WO2017014599A9 - Composition pour stabiliser la pureté radiochimique de [18f]fluoro-dopa et procédé de préparation associé - Google Patents
Composition pour stabiliser la pureté radiochimique de [18f]fluoro-dopa et procédé de préparation associé Download PDFInfo
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- WO2017014599A9 WO2017014599A9 PCT/KR2016/008049 KR2016008049W WO2017014599A9 WO 2017014599 A9 WO2017014599 A9 WO 2017014599A9 KR 2016008049 W KR2016008049 W KR 2016008049W WO 2017014599 A9 WO2017014599 A9 WO 2017014599A9
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- A—HUMAN NECESSITIES
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
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- the present invention is [18 F] fluoro-as for the method for producing the composition and its stabilizing the radiochemical purity of the waveguide, and more particularly, to a [18 F] fluoro By inhibiting for a predetermined time, impurity generation-guided radiation of the chemical It relates to a composition for stabilizing purity and a method for preparing the same.
- Positron emission tomography is a method of imaging the distribution and biochemical changes of radiopharmaceuticals in vivo by intravenous injection of an organic compound labeled with a radioisotope that emits positrons in vivo. Therefore, positron emission tomography can quantitatively measure the biochemical changes of living organisms at the site of lesions, thereby measuring disease development and predicting the extent of treatment (A.
- Radioactive isotopes used for positron emission tomography include fluoride ([ 18 F] F), carbon ([ 15 C] C), nitrogen ([ 13 N] N), oxygen ([ 15 O] O) and gallium ([ 68 Ga] Ga), among which [ 18 F] fluoride has a size similar to that of hydrogen, forms a stable bond with carbon of an organic compound, is easy to produce, and has an appropriate half-life (110 minutes). It is reported to be very suitable for performing positron emission tomography (Lasne, MC; Perrio, C .; Rouden, J .; Barre, L .; Roeda, D .; Dolle, F .; Crouzel, C).
- [ 18 F] fluorides are generally prepared by investigating protons in [ 18 O] H 2 O using cyclotron, a circular accelerator (MR Kilbourn, JT Hood, MJ Welch, Int. J. Appl. Radiat. Isot. 1984 , 35, 599 .; GK Mulholland, RD Hichwa, MR Kilbourn, J. Moskwa, J. Label.Compd. Radiopharm. 1989 , 26, 140.).
- FDOPA fluorinated L-DOPA and the bioclassification of FDOPA is similar to the normal classification of L-DOPA (http://interactive.snm.org/docs/PET_PROS/FDOPA.pdf).
- L-DOPA is known to be unstable in aqueous alkaline solutions and well oxidized by oxygen (https://www.sigmaaldrich.com/content/dam/sigmaaldrich/docs/Sigma/Product_Information_Sheet/d9628pis.pdf).
- Prior art documents related to the present invention include Korean Patent Application No. 10-2007-7020237 (name of the invention: a new pharmaceutical composition useful for treating Parkinson's disease, filed on Sep. 04, 2007).
- the present invention provides a composition for stabilizing the radiochemical purity of [ 18 F] fluoro-dopa that does not require refrigeration and has a radiochemical purity that can be used as a radiopharmaceutical even at room temperature.
- [ 18 F] fluoro-dopa Ethanol at a concentration of 5% to 30% (V / V) relative to the total composition;
- a composition comprising a buffer having a value of pKa 6 to 8.1 at 25 ° C. to stabilize the radiochemical purity of the [ 18 F] fluoro-waveguide by inhibiting the generation of impurities for a predetermined time.
- the composition is a composition which exhibits at least 90% radiochemical purity by inhibiting the generation of impurities for 2-6 hours after the synthesis of the [ 18 F] fluoro-dopa at pH 6-8.
- the composition is a composition that exhibits at least 90% of radiochemical purity by inhibiting the generation of impurities for 2 to 6 hours after the synthesis of the [ 18 F] fluoro-dopa at room temperature.
- the buffer having a value of pKa 6.1 to 8.1 at 25 ° C is PBS (PHOSPHATE BUFFERED SALINE), Citrate Buffer (CITRATE BUFFER), MES (2- (NMORPHOLINO) ETHANESULFONIC ACID), BIS-TRIS (2,2-BIS (HYDROXYMETHYL) -2,2 ', 2' '-NITRILOTRIETHANOL) Buffer, MOPSO (3-MORPHOLINO-2-HYDROXYPROPANESULFONIC ACID) Buffer, HEPES (4- (20HYDROXETHYL) -1-PIPERAZINEETHANSFULFONIC ACID) Buffer, and TRIS (TRIS (HYDROXYMET) ) AMINOMETHANE) at least one selected from the group consisting of buffers.
