CN118045208A - Preparation method of fluorine-18 aluminum fluoride marked NOTA-octreotide - Google Patents
Preparation method of fluorine-18 aluminum fluoride marked NOTA-octreotide Download PDFInfo
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- CN118045208A CN118045208A CN202410056661.XA CN202410056661A CN118045208A CN 118045208 A CN118045208 A CN 118045208A CN 202410056661 A CN202410056661 A CN 202410056661A CN 118045208 A CN118045208 A CN 118045208A
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- nota
- octreotide
- fluorine
- medicine box
- freeze
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Links
- 229960002700 octreotide Drugs 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- IRPGOXJVTQTAAN-UHFFFAOYSA-N 2,2,3,3,3-pentafluoropropanal Chemical compound FC(F)(F)C(F)(F)C=O IRPGOXJVTQTAAN-UHFFFAOYSA-N 0.000 title claims abstract description 28
- KLZUFWVZNOTSEM-UHFFFAOYSA-K Aluminum fluoride Inorganic materials F[Al](F)F KLZUFWVZNOTSEM-UHFFFAOYSA-K 0.000 title claims abstract description 28
- YCKRFDGAMUMZLT-BJUDXGSMSA-N fluorine-18 atom Chemical compound [18F] YCKRFDGAMUMZLT-BJUDXGSMSA-N 0.000 title claims abstract 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 134
- 239000003814 drug Substances 0.000 claims abstract description 59
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- -1 fluorine-18 ions Chemical class 0.000 claims abstract description 27
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- 238000000034 method Methods 0.000 claims abstract description 18
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
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- 230000003471 anti-radiation Effects 0.000 claims abstract description 9
- 238000002386 leaching Methods 0.000 claims abstract description 9
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- 230000000536 complexating effect Effects 0.000 claims abstract description 3
- 238000001914 filtration Methods 0.000 claims abstract description 3
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical group OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 14
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 13
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 11
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical group [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
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- 235000010378 sodium ascorbate Nutrition 0.000 claims description 9
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 9
- 229960005055 sodium ascorbate Drugs 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
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- 239000008215 water for injection Substances 0.000 claims description 7
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 6
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- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical group [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 claims description 4
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Classifications
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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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
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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
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/121—Solutions, i.e. homogeneous liquid formulation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dispersion Chemistry (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention relates to a preparation method of fluorine-18 aluminum fluoride marked NOTA-octreotide, which comprises the following steps: preparing a freeze-dried medicine box from a NOTA-octreotide reagent required by synthesis, and storing the freeze-dried medicine box for preparing medicines; during the preparation of the medicine, fluorine-18 ions produced by the accelerator are transferred to a Mini-QMA column; taking the medicine box as a reaction bottle, and leaching fluorine-18 ions into the medicine box by using small-volume physiological saline; adding a small amount of absolute ethyl alcohol into the medicine box, heating and complexing, and evaporating the ethyl alcohol to obtain a medicine intermediate; directly purifying the prepared drug intermediate through a non-reversed phase chromatographic column, then adding the drug intermediate into a transfer bottle, adding an anti-radiation stabilizer, and then filtering through a sterile membrane to obtain 18 F-NOTA-octreotide injection. The preparation process is simple, the synthesis efficiency is 35-40%, the amplification purity of the final product is more than 95%, the ethanol content is lower than 3%, and the process ensures the effectiveness and the safety of 18 F-NOTA-octreotide.
Description
Technical Field
The invention belongs to the technical field of preparation of radiopharmaceuticals, and particularly relates to a preparation method of fluorine-18 aluminum fluoride marked NOTA-octreotide.
Background
Neuroendocrine tumors (NET) are tumors of the nervous and endocrine tissues characterized by excessive release of growth factors, cytokines, hormones or neurotransmitters. NET is difficult to find early, and more than half of patients have metastasized at diagnosis. Thus, early diagnosis, early treatment is critical for treating NET.
