CN117159753A - Preparation method and application of radiolabeled Evansi blue derivative drug - Google Patents

Preparation method and application of radiolabeled Evansi blue derivative drug Download PDF

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CN117159753A
CN117159753A CN202311356940.XA CN202311356940A CN117159753A CN 117159753 A CN117159753 A CN 117159753A CN 202311356940 A CN202311356940 A CN 202311356940A CN 117159753 A CN117159753 A CN 117159753A
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solution
reaction
formula
radionuclide
stabilizer
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田佳乐
郝晋
杜泽天
阳国桂
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Beijing Cotimes Biotech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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Abstract

The application relates to a preparation method of a radiopharmaceutical aqueous solution, which comprises a complex formed by a targeting molecule modified by an Evan Blue (EB) fragment and a radioactive metal nuclide and a stabilizer, wherein the stabilizer is preferably one or more of gentisic acid, ethanol and methionine.

Description

Preparation method and application of radiolabeled Evansi blue derivative drug
The present application is the divisional application of the application patent application with the application date of 2022, 4-month and 20-day, the application number of 202210416293.6 and the application name of 'the preparation method and the application of the radiolabeled Evan blue derivative drug'.
Technical Field
The application relates to a radiopharmaceutical aqueous solution with high chemical stability and high radiochemical stability and a preparation method thereof, in particular to a radionuclide complex modified by an Evan Blue (EB) fragment.
Background
Radionuclide-labeled compounds are a modern reagent widely used in the technical field of isotope labeling in many disciplines. The generation of diagnostic or therapeutic effects based on the arrival of radionuclides at the tumor site to emit particles or radiation is one of the main directions of application of radiopharmaceuticals. When administered to a tumor patient, the radiopharmaceuticals are delivered to the tumor cells due to the property of their carrier molecules to specifically target a target, and diagnostic effects are achieved by monitoring, locating, grading, etc. the tumor by capturing radioactive signals in vitro, or by killing the tumor cells by the energy released during the radionuclide decay process, while avoiding to a maximum extent adverse effects of particles or rays on healthy tissue in the vicinity of the tumor.
However, as radionuclides continue to decay to release energetic particles or rays, the covalent bonds of the molecules in the pharmaceutical formulation break during production and storage of the radiopharmaceutical, a phenomenon known as radiolysis, also known as radiolysis. Radiation degradation will result in an increase in chemical and radiochemical impurities in the radiopharmaceutical formulation, i.e., a decrease in chemical and radiochemical purity of the pharmaceutical active ingredient (API). Radiolytic impurities, particularly radiolytic impurities, can increase the noise signature of the diagnostic radiopharmaceutical, cause insufficient therapeutic efficacy of the therapeutic radiopharmaceutical, and can cause unnecessary radiation damage to other normal tissues. This also makes the radiolysis problem a significant problem in the development of radiopharmaceuticals. This affects the effectiveness and usability of the drug to a large extent. How to effectively maintain the stability of the API and reduce the generation of radiolytic impurities becomes a problem to be solved by the technicians in the field.
Evan's blue is an azo dye, which is commonly used for the detection of blood brain barrier integrity, vascular permeability, blood volume and cellular activity due to its high affinity for serum albumin. The structural fragment of the Evan's blue dye molecule is used for carrying out structural modification on a targeting molecule (such as DOTATATE, PSMA-617, etc.), and the obtained Evan's blue derivative molecule such as DOTA-EB-TATE, EB-PSMA, etc. can be used as a reversible carrier of a drug molecule by carrying out reversible combination of the molecule and endogenous serum albumin, so as to prolong the half life of the drug molecule in blood. The literature (Bioconjugate chem.2018,29, 3213-3221) reports that the Evan's blue derivative has longer in vivo circulation half-life, higher tumor uptake rate and longer retention time in tumor, and can further improve the curative effect of the drug, reduce the dosage and frequency of administration and reduce the toxicity of the drug due to the prolonged in vivo half-life.