- the dopa includes levodopa (L-dopa), carbadopa, dopamine or derivatives thereof.
- the [ 18 F] fluoro-dopa is included at a radioactive concentration of 37 to 37,000 MBq / ml and the ethanol and the buffer
- the total volume of 100% (V / V) of the total composition is included.
- the buffer is 70% of the total composition. % To 95%, so that the sum of the buffer concentration and the concentration of ethanol can be 100% (V / V).
- [ 18 F] fluoro-dopa In case the total composition from about 5% to about 30% (V / V) of ethanol and 25 °C of concentrations, including the steps of mixing the buffer with a value of pKa 6 to 8.1, inhibit impurities generated for a predetermined period of time the [18 F] A method of preparing a composition for stabilizing the radiochemical purity of fluoro-dopa is provided.
- composition inhibits the generation of impurities for 2-6 hours after the synthesis of the [ 18 F] fluoro-dopa at pH 6-8, resulting in at least 90% radiochemical purity.
- composition inhibits the generation of impurities for 2-6 hours after the synthesis of the [ 18 F] fluoro-dopa at room temperature to exhibit at least 90% radiochemical purity.
- the buffer having a value of pKa 6.1 to 8.1 at 25 ° C is PBS (PHOSPHATE BUFFERED SALINE), Citrate Buffer (CITRATE BUFFER), MES (2- (NMORPHOLINO) ETHANESULFONIC ACID), BIS-TRIS (2,2-BIS (HYDROXYMETHYL) -2,2 ', 2' '-NITRILOTRIETHANOL) Buffer, MOPSO (3-MORPHOLINO-2-HYDROXYPROPANESULFONIC ACID) Buffer, HEPES (4- (20HYDROXETHYL) -1-PIPERAZINEETHANSFULFONIC ACID) Buffer, and TRIS (TRIS (HYDROXYMET) ) AMINOMETHANE) at least one selected from the group consisting of buffers.
- the dopa comprises levodopa (L-dopa), carbadopa, dopamine or derivatives thereof.
- [18 F] fluoro-composition and its stabilizing the radiochemical purity of the waveguide - in [18 F] fluoro after synthesis of the waveguide 2 to during 6 hours even with the available radiochemical purity as a radiopharmaceutical A manufacturing method is provided.
- composition for stabilizing the radiochemical purity of [ 18 F] fluoro-dopa that does not require refrigeration and has a radiochemical purity that can be used as a radiopharmaceutical even at room temperature.
- FIG. 2 is an HPLC chromatogram of ethanol-free [ 18 F] fluoro-dopa formulation showing impurity formation 6 hours after neutralization;
- FIG. 3 is a graph showing the radiochemical purity of ethanol free and added [ 18 F] fluoro-dopa formulations over time after neutralization to pH 6;
- FIG. 4 is a graph showing the radiochemical purity of ethanol free and added [ 18 F] fluoro-dopa formulations over time after neutralization to pH 7.
- FIG. 5 is a graph showing the radiochemical purity of ethanol free and added [ 18 F] fluoro-dopa formulations over time after neutralization to pH 8;
- FIG. 6 is a TLC chromatogram of [ 18 F] fluoro-dopa formulation with 10% ethanol showing impurity formation 1 hour after neutralization;
- FIG. 7 is a graph showing the radiochemical purity of ethanol free and added [ 18 F] fluoro-dopa formulations, depending on the storage temperature after neutralization.
- FIG. 8 is a PET image of ethanol addition buffer without addition [ 18 F] fluoro-dopa formulation over time after neutralization
- FIG. 9 is a graph depicting the radiochemical purity of ethanol and buffer addition [ 18 F] fluoro-dopa formulations over time after neutralization.
- the present invention is directed to [ 18 F] fluoro-dopa; Ethanol at a concentration of 5% to 30% (V / V) relative to the total composition;
- a composition comprising a buffer having a value of pKa 6 to 8.1 at 25 ° C. to inhibit impurity production for a predetermined time to stabilize the radiochemical purity of the [ 18 F] fluoro-waveguide.