Somatostatin receptors (SSTR) are useful biomarkers in NET diagnostics, employing radiolabeled somatostatin analogs, and can be used for molecular imaging and targeted radionuclide therapy to treat unresectable neuroendocrine tumors, etc. Radiolabeled somatostatin receptor agonist (SSA) was at the earliest 111 In-spray peptide (pentetreot ide) followed by 99m Tc labeled EDDA/HYNIC-Tyr3-Octreot ide (Tektrotyd), but positron nuclide 68 Ga labeled SSA (68 Ga DOTA-octreotide) has gradually replaced 111 In-DTPA octreotide for use In NET patients for SSTR imaging. 68 Ga-labeled somatostatin analogues commonly used for PET imaging are: 68Ga-DOTA-TOC、68 Ga-DOTA-NOC and 68 Ga-DOTA-TATE, which are advantageous for clinical use, wherein 68 Ga-DOTA-TATE is very selective for SSTR 2, which is the most common of NETs, and therefore the nuclide therapeutic drug of NET is commonly used 177 Lu-DOTA-TATE, which was approved by European drug administration for the first time in 2017 and by the FDA in 2018. To accommodate 177 Lu-DOTA-TATE clinical treatment, the United states approved 68 Ga-DOTA-TOC/TATE for pre-treatment screening and post-treatment evaluation. A number of units in China have developed the diagnosis of 68 Ga-DOTA-Octreot ide/TATE, and have developed the registered clinical study of 177 Lu-DOTA-TATE, and it is expected that PET/CT scanning for NET will be a new growth point for imaging medicine.
However, 68 Ga has a short half-life (67.7 minutes) and is not suitable for commercial delivery; there are also the problems of low production lot yields of 68 Ga (up to 50 mCi) and high costs of 68Ge/68 Ga generators. Compared with gallium-68, fluorine-18 has obvious advantages, besides a large amount of fluorine-18 can be produced by a medical cyclotron and the half life period is long (109.8 minutes), the positron energy of the fluorine-18 is lower than that of the gallium-68, and the PET image of the fluorine-18 is obviously superior to that of the gallium-68. Clinically, 18 F is gradually adopted to replace the original 68 Ga-marked positron polypeptide radiopharmaceuticals.
The current method for labeling octreotide with fluorine-18 is aluminum fluoride complexation [ J Nucl Med.2010;51:454-6, i.e., a method in which fluorine-18 is strongly bound to aluminum ions by chelating agents to form [ 18 F ] AlF. Studies have shown that: [ 18 F ] AlF-NOTA-octreotide has the same high affinity for SSTR in vitro; has good in vivo stability. The labeling and clinical (comparison-containing) research work of [ 18 F ] AlF-NOTA-octreotide are sequentially carried out at home and abroad. Acetic acid is adopted as a buffer system in China, marked in an acetonitrile organic phase, purified by HPLC, and subjected to solid-phase extraction by a reversed phase C-18 column to obtain [ 18 F ] AlF-NOTA-NOC [ Cl in Nucl Med.2019 ] containing 13.3% ethanol; 44:452-8); the full-automatic synthesis of [ 18 F ] AlF-NOTA-NOC under the GMP condition is reported abroad, an acetic acid buffer system is adopted, fluoride ions and aluminum ions are reacted in advance, then precursors are added, the precursors are marked in an ethanol organic phase, and the precursors are directly subjected to solid-phase extraction by a reversed-phase C-18 column to obtain a final product [ EJNMMI Radiopharmacy and Chemi try.2020,5:4 ] containing 10% ethanol. However, the preparation process and the purification process of the F-18 octreotide have the following problems:
(1) In all literature reported 18 F labeled NOTA-octreotide procedures, all reagents required are added on site, and trace amounts of aluminum trichloride (generally below 10 mu L), NOTA-octreotide (generally 200 micrograms), buffer (generally acetic acid) and the like are added into a reagent bottle or a reaction tube before synthesis; aluminum trichloride is a sensitive reagent, and can be hydrolyzed into aluminum hydroxide precipitate in water to be invalid; furthermore, aluminum fluoride-labeled polypeptides are pH sensitive reactions, typically requiring a pH between 4.0 and 4.5; the buffer solution added on site is easy to cause pH drift, so that the efficiency and the product quality repeatability of each synthesis are poor; meanwhile, various reagents are operated on site, and errors are easy to occur.