The structural formula of the Evan blue dye is shown in a formula VI:
the relatively large molecular weight of the Evan's blue fragment and the linking group (Linker) introduced in the molecular structure of the drug greatly affects the physicochemical properties of the molecule, making aqueous drug solutions containing Evan's blue derivatives more challenging in the research of prescription processes. For example, PLUVLCTO, a drug for treating PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) TM (lutetium Lu 177vipivotide tetraxetan) in the injection, the pharmaceutically active ingredient (API) is [ 177 Lu]Lu-PSMA-617, stabilizer 0.39mg/mL gentisic acid, 50.0mg/mL sodium ascorbate. In use Evan blue fragment pair [ 177 Lu]Structural modification of Lu-PSMA-617, and the resultant fractionSon [ 177 Lu]Stability Properties of Lu-EB-PSMA [ [ Co., ltd.) 177 Lu]The addition of ascorbic acid and its salts, which are totally different from Lu-PSMA-617, not only does not act as a stabilizer, but it accelerates instead [ 177 Lu]Radiolysis of Lu-EB-PSMA.
There is currently no commercial collection of radiopharmaceuticals comprising an evans blue derivative for the radiation treatment and/or diagnosis of tumors. Thus, there remains a need to develop stable formulations and suitable production processes for aqueous pharmaceutical solutions comprising Evan's blue derivatives that provide higher initial radiochemical purity, and that are capable of maintaining the stability of radiopharmaceuticals over longer periods of time.
Disclosure of Invention
The application aims to provide a preparation method and application of a radiopharmaceutical aqueous solution, wherein an active ingredient in the radiopharmaceutical aqueous solution is a complex formed by a targeting molecule modified by an Evan Blue (EB) fragment and a radionuclide. In particular, the application relates to the following:
1. a method of preparing an aqueous radiopharmaceutical solution comprising a complex of a radionuclide and an evans blue derivative molecule, comprising the steps of:
mixing a solution containing a first stabilizer with a solution containing a radionuclide in a reaction container;
after a given time, adding a solution containing the evans blue derivative molecules to the reaction vessel, preferably the given time is 0.1 minutes to 20 minutes, more preferably 3 minutes to 10 minutes;
the Evan blue derivative molecule reacts with a radionuclide to obtain a radionuclide complex;
adding a solution containing a second stabilizer to the reaction vessel after a given period of reaction;
recovering the resulting aqueous radiopharmaceutical solution;
wherein the Evan's blue derivative molecule is a compound shown in a formula I or pharmaceutically acceptable ester, amide, solvate, salt thereof, or salt of a compound shown in a formula I or pharmaceutically acceptable ester thereof, or salt of a compound shown in a formula I or pharmaceutically acceptable amide thereof, or solvate of a compound shown in a formula I or pharmaceutically acceptable ester thereof, or solvate of a compound shown in a formula I or pharmaceutically acceptable amide thereof, or solvate of a compound shown in a formula I or pharmaceutically acceptable salt thereof,
Wherein,
L 1 is- (CH) 2 ) m Wherein m is an integer from 0 to 12, wherein each CH 2 Can be independently used as-O-, -NH (CO), -or- (CO) NH-substitution, provided that there are no two adjacent CH 2 The groups are replaced;
L 2 is C 1 -C 60 A linking group, a group attached to the base, optionally comprising-O-, -S-, S S (O) -S (O) 2 —、—N(R)—、—C(＝O)—、—C(＝O)O—、—OC(＝O)—、—N(R)C(＝O)—、—C(＝O)N(R)—、—OC(＝O)O—、—N(R)C(＝O)O—、—OC(＝O)N(R)—、Wherein each R is H or C 1 -C 6 An alkyl group;
L 3 is- (CH) 2 ) n Wherein n is an integer from 0 to 12, wherein each CH 2 Can be independently used as-O-, -NH (CO), -or- (CO) NH-substitution, provided that there are no two adjacent CH 2 The groups are replaced;
ch is a chelating group;
tg is a targeting group.
2. The method of item 1, wherein the radionuclide is selected from the group consisting of 177 Lu、 99m Tc、 68 Ga、 64 Cu、 67 Cu、 111 In、 86 Y、 90 Y、 89 Zr、 186 Re、 188 Re、 153 Sm、 82 Rb、 166 Ho、 225 Ac、 212 Pb、 213 Bi. 212Bi or 227Th.