- [ 18 F] fluoro-dopa is levodopa (LEVODOPA, L-DOPA), carbidopa (CARBIDOPA), dopamine or derivatives thereof, preferably levodopa (LEVODOPA, L-DOPA) [ 18 F] fluoride It is prepared by labeling through a nucleophilic substitution reaction, and the labeling method thereof is according to a known procedure (Source: Appl. Radiat. Isot. 67 2009 1650-1653).
- [ 18 F] fluoride source a fluorine salt which is a compound containing fluorine-18 may be used, and a known fluorine salt may be used.
- the labeling of [ 18 F] fluoride can achieve radiolabeling with fluorine by electrophilic fluorination using 18 [F] F fluorine gas, preferably to [ 18 F] -fluoride ions By nucleophilic substitution of the appropriate leaving group.
- [ 18 F] fluoro-dopa retains the chemical properties of levodopa (LEVODOPA, L-DOPA), which is unstable in aqueous alkaline solutions, oxidized well by oxygen and should be stored at 2-8 ° C.
- L-DOPA levodopa
- [ 18 F] fluoro-dopa which has been reported so far due to this chemical property of levodopa, is also difficult to store and use. Since [ 18 F] fluoro-dopa is unstable in neutral state, in acidic and refrigerated state It is known to be stored and distributed, and to be neutralized for administration to the human body, and to be neutralized immediately before use, and to be used within 2 hours after neutralization.
- the inventors of the present invention is [18 F] fluoro-Waveguide synthesis after storage pH, hours of use, the [18 F] fluoro receiving a lot of effect on the storage temperature reason radiation affecting radiochemical purity since the waveguide synthetic chemical It was found that impurities were produced. Accordingly, the present inventors have studied the [ 18 F] fluoro-dopa formulation that can be stored at neutral pH, prolonged use time after neutralization, storage at room temperature after neutralization, 5% to 30% (V / V) concentration of the total composition With ethanol; The present invention was completed by confirming that a buffer having a value of pKa 6 to 8.1 at 25 ° C can inhibit the production of radiochemical impurities.
- Ethanol can be used to purchase 100% pure ethanol from the manufacturer, it can be used 5% to 30% (V / V) concentration of the total composition. Since the formation of the first and second radiochemical impurities affected by hydrogen ion concentration and storage time, which is detected by HPLC after neutralization from [ 18 F] fluoro-dopa synthesized by ethanol addition, is inhibited [ 18 F] ] The radiochemical purity of the fluoro-waveguide can be maintained at least 90% or more.
- Buffers with pKa 6 to 8.1 at 25 ° C. can also be purchased from the manufacturer.
- [ 18 F] fluoro-waveguided by the addition of a buffer of the above conditions inhibits the formation of a third radiochemical impurity affected by the storage temperature, which is detected by TLC after neutralization from [ 18 F] fluoro-waveguided
- the radiochemical purity of may be maintained at least 90% or more.
- composition according to the present invention can exhibit radiochemical purity of at least 90% by inhibiting the generation of impurities for 2 to 6 hours after the synthesis of the [ 18 F] fluoro-dopa at pH 6-8.
- composition according to the present invention may exhibit at least 90% of radiochemical purity by inhibiting the generation of impurities for 2 to 6 hours after the synthesis of the [ 18 F] fluoro-dopa at room temperature.
- composition according to the present invention can exhibit radiochemical purity of at least 90% by inhibiting the generation of the impurities for 2 to 6 hours after the synthesis of the [ 18 F] fluoro-dopa at pH 6 ⁇ 8 and room temperature conditions have.
- the [ 18 F] fluoro-dopa prepared by the above known synthesis method is in an acidic state of pH 2-4, which needs to be adjusted to a pH suitable for human or mammalian administration, for example pH 6-8.
- a pH suitable for human or mammalian administration for example pH 6-8.
- Sodium bicarbonate, sodium carbonate or mixtures thereof may be used.
- a composition for stabilizing the radiochemical purity of [ 18 F] fluoro-dopa according to the present invention is supplied to a clinical syringe or container provided with a seal suitable for single or multiple puncture with a hypodermic needle while maintaining sterile integrity It is provided, for example, in a single vial or multi-use vial.
- the multi-use vial like a single-use vial, does not use the medicine contained in one vial to one patient, and discards the rest, but for injection that can use the medicine contained in one vial to two or more patients Refers to a glass container.