(2) The aluminum fluoride labeled polypeptide is a reaction with higher requirement on the water phase content, and in order to improve the labeling synthesis efficiency, an organic phase is added into a system of the labeled polypeptide so as to reduce the water content; however, 18 F ions require washing them from QMA (anion exchange column) with physiological saline; whereas the volume of the commercial Light-QMA aqueous rinse solution is 0.4-1.0mL, the aqueous phase of this volume will significantly affect the synthesis efficiency;
(3) The current aspect reports two purification modes for preparing 18 F-labeled NOTA-octreotide, ① is based on separation of acetonitrile as mobile phase under High Pressure Liquid Chromatography (HPLC) [ Cl in Nucl Med.2019; 44:452-8), collecting the product, and then converting the acetonitrile phase into an ethanol phase by using a reverse phase extraction column for the second solvent conversion; the method has the advantages of high chemical purity and radiochemical purity after HPLC separation, but has two disadvantages: firstly, the HPLC separation takes a long time, the HPLC column adsorbs the product, and the synthesis efficiency is low; secondly, the final product is leached from the reverse phase column by ethanol, the ethanol content is more than 10 percent, and the injection with high ethanol has great stimulation to veins and is unsafe to use; ② Direct purification based on reversed-phase C-18 column [ EJNMMI Radiopharmacy and chemistry.2020,5:4 ], direct reversed-phase C-18 column chromatography purification has the advantages of simple method, but obviously contains fluorine-18 ions in the product, the product has low release purity, the ethanol content is 10 percent, and the same is higher, which is unfavorable for clinical application;
(4) 18 F labeled NOTA-octreotide is the same as other positron medicine radiopharmaceuticals, and the product is unstable in vitro due to high-energy gamma rays and large dosage, and an anti-radiation stabilizer is generally added after preparation, such as: ethanol, ascorbic acid, gentisic acid, and the like. Because the radioactive dose of the conventional preparation is very large and exceeds 200mCi, the radiation dose of operators can be increased by manually adding the radiation-resistant stabilizer after the preparation; automatic addition can be designed, but it complicates the synthesis equipment, and thus a simple and effective solution is highly desirable.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of fluorine-18 aluminum fluoride marked NOTA-octreotide, which has the advantages of simple process, high synthesis efficiency, high final product purity and low ethanol content.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
a method for preparing fluorine-18 aluminum fluoride marked NOTA-octreotide, comprising the following steps:
Preparing a freeze-dried kit for storage for preparing a medicine from a NOTA-octreotide reagent required for synthesis, wherein the NOTA-octreotide reagent comprises the following components: precursor NOTA-octreotide, aluminum trichloride, buffer;
During the preparation of the medicine, fluorine-18 ions produced by the accelerator are transferred to a Mini-QMA column;
Taking the medicine box as a reaction bottle, and leaching fluorine-18 ions into the medicine box by using small-volume physiological saline;
adding a small amount of absolute ethyl alcohol into the medicine box, heating and complexing, and evaporating the ethyl alcohol to obtain a medicine intermediate;
directly purifying the prepared drug intermediate through a non-reversed phase chromatographic column, then adding the drug intermediate into a transfer bottle, adding an anti-radiation stabilizer, and then filtering through a sterile membrane to obtain 18 F-NOTA-octreotide injection.
Further, the preparation method of the fluorine-18 aluminum fluoride marked NOTA-octreotide comprises the steps of preparing a freeze-drying medicine box in batches in advance, preparing 150-250 mug of precursor NOTA-octreotide, 15-40 mug of aluminum trichloride and 5-25 mg of buffer into an aqueous solution, adding 5-20 mg of anti-radiation stabilizer (preventing high-dose rays from carrying out radiation decomposition on products in the synthesis process), adjusting the pH value, then placing the freeze-drying medicine box in a freeze vacuum dryer for low-temperature dehydration to form powder, and packaging the powder into the freeze-drying medicine box for low-temperature storage.
Furthermore, the buffering agent adopts potassium hydrogen phthalate, the radiation-resistant stabilizer adopts sodium ascorbate, and the pH value is regulated to be between 4.0 and 4.5 by sodium acetate.
Further, according to the method for producing a fluorine-18 aluminum fluoride-labeled NOTA-octreotide as described above, wherein the Mini-QMA column is a column in which an anion exchange resin in QMA is packed in a small column, and the amount of the anion exchange resin is 20 to 100mg.