3. The method of item 1, wherein Ch in formula I is selected from Preferably +.>
4. The method according to claim 1, wherein Tg in formula i is selected from a group of compounds capable of targeting somatostatin receptors (SSTR), prostate Specific Membrane Antigen (PSMA), fibroblast Activation Protein (FAP), folate Receptor (FR), epidermal growth factor receptor or integrins.
5. The method according to item 1, wherein the Evan's blue derivative molecule is selected from the group consisting of compounds of formula II, formula III, formula IV or formula V,
6. The method of any one of claims 1-5, wherein the radionuclide-containing solution is added to the reaction container after being removed from a source bottle, the method further comprising:
and flushing the raw material bottle with flushing liquid, and transferring the flushed solution into the reaction container to be mixed with the solution containing the radionuclide.
7. The method according to claim 6, wherein the flushing liquid is an aqueous solution, preferably selected from the group consisting of a solution containing a first stabilizer, a solution containing a buffer salt, water or sodium chloride injection; more preferably, the rinsing with rinsing liquid is repeated one or more times.
8. The method according to claim 1, characterized in that in the step of reacting the evans blue derivative molecule with a radionuclide, the molar ratio between the evans blue derivative molecule and the radionuclide is between 1.5 and 50, preferably between 5 and 20.
9. The method according to claim 1, wherein in the step of reacting the evans blue derivative molecule with a radionuclide, the reaction temperature is 50-100 ℃, preferably 60-80 ℃, and the reaction time is 5-60 minutes, preferably 10-30 minutes.
10. The method according to claim 1, wherein the first stabilizer is selected from one or more of gentisic acid and salts thereof, ascorbic acid and salts thereof, histidine, cysteine and salts thereof, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid.
11. The method according to item 10, wherein in the step of reacting the evans blue derivative molecule with a radionuclide, the concentration of the first stabilizer in the reaction phase solution is 0.6-20.0mg/mL.
12. The method according to claim 1, wherein the second stabilizer is selected from one or more of gentisic acid and its salts, ascorbic acid and its salts, histidine, cysteine and its salts, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid, ethanol or methionine.
13. The method of claim 12, wherein the concentration of the second stabilizing agent in the aqueous radiopharmaceutical solution is 0-400mg/mL.
14. The method according to claim 1, wherein a buffer salt solution is added before the reaction of the evans blue derivative molecule with the radionuclide, preferably the buffer salt solution is present in the solution containing the first stabilizer.
15. The method according to claim 14, wherein the buffer salt solution is selected from acetate, citrate, phosphate or formate solutions, preferably acetic acid-sodium acetate buffer salt solution.
16. The method of claim 1, wherein the step of adding a solution comprising a second stabilizer to the reaction vessel after a given period of time of the reaction further comprises adding a co-solvent to the reaction vessel.
17. The method according to claim 16, wherein the cosolvent is selected from one or more of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, polyoxyethylated castor oil, span, ethanol, propylene glycol, glycerol, polyethylene glycol (average molecular weight 200-8000), sorbitol, dimethyl sulfoxide, sodium dodecyl sulfate, preferably polysorbate 80.
18. The method of claim 1, wherein the step of adding a solution comprising a second stabilizer to the reaction vessel after a given period of reaction further comprises adding a free nuclide chelating agent to the reaction vessel, the chelating agent being selected from pentetic acid and salts thereof, preferably pentetic acid.
19. The method of any one of claims 1 to 18, further comprising filter sterilizing the aqueous radiopharmaceutical solution through a 0.22 μm filter, preferably after adding the solution comprising the second stabilizer.
20. The method according to any one of claims 1 to 19, further comprising diluting the aqueous radioactive solution, preferably by adding sodium chloride injection after adding the solution comprising the second stabilizer.