- composition for stabilizing the radiochemical purity of [ 18 F] fluoro-waveguide according to the present invention may be for positron emission tomography (PET) imaging, PET / CT combined with the PET or computed tomography, or the PET and magnetic resonance imaging may be used for imaging such as PET / MRI.
- PET positron emission tomography
- CT combined with the PET or computed tomography
- magnetic resonance imaging may be used for imaging such as PET / MRI.
- the radiochemical purity refers to the ratio of the presence of other radionuclides to the radionuclide of interest, and in the present invention, the RCP is [ 18 F] fluoro- with respect to the total radioactivity present in the sample. Expressed in% of waveguide activity.
- the present invention provides [ 18 F] fluoro-dopa; In case the total composition from about 5% to about 30% (V / V) of ethanol and 25 °C of concentrations, including the steps of mixing the buffer with a value of pKa 6 to 8.1, inhibit impurities generated for a predetermined period of time the [18 F] A method of preparing a composition for stabilizing the radiochemical purity of fluoro-dopa is provided. The same or similar description with respect to the composition is omitted herein.
- [ 18 F] fluoro-dopa (100% radiochemical purity) was prepared according to a known procedure (Appl. Radiat. Isot. 67 2009 1650-1653) and [ 18 F] fluoro-dopa prepared above
- the initial hydrogen ion concentration (100% of radiochemical purity) is 4. This was formulated with physiological saline, and the sodium ion concentration was adjusted to 6, 7, and 8, respectively, followed by HPLC (high performance liquid) every 0 hours, 2 hours, 4 hours, and 6 hours at room temperature (or room temperature). Chromatograph) was used to measure radiochemical purity, and the results are shown in Table 1.
- [ 18 F] FLT (100% radiochemical purity) was prepared according to known procedures (Eur. J. Nucl. Med. Mol. Imaging. 2007, 34, 1406-1409), formulated with physiological saline and bicarbonate at room temperature Adjust the hydrogen ion concentration to 6, 7, and 8 using sodium, and then use the HPLC (High Performance Liquid Chromatograph) at 0, 2, 4, and 6 hours at room temperature (or room temperature). Was measured, and the results are shown in Table 1.
- the numerical values in Table 1 are in units of hydrogen ion concentration and time, based on 100% of the radiochemical purity of each of the originally prepared [ 18 F] fluoro-dopa, [ 18 F] FDG and [ 18 F] FLT, respectively. Shows the change in radiochemical purity over time.
- [ 18 F] FDG of Comparative Example 1 and [ 18 F] FLT of Comparative Example 2 were formulated in physiological saline after synthesis and 90% even if time elapsed at neutral pH (pH 6-8). While it can be used as a radiopharmaceutical with the above radiochemical purity, the [ 18 F] fluoro-dopa of Experimental Example 1 rapidly decreases over time at a neutral pH (pH 6-8), resulting in a rapid decrease in radiochemical purity for 2 hours. Thereafter it showed radiochemical purity that cannot be used as a radiopharmaceutical. This was due to the characteristics of [ 18 F] fluoro-dopa, and non-enzymatic oxidation occurred at room temperature and neutral pH, and it was confirmed that it is not worth it as an anti-drug medicine after 2 hours.
- the first impurity (IMP 1) was produced when 2 hours had elapsed after neutralizing to pH 7 at room temperature, and after neutralizing to pH 7 at room temperature as shown in FIG. 2. After 6 hours, it was confirmed that the first impurity (IMP 1) and the second impurity (IMP 2) were produced.
- Table 1 after 2 hours of neutralization to pH 7 at room temperature, the radiochemical purity of [ 18 F] fluoro-dopa is 92.02%, and after 6 hours, it is significantly lowered to 63.81%. As time passed after neutralization, it was shown that impurities were generated due to oxidation of [ 18 F] fluoro-dopa, thereby reducing radiochemical purity.
- [ 18 F] fluoro-dopa (radiochemical purity of 100%) was prepared according to known procedures under conditions of hydrogen ion concentration 4 (Appl. Radiat. Isot. 67 2009 1650-1653), ethanol (purity 100 %) was purchased from Merck and used. Thereafter, the [ 18 F] fluoro-dopa was added to the prepared vial, and then 1.0%, 5.0%, 10.0%, 20.0% and 30.0% (v / v) of ethanol were added to the vial, respectively, relative to the total composition. Neutralize pH to 6, 7, and 8 using sodium bicarbonate, and neutralize pH by performing HPLC (High Performance Liquid Chromatograph) every 0 hours, 2 hours, 4 hours, and 6 hours, respectively. After that, the change in radiochemical purity of [ 18 F] fluoro-dopa according to ethanol content was examined.
