significant degradation of the product.

Experiment 1: Ethanol added to the final FDG product In this experiment, the final product was prepared with an initial radioactivity concentration of 10.8 GBq / ml (292 mCi / ml). The product was divided into 4 equal portions of 2 ml to give samples 1-4, and different amounts of ethanol were added to each using a microsyringe. Samples were stored in the same sealed bottles used for FDG storage and customer delivery. RCP was measured at the time of manufacture and after 14 hours. The ethanol concentration in each sample was measured using the GC method described above. Table 1 shows the results.

(Table 1)
Sample number Ethanol (%) Initial RCP 14 hours later RCP
1 0.05% 97.2% 87%
2 0.24% “97%
3 0.48% “96%
4 1.07% “97%

  As Table 1 shows, 0.05% is not high enough to maintain an RCP that meets US Pharmacopoeia conditions, but within experimental error, concentrations above 0.24% are subject to negligible degradation of RCP. It was. 1.07% is clearly above the pharmacopoeia limit, 0.48% is too close to the limit.

Experiment 2: Ethanol added to NaOH solution In this experiment, ethanol was added to the NaOH hydrolysis used in the hydrolysis step to simplify the manufacturing process and provide the added benefit of stabilizing the intermediate product. Added to the degradation reagent solution. It was added in an amount calculated after dilution with water so that the concentration in the final product was about 0.05%. In this experiment, the final product had an initial radioactivity concentration of about 11.8 GBq / ml (320 mCi / ml).
From the final product, 2 ml each of samples 1, 2 and 3 were taken. To see if the storage conditions affected the results, samples 1 and 2 were stored in bottles and sample 3 was stored in the same syringe used to deliver FDG to the user. At the end of the 15 hour waiting period, each sample was analyzed by the TLC and GC methods described above. Table 2 shows the results.

(Table 2)
Sample number Ethanol (%) Initial RCP 14 hours later RCP
1 0.04% 98.9% 89.7%
2 0.04% “89.8%
3 0.05% “87.8%

  Experimental results show that ethanol concentrations of 0.04% to 0.05% are not sufficient even when added to NaOH solution. At the end of the storage period, the product had a loss of RCP so large that the 90% RCP, the RCP limit set by the US Pharmacopoeia, was not obtained. Syringe storage seems to have been the worst, but probably within experimental error.

Experiment 3: Increased ethanol added to the NaOH solution These experiments were performed except that the amount of ethanol added to the NaOH solution was doubled, resulting in an ethanol concentration of about 0.1% in the final product. The same as Experiment 2. Two different radioactivity concentrations and storage times were attempted. Samples 1 and 2 were stored in bottles and samples 3 and 4 were stored in syringes, respectively.
Table 3 shows the results after 21 hours when the initial radioactivity concentration is 9.7 GBq / ml (263 mCi / ml).

(Table 3)
Sample number Ethanol (%) Initial RCP 21 hours later
1 0.09% 99.5% 94.4%
2 0.09% “94.7%
3 0.11% “95.6%
4 0.11% “95.2%

  Table 4 shows the results after 15 hours when the initial radioactivity concentration is 11.2 GBq / ml (303 mCi / ml).

(Table 4)
Sample number Ethanol (%) Initial RCP 15 hours later
1 0.08% 98% 94.6%
2 0.09% “94.2%
3 0.10% “94.5%
4 0.11% “95.1%

Although significant loss of RCP was observed, all samples met the US Pharmacopoeia limit of 90% RCP at the end of the 15-hour and 21-hour storage periods. Therefore, the stabilizing effect of ethanol concentration of 0.1% is sufficient at FDG radioactivity concentrations up to at least 11.2 GBq / ml (303 mCi / ml). The ethanol concentration of 0.1% is well below the limit of 0.5% established by the European and US Pharmacopeia.
As expected, the loss of RCP after 21 hours is not significantly worse than after 15 hours due to the decrease in decay of ¹⁸ F and the decrease in radioactivity concentration. The difference in storage method had little effect on RCP.
In summary, for an FDG solution with a radioactivity concentration of about 10 GBq / ml, an ethanol concentration of at least about 0.1% (v / v) is a solution against radiolysis to obtain a 90% RCP after 12 hours. It is effective to stabilize The pharmacopoeia limits are higher, but as a rule it is always desirable to use as low an additive as possible for the formulation. As already pointed out, the smaller the amount, the more certain that the limit value is not exceeded.