Further, the preparation method of the fluorine-18 aluminum fluoride marked NOTA-octreotide comprises the following steps of, wherein the small volume of normal saline is 0.2-0.4 mL of normal saline or 0.4-0.6 mL of ethanol/normal saline mixed solution, and the volume ratio of ethanol to normal saline is 1:1.
Further, the preparation method of the fluorine-18 aluminum fluoride marked NOTA-octreotide comprises the step of controlling the ethanol content of a final product to be below 3% through negative pressure or introducing ethanol in a nitrogen evaporation system after the heating complexation reaction.
Further, the preparation method of the fluorine-18 aluminum fluoride marked NOTA-octreotide as described above, wherein the component of the non-reversed phase chromatographic column is aluminum oxide or a mixture of aluminum oxide and QMA anion exchange resin; the alumina column can be independently used, and the alumina and QMA anion exchange resin columns can be connected in series for use; the loading of the aluminum oxide is between 500 mg and 800 mg, and the ratio of the column length to the column diameter is (10-50): 1.
Further, in the preparation method of the fluorine-18 aluminum fluoride marked NOTA-octreotide, the radiation-resistant stabilizer which is added into the transfer bottle in advance can be gentisic acid or sodium ascorbate (30-700 mg), and the concentration of the final product is 2-50 mg/mL.
Further, the preparation method of the fluorine-18 aluminum fluoride marked NOTA-octreotide comprises the following steps:
(1) The NOTA-octreotide reagent freeze-dried medicine box, ethanol, normal saline and 8-16 mL of water for injection are arranged on a synthesis module;
(2) Transferring fluorine-18 ions from the accelerator to a Mini-QMA column of a fluorine-18 ion capturing and releasing module;
(3) Leaching the Mini-QMA column by using 0.4-0.6 mL of ethanol/normal saline mixed solution, so that fluorine-18 ions directly enter a NOTA-octreotide reagent freeze-dried medicine box;
(4) Adding 0.5-1.5 mL of absolute ethyl alcohol into the freeze-drying medicine box;
(5) Heating the freeze-dried medicine box to 100 ℃ and maintaining for 8-15 min;
(6) Heating the freeze-dried medicine box bottle under negative pressure or heating and introducing nitrogen, and evaporating ethanol to 0.1-0.3 mL;
(7) Adding water for injection into the freeze-dried medicine box for 2 to 3 times, and directly purifying by a non-reversed phase chromatographic column; the non-reversed phase chromatographic column comprises a mixture of aluminum oxide and QMA, or two columns are used in series, or aluminum oxide columns are independently used;
(8) And (3) putting the purified product into a transfer bottle, adding gentisic acid or ascorbic acid sodium salt aqueous solution with the concentration of 2-50 mg/mL on line, and obtaining the final 18 F-NOTA-octreotide injection after the mixed solution passes through a sterile filter membrane.
The beneficial effects of the invention are as follows:
The NOTA-octreotide freeze-dried medicine box provided by the invention is suitable for batch production, reduces the workload during marking, and also increases the stability between batch preparations, and the medicine box can be stored for one year at 4 ℃; the NOTA-octreotide freeze-dried medicine box is used as a reaction bottle, so that the loss and the workload of reagent transfer are reduced; the Mini-QMA column is used for replacing the conventional Ligh-QMA to capture/release fluorine-18, so that the water proportion in a reaction system can be reduced, and the conventional synthesis efficiency is improved from 25% to 35-40%; in the purification process, the non-reversed phase chromatographic column is adopted for direct purification, so that the synthesis step can be simplified, the synthesis success rate can be improved, and the ethanol of a final product can be obviously reduced by combining with evaporating ethanol; the radiation dose of the staff can be reduced by the method of adding the radiation-resistant stabilizer to the medium rotary bottle on line. The synthesis efficiency of the preparation process is 35-40%, the amplification purity of the final product is more than 95%, the ethanol content is less than 3%, and the storage stability of the product at room temperature is more than 8 hours.