21. An aqueous radiopharmaceutical solution prepared by the method of any one of claims 1 to 20.
Effects of the application
The radionuclide complex provided by the application has the following beneficial effects:
in the application, the concentration of gentian acid in the reaction phase solution is controlled to be 0.6-20.0mg/mL. Below 0.6mg/mL, the radiolysis resistance of gentisic acid is insufficient, and above 20.0mg/mL, high concentration of gentisic acid delays the kinetics of the reaction, disadvantageously extending the time required for the reaction. The control range is to reduce the concentration of gentian acid as much as possible on the premise of ensuring the stability of the solution so as to avoid adverse effects on the reaction kinetics.
Before the solution containing the Evan's blue derivative molecules is mixed with the nuclide solution, the nuclide solution is mixed with the solution containing the first stabilizer, and after a given time, the solution containing the Evan's blue derivative molecules is added, so that the first stabilizer is fully contacted with the nuclide solution, a large amount of free radicals brought by radiation decomposition in the nuclide solution are quenched, thereby protecting the Evan's blue derivative molecules added into a reaction system after protection from being attacked by active free radicals, and ensuring the initial amplification purity of the product. The process can lead the initial amplification purity to reach 95.0-99.5%, and the initial amplification purity of the product obtained by the synthesis process of directly mixing the solution containing the Evan's blue derivative molecules with the nuclide solution is about 89% -93%.
The process method can at least ensure that the marking rate is more than 90%, preferably more than 95%, and most preferably more than 99%. In some embodiments provided herein, the reaction is followed by no purification steps to remove radioactive impurities, such as preparative liquid phase separations, solid phase extraction separations, and the like. If sterility of the radionuclide complex solution is required, the step of recovering the product may further comprise passing the resulting solution through a 0.22 μm sterile filter, and optionally further diluting the solution.
Detailed Description
The present application is described in further detail below in conjunction with the detailed description of the application, examples are given to provide a better understanding of the present application and to fully convey the scope of the application to those skilled in the art.
It should be noted that certain terms are used throughout the description and claims to refer to particular components. Those of skill in the art will understand that a person may refer to the same component by different names. The specification and claims do not identify differences in terms of components, but rather differences in terms of the functionality of the components. As referred to throughout the specification and claims, the terms "include" or "comprising" are used in an open-ended fashion, and thus should be interpreted to mean "include, but not limited to. The description hereinafter sets forth a preferred embodiment for practicing the application, but is not intended to limit the scope of the application, as the description proceeds with reference to the general principles of the description. The scope of the application is defined by the appended claims.
The application relates to a radiopharmaceutical aqueous solution which comprises a complex formed by a targeting molecule modified by an Evan Blue (EB) fragment and a radionuclide and a stabilizer.
In a specific embodiment, the modified targeting molecule (or the "evans blue derivative molecule" as described herein) is a compound of formula i or a pharmaceutically acceptable ester, amide, solvate, salt thereof, or a salt of a compound of formula i or a pharmaceutically acceptable ester thereof, or a salt of a compound of formula i or a pharmaceutically acceptable amide thereof, or a solvate of a compound of formula i or a pharmaceutically acceptable ester thereof, or a solvate of a compound of formula i or a pharmaceutically acceptable amide thereof, or a solvate of a compound of formula i or a pharmaceutically acceptable salt thereof.
Wherein,
L 1 is- (CH) 2 ) m Wherein m is an integer from 0 to 12, wherein each CH 2 Can be independently used as-O-, -NH (CO), -or- (CO) NH-substitution, provided that there are no two adjacent CH 2 The groups are replaced;
L 2 is C 1 -C 60 A linking group, a group attached to the base, optionally comprising-O-, -S-, S S (O) -S (O) 2 —、—N(R)—、—C(＝O)—、—C(＝O)O—、—OC(＝O)—、—N(R)C(＝O)—、—C(＝O)N(R)—、—OC(＝O)O—、—N(R)C(＝O)O—、—OC(＝O)N(R)—、Wherein each R is H or C 1 -C 6 An alkyl group;
L 3 is- (CH) 2 ) n Wherein n is an integer from 0 to 12, wherein each CH 2 Can be independently used as-O-, -NH (CO), -or- (CO) NH-substitution, provided that there are no two adjacent CH 2 The groups are replaced;
ch is a chelating group;
tg is a targeting group.