  Therefore, it is useful to know the minimum effective dose for other radioactivity concentrations. Based on the above experimental results showing that a 0.1% ethanol concentration is effective for a radioactivity concentration of 10 GBq / ml, a person skilled in the art prepares FDG with different practical radioactivity concentrations, and sets the required ethanol concentration. It is preferable to make some effort to decide.

However, using an ethanol concentration that is directly proportional to the radioactivity concentration, ie 0.01% (v / v) / GBq / ml, the effort is considerably reduced. This, ¹⁸ F- density of labeled FDG and ethanol molecules is because low. There is almost no interaction between the respective molecules in the aqueous solution. In the case of 10 GBq / ml, the density is about 10 ^ 14 FDG molecules / cc with about 20,000 nm between them. In an aqueous solution having a density of about 3 × 10 22 molecules / cc and an intermolecular spacing of about 0.3 nm, the density is about 1.3 × 10 19 molecules / cc and the spacing is about 500 nm in the case of 0.1% ethanol.

¹⁸ F positron emission, if not blocked by ethanol molecules, is thought to generate a cascade of free radical species that react with O ^* , OH ^* and other FDG. Whether true or not, it is clear that most of the positrons interact with water molecules. This is a direct function of the number of ¹⁸ F emitters in solution (emitter). If ethanol has a protective effect, the required amount is preferably linear with the number of free radicals and ¹⁸ F density.

  Although experimental confirmation is always desirable when dealing with injected radiopharmaceuticals, it is preferred that the linear approximation to the minimum effective ethanol concentration be fairly close to the pharmacopoeia limit of 0.5% ethanol.

Claims (9)

[ ¹⁸ F] A radioactive composition comprising an aqueous 2-fluoro-2-deoxy-D-glucose solution and ethanol, wherein the ethanol concentration in the composition is 0.5% (v / v) or less. and ¹⁸ F activity concentration 1GBq / 0.007% per ml of the composition (v / v) or more, preferably ¹⁸ F activity concentration 1GBq / 0.01% per ml of the composition (v / v) or higher Said radioactive composition characterized by the above-mentioned. The composition according to claim 1, wherein the ¹⁸ F radioactivity concentration is 10 GBq / ml, and the ethanol concentration is 0.1% or more.   The composition according to claim 1 or 2, wherein the ethanol concentration is 0.25% (v / v) or less.   The composition according to claim 1, wherein the ethanol concentration is in the range of 0.1% to 0.25% (v / v). 5. The ethanol according to claim 1, wherein the ethanol is added to a hydrolysis reagent used in the preparation of the [ ¹⁸ F] 2-fluoro-2-deoxy-D-glucose aqueous solution. 2. The composition according to item 1. A method for preparing and stabilizing an [ ¹⁸ F] 2-fluoro-2-deoxy-D-glucose aqueous solution comprising a nucleophilic ¹⁸ F fluorination step followed by a hydrolysis step, said method In the process, the concentration of the ethanol in the final product is 0.5% (v / v) or less and 0.007% per 1 GBq / ml of ¹⁸ F radioactivity concentration of the final product (V / v) or more, preferably 0.01% (v / v) or more per 1 GBq / ml of ¹⁸ F radioactivity concentration of the final product.   The method according to claim 6, wherein the ethanol is added to a hydrolysis reagent used in the hydrolysis step.   The method according to claim 6 or 7, wherein the ethanol concentration is 0.25% (v / v) or less.   The method according to claim 6 or 7, wherein the ethanol concentration is in the range of 0.1% to 0.25% (v / v).