Drawings
FIG. 1 is a flow chart of a preparation method of the fluorine-18 aluminum fluoride marked NOTA-octreotide;
FIG. 2 is a Radio-HPLC plot of 18 F-NOTA-octreotide prepared in accordance with the present invention;
FIG. 3 is a Radio-TLC diagram of 18 F-NOTA-octreotide prepared according to the present invention;
FIG. 4 is a PET/CT image of 18 F-NOTA-octreotide prepared according to the present invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
As shown in fig. 1, the invention provides a preparation method of fluorine-18 aluminum fluoride marked NOTA-octreotide, the used reagents comprise NOTA-octreotide, fluorine-18 ions, aluminum trichloride, a buffer and ethanol, the steps comprise a preparation process and a purification process, the preparation process directly uses a NOTA-octreotide freeze-drying kit (powder of a precursor, aluminum trichloride and the buffer in a whole), a Mini-QMA column to capture/release fluorine-18, and heating for complexation reaction, and heating for evaporating ethanol after the reaction is finished; the purification process is that the drug intermediate is directly purified by a non-reversed phase chromatographic column, and then a 18 F-NOTA-octreotide injection product is obtained by a sterile membrane after a medium-rotating bottle of an anti-radiation stabilizer is added on line. The synthesis efficiency of the preparation method provided by the invention is 35% -40%, the final product is more than 95% pure, the ethanol content is lower than 3%, and the storage stability of the product at room temperature is more than 8 hours.
First, reagents for synthesizing the desired NOTA-octreotide: the precursor NOTA-octreotide, aluminum trichloride, buffer and the like are prepared into a freeze-drying medicine box. The freeze-dried medicine box is prepared in batches in advance, namely a buffer agent of NOTA-octreotide precursor (150-250 mug), aluminum trichloride (15-40 mug) and potassium hydrogen phthalate (5-25 mg) is prepared into an aqueous solution, sodium ascorbate (5-20 mg) is added as an anti-radiation stabilizer, and sodium acetate is used for regulating the pH value to 4.0-4.5. The chemical quantity required by a single dose can be amplified by 20 times or more (1000 bottles in a batch), divided into 20 ampoule bottles of 10mL, and placed in a freeze vacuum drier for low-temperature dehydration into powder. The lyophilized kit can reduce errors during temporary handling, improve stability between batch preparations, and can be used as a reaction bottle for the next step to reduce handling and loss of reagent transfer.
The invention uses Mini-QMA column to replace conventional Ligh-QMA to capture/release fluorine-18, wherein the Mini-QMA column is that anion exchange resin in QMA is arranged in Mini small column, and the anion exchange resin is arranged on a clamping sleeve of a synthesis module, and the amount of the anion exchange resin in the Mini small column is 20-100 mg. Leaching fluorine-18 ions by using small-volume physiological saline, wherein the small-volume physiological saline is 0.2-0.4 mL physiological saline or 0.4-0.6 mL ethanol/physiological saline mixed solution, and the volume ratio of ethanol to physiological saline is 1:1. the water content in the reaction system can be obviously reduced by leaching the fluorine-18 ions with small-volume physiological saline, and the conventional 0.4-0.6 mL is reduced to 0.2mL.
The invention takes the medicine box directly as a reaction bottle, the leached fluorine-18 ions enter the medicine box, then a small amount of absolute ethyl alcohol is added into the medicine box, after the system is heated and complexed, the ethanol content in the reaction system is reduced by negative pressure or introducing ethanol in a nitrogen evaporation system, so that the ethanol content of the final product is controlled below 3%.
Then, directly purifying the prepared intermediate by a non-reversed phase chromatographic column (the conventional method is to use a reversed phase extraction column, adsorb the intermediate on the reversed phase column, then use ethanol to leach the product), and the purification by the non-reversed phase chromatographic column has the advantages of simplicity and rapidness; the crude product is directly purified by a non-reversed phase chromatographic column, and impurities in the preparation of the product by adsorption of the product through an aluminum oxide column and QMA (quality control analysis) are as follows: fluorine-18 ions and aluminum ions, the product is adsorbed in a small amount, but the product can be leached out by water for injection later; small amounts of fluoride ions in the product are adsorbed by QMA. The key of the process is the amount of the alumina column and the ratio of the column length to the column diameter, wherein the amount of the alumina column is between 500 mg and 800 mg, and the ratio of the column length to the column diameter is (10-50): 1. the QMA column is a commercial Light QMA or Plus QMA column. The aluminum oxide columns can be independently used, and the two columns can be connected in series for use.