Evans Blue (EB) is a non-membrane permeable azo dye preparation, and because of the high affinity of Evans Blue with serum albumin in blood, the targeting molecule is modified by a truncated EB fragment (truncated Evans Blue, tEB) by utilizing the property of Evans Blue with serum albumin, so that the targeting molecule can be reversibly combined with endogenous serum albumin through the tEB fragment, and the serum albumin is used as a reversible carrier of a drug molecule, so that the half-life of the drug molecule in blood is prolonged, the availability of the drug molecule is increased, and the accumulation and retention time of the drug molecule in tumors are further increased. Evans Blue (EB) dye has a structural formula shown in a formula VI:
in some embodiments of the application, the Evan's blue derivative molecule is a compound of formula I. In other specific embodiments, the Evan's blue derivative molecule is a pharmaceutically acceptable ester, amide, solvate or salt of a compound of formula I. In other embodiments, the Evan's blue derivative molecule is a salt of a pharmaceutically acceptable ester of a compound of formula I. In other embodiments, the Evan's blue derivative molecule is a salt of a pharmaceutically acceptable amide of formula I. In other embodiments, the Evan's blue derivative molecule is a solvate of a pharmaceutically acceptable ester of a compound of formula I. In other specific embodiments, the Evan's blue derivative molecule is a solvate of a pharmaceutically acceptable amide of formula I. In other embodiments, the Evan's blue derivative molecule is a solvate of a pharmaceutically acceptable salt of a compound of formula I. The evans blue derivative molecule may be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods.
In a specific embodiment, L in formula I 1 is-NH (CO) -L 3 is-NH (CO) CH 2 The compounds of the formula I are compounds of the formula VII:
in a particular embodiment, the chelating group Ch in formula I is selected from
Preferably, the chelating group Ch in formula I is
Chelating groups have two or more coordinating atoms and are capable of binding to the same central atom to form a cyclic structure, which may form two or more separate coordination bonds with a single central atom, typically a metal ion. Chelating groups in the present application are organic groups having multiple N, O or S heteroatoms and have a structure that allows two or more heteroatoms to form bonds with the same metal ion. In a specific embodiment of the application, the chelating group is used in a structure that forms a bond with a radiometal species.
In a specific embodiment of the application, the targeting group Tg in formula i is a compound capable of specifically targeting a biological target. In some embodiments, tg is selected from a compound group capable of targeting somatostatin receptor (SSTR), prostate Specific Membrane Antigen (PSMA), fibroblast Activation Protein (FAP), folate Receptor (FR), epidermal growth factor receptor, or integrin. In some embodiments, the targeting group Tg is selected from
In one embodiment of the present application, the compound of formula I is EB-PSMA, and the structural formula is shown as formula II:
in a specific embodiment of the application, the compound of formula I is DOTA-EB-TATE, and the structural formula is shown in formula III:
in a specific embodiment of the application, the compound of formula I is EB-FAPI, and the structural formula is shown in formula IV:
in one embodiment of the application, the compound of formula I is NMEB-RGD, and the structural formula is shown as formula V:
in a specific embodiment of the present application, the radiometal species forming a complex with an Evan's blue derivative molecule is selected from 177 Lu、 99m Tc、 68 Ga、 64 Cu、 67 Cu、 111 In、 86 Y、 90 Y、 89 Zr、 186 Re、 188 Re、 15 3Sm、 82 Rb、 166 Ho、 225 Ac、 212 Pb、 213 Bi、 212 Bi、 227 Th. The radiometal nuclides may be bound to the chelating group Ch by chelation, or by other means, such as conventional covalent or ionic bonds as known in the chemical arts. Radionuclides may be suitable for purposes such as radiation therapy and/or diagnosis.
In a specific embodiment of the application, the radiometal nuclides are present in the pharmaceutical aqueous solution formulation in a volumetric radioconcentration of 0.037-1850 MBq/mL.