- Table 2 The numerical values in Table 2 are shown in%, which shows the ethanol addition amount and the change in radiochemical purity over time based on 100% of the radiochemical purity of the originally prepared [ 18 F] fluoro-dopa.
- Table 3 The numerical values in Table 3 are shown in%, showing the ethanol addition amount and the change in radiochemical purity over time based on 100% of the radiochemical purity of the originally prepared [ 18 F] fluoro-dopa.
- Table 4 The numerical values in Table 4 are shown in%, which shows the ethanol addition amount and the change in radiochemical purity over time based on 100% of the radiochemical purity of the originally prepared [ 18 F] fluoro-dopa.
- FIG. 6 is a TLC chromatogram of [ 18 F] fluoro-dopa prepared by adding 10% of ethanol 1 hour after neutralization, and as shown in FIG. 6, a third impurity ([ 18 F] The production of fluoride, IMP3) could be confirmed.
- 7 is a diagram showing the results of Table 5 in the drawings, it can be seen that the difference in the amount of decrease in radiochemical purity in the case of cold storage and freezing storage and room temperature storage.
- [ 18 F] fluoro-dopa (radiochemical purity of 100%) was prepared according to a known procedure under a condition of hydrogen ion concentration 4, and added to a vial, 5.0% (v) of the total composition. / v) ethanol and a buffer having a value of pKa 6 to 8.1 at 25 ° C. and neutralized to pH 7 with sodium bicarbonate, followed by 0, 10, 20, 30, 60, 90,
- the production of the third impurity was confirmed by measuring radiochemical purity at 120, 180, 240, 300 and 360 minutes using HPLC (High Purity Liquid Chromatography) and TLC (Thin Film Chromatography). The results are shown in Table 6 below.
- the numerical values of the results in Table 6 are in%, showing the change in radiochemical purity according to the type of buffer added with ethanol based on 100% of the radiochemical purity of the originally prepared [ 18 F] fluoro-dopa.
- the sum of the HPLC measurement value and the TLC measurement value was expressed as the negative value at the initial radiochemical purity of 100%. This can finally confirm whether the production of the first and second impurities measured by HPLC and the third impurities measured by TLC is suppressed.
- the buffer having a value of pKa 6 to 8.1 at 25 ° C is PBS (PHOSPHATE BUFFERED SALINE), Citrate Buffer (CITRATE BUFFER), MES (2- (N-MORPHOLINO) ETHANESULFONIC ACID), BIS-TRIS (2,2 -BIS (HYDROXYMETHYL) -2,2 ', 2' '-NITRILOTRIETHANOL) Buffer, MOPSO (3-MORPHOLINO-2-HYDROXYPROPANESULFONIC ACID) Buffer, HEPES (4- (20HYDROXETHYL) -1-PIPERAZINEETHANSFULFONIC ACID) Buffer and TRIS (TRIS (HYDROXYMETHYL) AMINOMETHANE) and each of them was tested.
- Figure 9 shows the results of Table 6 above by using the ethanol and each buffer of the present invention, even after the storage time at room temperature after neutralization maintains the radiochemical purity of [ 18 F] fluoro-dopa at least 95% It was clearly confirmed that this was confirmed that this is the result of suppressing the production of the first to third impurities by ethanol and buffer.
- the present invention can be used in a composition for stabilizing the radiochemical purity of [ 18 F] fluoro-dopa and a method for preparing the same.
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US15/746,673 US20190134234A1 (en) | 2015-07-22 | 2016-07-22 | Composition for stabilizing radiochemical purity of [18f] fluoro-dopa and method for preparing same |
AU2016297308A AU2016297308B2 (en) | 2015-07-22 | 2016-07-22 | Composition for stabilizing radiochemical purity of [18F]fluoro-dopa and method for preparing same |
CN201680042474.XA CN107921152A (zh) | 2015-07-22 | 2016-07-22 | 使[18f]氟‑多巴的放射化学纯度稳定化的组合物及其制备方法 |
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KR1020160092604A KR101850479B1 (ko) | 2015-07-22 | 2016-07-21 | [18F]플루오로-도파의 중성 pH 안정화 방법 |
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