Directly purifying the prepared drug intermediate by a non-reversed phase chromatographic column, then adding into a transfer bottle, adding an anti-radiation stabilizer, namely gentisic acid or sodium ascorbate, into the transfer bottle on line, and obtaining an injection product by passing through a sterile membrane, wherein the concentration of the gentisic acid or sodium ascorbate is 2-50 mg/mL. The radiation dose of workers can be reduced by adopting an online adding mode, and meanwhile, the product is stable for more than 8 hours at room temperature.
The following describes a specific preparation process of the fluorine-18 aluminum fluoride labeled NOTA-octreotide (TATE is adopted below) drug, which comprises the following steps:
(1) An ampoule containing 200 micrograms of NOTA-TATE freeze-dried drug (the ampoule also contains 25 micrograms of aluminum trichloride, 10 milligrams of sodium ascorbate and 10 milligrams of potassium hydrogen phthalate) is mounted on a synthesis module;
(2) 0.2mL of physiological saline solution or 0.4mL of ethanol/physiological saline (50:50V: V) mixed solution, 1mL of absolute ethanol, and 10mL of water for injection are mounted on a synthesis module;
(3) Delivering fluorine-18 ions produced by the accelerator to a Mini-QMA column of a synthesis module, and separating the fluorine-18 ions from raw material oxygen-18 water;
(4) Starting a synthesis module, and automatically running equipment; leaching fluorine-18 ions from the Mini-QMA column into an ampoule of NOTA-TATE freeze-dried medicine by using leaching solution;
(5) 1.0mL of absolute ethanol is added into the ampoule;
(6) Heating the ampoule to 100deg.C for 12min;
(7) Heating the ampoule under negative pressure, and evaporating ethanol until 0.1-0.3 mL of liquid remains in the ampoule;
(8) 5mL of water for injection was added to the ampoule to dilute, and the mixture was directly purified by a column of aluminum oxide (700 mg, column length/column diameter ratio 20) and Plus-QMA; the purified liquid was collected in a medium-rotating bottle containing 150 mg of sodium ascorbate;
(9) The liquid in the medium rotary bottle is filtered by a sterile filter membrane to obtain the final 18 F-NOTA-TATE injection; the synthetic efficiency is measured to be between 35 and 45 percent.
18 F-NOTA-TATE is subjected to Radio-HPLC quality control, and shows double peaks on HPLC, and the radiochemical purity is more than 95 percent (shown in figure 2); radio-TLC indicated less than 3% free fluorine-18 ions (as shown in figure 3); GC headspace confirmed ethanol content below 3%.
Clinical results prove that the effect of the final product is consistent with the preparation effect of an HPLC separation method, radioactivity is mainly distributed in the liver, the spleen and the kidney, and bone nonspecific ingestion is not seen; the pancreas had a pronounced radioconcentration, which was the tumor focus (see fig. 4).
Other embodiments of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application disclosed herein. This application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains. Thus, if such modifications and application adaptations to the present application fall within the scope of the claims and their equivalents, the present application is intended to include such modifications and application adaptations as well.
The above embodiments are merely illustrative of the present invention, and the present invention may be embodied in other specific forms or with other specific forms without departing from the spirit or essential characteristics thereof. The described embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. The scope of the invention is indicated by the appended claims, and any changes that are equivalent to the purview and scope of the claims are intended to be embraced therein.
Claims (10)
1. A method for preparing fluorine-18 aluminum fluoride marked NOTA-octreotide, which is characterized by comprising the following steps:
Preparing a freeze-dried kit for storage for preparing a medicine from a NOTA-octreotide reagent required for synthesis, wherein the NOTA-octreotide reagent comprises the following components: precursor NOTA-octreotide, aluminum trichloride, buffer;
During the preparation of the medicine, fluorine-18 ions produced by the accelerator are transferred to a Mini-QMA column;
Taking the medicine box as a reaction bottle, and leaching fluorine-18 ions into the medicine box by using small-volume physiological saline;
adding a small amount of absolute ethyl alcohol into the medicine box, heating and complexing, and evaporating the ethyl alcohol to obtain a medicine intermediate;
directly purifying the prepared drug intermediate through a non-reversed phase chromatographic column, then adding the drug intermediate into a transfer bottle, adding an anti-radiation stabilizer, and then filtering through a sterile membrane to obtain 18 F-NOTA-octreotide injection.