In a specific embodiment of the present application, the stabilizer in the aqueous solution of the radiopharmaceutical is a stabilizer against degradation by radiolysis, specifically, the stabilizer is one or more selected from gentisic acid and its salts, ascorbic acid and its salts, histidine, cysteine and its salts, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably one or more selected from gentisic acid, ethanol, methionine.
In a specific embodiment, the total concentration of the stabilizer in the aqueous drug solution is 0.5-400mg/mL, for example, 0.5, 100, 150, 200, 250, 300, 350, 400mg/mL. Preferably, the concentration is 1-80mg/mL, and for example, 1, 10, 20, 30, 40, 50, 60, 70, 80mg/mL can be used.
In a specific embodiment, the stabilizer is added separately during the complexation reaction to form the nuclide complex and after the reaction is completed. Wherein said adding during the complexation reaction means that the stabilizer and the solution of the radionuclide and the solution of the Evan's blue derivative molecules forming the complex together form a reaction phase solution when conditions sufficient for the complexation reaction to occur are achieved; the addition after the reaction is finished means that the complexing reaction takes place for a certain time and the stabilizer is added after the complex has been formed. Further, the stabilizer added during the complexation reaction is a first stabilizer, and the stabilizer added after the reaction is completed is a second stabilizer. The first stabilizer is typically a small molecule compound having antioxidant properties to reduce radiolysis under high irradiation. The primary function of the second stabilizer is to maintain the stability of the formulation during storage. The first stabilizer and the second stabilizer may be selected from the same stabilizer or may be selected from different stabilizers.
In a specific embodiment, the first stabilizer is selected from one or more of gentisic acid and its salts, ascorbic acid and its salts, histidine, cysteine and its salts, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid.
In a specific embodiment, the second stabilizer is selected from one or more of gentisic acid and its salts, ascorbic acid and its salts, histidine, cysteine and its salts, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid, ethanol or methionine.
In a preferred embodiment, the first stabilizer and the second stabilizer are the same and are both selected from gentisic acid or a salt thereof. Wherein gentisic acid (i.e. the first stabilizer) is added during the complexation reaction, and the concentration of gentisic acid in the reaction system is in the range of 0.6-20mg/mL, preferably 2-10mg/mL, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10mg/mL. Gentisic acid (i.e., the second stabilizer) is continuously added to the formulation after the end of the reaction so that it is present in the overall aqueous pharmaceutical solution at a total concentration of 0.1-10mg/mL, preferably 0.5-5mg/mL, and may be, for example, 0.5, 1.0, 1.5, 2.0, 2.5, 2.8, 3.0, 3.2, 3.5, 3.8, 4.0, 4.5, 5.0mg/mL.
In other preferred embodiments, the stabilizer is two different stabilizers.
In a specific embodiment, the first stabilizer added to the reaction system during the complexation reaction is gentisic acid or a salt thereof. It is present in the aqueous pharmaceutical solution at a concentration of 0.5-5mg/mL, preferably 0.5-2mg/mL, for example, 0.5, 0.8, 1.0, 1.2, 1.5, 1.8, 2.0mg/mL. The second stabilizer added after the end of the reaction is ethanol, which is present in the aqueous pharmaceutical solution at a concentration of 0-400mg/mL, preferably 10-120mg/mL, and may be, for example, 10, 30, 50, 60, 70, 80, 100, 120mg/mL. The volume fraction is 0% to 50%, preferably 1% to 15%, for example 1%, 3%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%.
In a specific embodiment, the first stabilizer added to the reaction system during the complexation reaction is gentisic acid or a salt thereof, which is present in the aqueous pharmaceutical solution at a concentration of 0.5-5mg/mL, preferably 0.5-2mg/mL, for example, 0.5, 0.8, 1.0, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2.0mg/mL. The second stabilizer added after the end of the reaction is L-methionine, which is present in the aqueous pharmaceutical solution at a concentration of 0-50mg/mL, preferably 1-10mg/mL, and may be, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10mg/mL.
In other embodiments, both stabilizers are preferably free of ascorbic acid and salts thereof.