2. The preparation method of fluorine-18 aluminum fluoride marked NOTA-octreotide according to claim 1, wherein the freeze-drying medicine box is prepared in batches in advance, 150-250 mug of precursor NOTA-octreotide, 15-40 mug of aluminum trichloride and 5-25 mg of buffering agent are prepared into aqueous solution, 5-20 mg of anti-radiation stabilizer is added, the pH value is regulated, and then the aqueous solution is placed in a freeze vacuum dryer for low-temperature dehydration to form powder, and the powder is packaged into the freeze-drying medicine box for low-temperature storage.
3. The method for preparing fluorine-18 aluminum fluoride marked NOTA-octreotide according to claim 2, wherein the buffer agent is potassium hydrogen phthalate, the radiation-resistant stabilizer is sodium ascorbate, and the pH value is adjusted to be between 4.0 and 4.5 by sodium acetate.
4. The method for producing fluorine-18 aluminum fluoride labeled NOTA-octreotide according to claim 1, wherein the Mini-QMA column is packed with an anion exchange resin in QMA in an amount of 20 to 100mg.
5. The method for preparing fluorine-18 aluminum fluoride marked NOTA-octreotide according to claim 1, wherein the small volume of physiological saline is 0.2-0.4 mL of physiological saline or 0.4-0.6 mL of ethanol/physiological saline mixed solution, and the volume ratio of ethanol to physiological saline is 1:1.
6. The method for preparing fluorine-18 aluminum fluoride marked NOTA-octreotide according to claim 1, wherein after the heating complexation reaction, ethanol of the final product is controlled to be below 3% by negative pressure or introducing ethanol in a nitrogen evaporation system.
7. A method of preparing a fluorine-18 aluminum fluoride labeled NOTA-octreotide as claimed in claim 1, wherein the non-reversed phase chromatography column comprises aluminum oxide or a mixture of aluminum oxide and QMA anion exchange resin; the alumina column can be independently used, or the alumina and the QMA anion exchange resin can be used in series.
8. The method for producing a fluorine-18 aluminum fluoride labeled NOTA-octreotide as claimed in claim 7, wherein the amount of aluminum oxide to be charged is 500 mg to 800 mg, and the ratio of column length to column diameter is (10 to 50): 1.
9. The method of claim 1, wherein the radiation-resistant stabilizer added to the bottle is gentisic acid or sodium ascorbate, and the final product has a concentration of 2-50 mg/mL.
10. A method for preparing a fluorine-18 aluminum fluoride labeled NOTA-octreotide as claimed in any one of claims 1 to 9, wherein the process for preparing the medicament comprises the steps of:
(1) The NOTA-octreotide reagent freeze-dried medicine box, ethanol, normal saline and 8-16 mL of water for injection are arranged on a synthesis module;
(2) Transferring fluorine-18 ions from the accelerator to a Mini-QMA column of a fluorine-18 ion capturing and releasing module;
(3) Leaching the Mini-QMA column by using 0.4-0.6 mL of ethanol/normal saline mixed solution, so that fluorine-18 ions directly enter a NOTA-octreotide reagent freeze-dried medicine box;
(4) Adding 0.5-1.5 mL of absolute ethyl alcohol into the freeze-drying medicine box;
(5) Heating the freeze-dried medicine box to 100 ℃ and maintaining for 8-15 min;
(6) Heating the freeze-dried medicine box bottle under negative pressure or heating and introducing nitrogen, and evaporating ethanol to 0.1-0.3 mL;
(7) Adding water for injection into the freeze-dried medicine box for 2 to 3 times, and directly purifying by a non-reversed phase chromatographic column; the non-reversed phase chromatographic column comprises a mixture of aluminum oxide and QMA, or two columns are used in series, or aluminum oxide columns are independently used;
(8) And (3) putting the purified product into a transfer bottle, adding gentisic acid or ascorbic acid sodium salt aqueous solution with the concentration of 2-50 mg/mL on line, and obtaining the final 18 F-NOTA-octreotide injection after the mixed solution passes through a sterile filter membrane.
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