In a specific embodiment, the aqueous pharmaceutical solution further comprises a buffer. The buffer may be added during the complexation reaction to adjust the pH of the reaction phase solution, or may be added again after the reaction is completed to adjust the pH of the formulation solution. The buffers added in two times may be the same or different. The buffer solution can be acetate system (such as acetic acid-sodium acetate system, sodium acetate system), citrate system (such as citric acid-sodium citrate system), phosphate system (such as sodium dihydrogen phosphate-disodium hydrogen phosphate system), and formate system (such as formic acid-sodium formate system). In a preferred embodiment, the concentration of buffer salt in the reaction phase solution is 0.01-2.0M. In a preferred embodiment, the total buffer salt concentration in the final aqueous drug solution is 0.005-0.5M.
In a specific embodiment, the aqueous pharmaceutical solution further comprises a co-solvent which acts to reduce adsorption of the API on the surfaces of the respective contact materials, in particular glass and plastic surfaces. The cosolvent is one or more selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, polyoxyethylene castor oil, span, ethanol, propylene glycol, glycerol, polyethylene glycol (average molecular weight is 200-8000), sorbitol, dimethyl sulfoxide, and sodium dodecyl sulfate, preferably polysorbate 80. In a specific embodiment, the concentration of the co-solvent in the aqueous drug solution is 0.01-10mg/mL, preferably 0.05-1.0mg/mL, and may be, for example, 0.05, 0.1, 0.3, 0.5, 0.6, 0.7, 0.8, 1.0mg/mL.
In a specific embodiment, the aqueous pharmaceutical solution further comprises a chelating agent for free metal species. The chelating agent acts to complex with unreacted free nuclide ions in the aqueous drug solution to reduce unnecessary irradiation of healthy tissue by free radionuclide ions in the body. Therefore, the chelating agent is required to have a strong capability of complexing with nuclide ions, and even after the injection is diluted by plasma in a living body, the chelating agent can rapidly react with free nuclide ions under a low concentration condition, and the complexing reaction needs to be rapid, mild in condition and can be completely performed under room temperature condition. In a specific embodiment, the chelating agent is pentetic acid or a salt thereof, preferably pentetic acid. The concentration of the chelating agent in the aqueous drug solution is 0.005-0.1mg/mL, for example, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1mg/mL. Within this range, the pentetic acid has sufficient complexing ability for free nuclide ions, and the complex can also maintain stability for at least 48 hours under the action of radiolysis, and more preferably can maintain stability for 72 hours, i.e., free nuclide ions are not released due to radiolysis of the chelating agent.
The application also provides a regimen for applying the aqueous drug solution to the radiation treatment and/or diagnosis of tumors comprising administering to a patient an effective amount of the aqueous drug solution, or a composition co-composed with one or more other oncologic therapeutic agents. In some specific embodiments, the aqueous pharmaceutical solution or composition comprising the same may be used to treat neuroendocrine tumor, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, liver cancer, lung cancer, colorectal cancer, melanoma, and the like. In other specific embodiments, the aqueous pharmaceutical solutions or compositions comprising the same provided herein may also be used in the preparation of a medicament for the prevention or treatment of diabetes, alzheimer's disease.
In a specific embodiment, the aqueous pharmaceutical solution provided by the present application is at least capable of providing an API having a radiochemical purity of not less than 90% within 48 hours, more preferably not less than 90% within 72 hours, at 32 ℃ and 60% RH storage conditions, said radiochemical purity being a value determined by HPLC.
The application also relates to a method for preparing an aqueous radiopharmaceutical solution, comprising in a specific embodiment the steps of:
Mixing a solution containing a first stabilizer with a solution containing a radionuclide in a reaction container;
after a given time, adding a solution containing the evans blue derivative molecules to the reaction vessel, preferably the given time is 0.1 minutes to 20 minutes, more preferably 3 minutes to 10 minutes;
the Evan blue derivative molecule reacts with a radionuclide to obtain a radionuclide complex;
adding a solution containing a second stabilizer to the reaction vessel after a given period of reaction;
recovering the resulting aqueous radiopharmaceutical solution;
wherein the Evan's blue derivative molecule is a compound shown in a formula I or pharmaceutically acceptable ester, amide, solvate, salt thereof, or a salt of a compound shown in a formula I or pharmaceutically acceptable ester thereof, or a salt of a compound shown in a formula I or pharmaceutically acceptable amide thereof, or a solvate of a compound shown in a formula I or pharmaceutically acceptable ester thereof, or a solvate of a compound shown in a formula I or pharmaceutically acceptable amide thereof, or a solvate of a compound shown in a formula I or pharmaceutically acceptable salt thereof,
/>
Wherein,
L 1 is- (CH) 2 ) m Wherein m is an integer from 0 to 12, wherein each CH 2 Can be independently used as-O-, -NH (CO), -or- (CO) NH-substitution, provided that there are no two adjacent CH 2 The groups are replaced;
L 2 is C 1 -C 60 A linking group, a group attached to the base, optionally comprising-O-, -S-, S S (O) -S (O) 2 —、—N(R)—、—C(＝O)—、—C(＝O)O—、—OC(＝O)—、—N(R)C(＝O)—、—C(＝O)N(R)—、—OC(＝O)O—、—N(R)C(＝O)O—、—OC(＝O)N(R)—、Wherein each R is H or C 1 -C 6 An alkyl group;
L 3 is- (CH) 2 ) n Wherein n is an integer from 0 to 12, wherein each CH 2 Can be independently used as-O-, -NH (CO), -or- (CO) NH-substitution, provided that there are no two adjacent CH 2 The groups are replaced;
ch is a chelating group;
tg is a targeting group.
In one embodiment of the application, the aqueous radiopharmaceutical solution comprises a radionuclide complex formed from a radionuclide and the evans blue derivative molecule.
In particular embodiments of the present application, the radionuclide-containing solution is a solution containing a radiometal element, and in some particular embodiments, the radionuclide is selected from the group consisting of 177 Lu、 99m Tc、 68 Ga、 64 Cu、 67 Cu、 111 In、 86 Y、 90 Y、 89 Zr、 186 Re、 188 Re、 153 Sm、 82 Rb、 166 Ho、 225 Ac、 212 Pb、 213 Bi、 212 Bi or Bi 227 Th. In a specific embodiment, the radionuclide is 177 Lu, and in the step of complexing with the evans blue derivative molecule, the radionuclide has a specific activity of not less than 20Ci/mg, preferably not less than 60Ci/mg, most preferably not less than 80Ci/mg. Radionuclides with too low a specific activity can affect the radiolabeling efficiency.
In the present application, the evans blue derivative molecule is a targeting molecule modified with a truncated evans blue fragment (truncated Evans Blue, tpeb). In some embodiments, the Evan's blue derivative molecule is a compound of formula I. In other specific embodiments, the Evan's blue derivative molecule is a pharmaceutically acceptable ester, amide, solvate or salt of a compound of formula I. In other embodiments, the Evan's blue derivative molecule is a salt of a pharmaceutically acceptable ester of a compound of formula I. In other embodiments, the Evan's blue derivative molecule is a salt of a pharmaceutically acceptable amide of formula I. In other embodiments, the Evan's blue derivative molecule is a solvate of a pharmaceutically acceptable ester of a compound of formula I. In other specific embodiments, the Evan's blue derivative molecule is a solvate of a pharmaceutically acceptable amide of formula I. In other embodiments, the Evan's blue derivative molecule is a solvate of a pharmaceutically acceptable salt of a compound of formula I.
In a specific embodiment, L in formula I 1 is-NH (CO) -L 3 is-NH (CO) CH 2 The compounds of the formula I are compounds of the formula VII:
in a particular embodiment, the chelating group Ch in formula I is selected from
Preferably, the chelating group Ch in formula I is
In a specific embodiment of the application, the targeting group Tg in formula i is a compound capable of specifically targeting a biological target. In some embodiments, tg is selected from a compound group capable of targeting somatostatin receptor (SSTR), prostate Specific Membrane Antigen (PSMA), fibroblast Activation Protein (FAP), folate Receptor (FR), epidermal growth factor receptor, or integrin. In some embodiments, the targeting group Tg is selected from
In one embodiment of the present application, the compound of formula I is EB-PSMA, and the structural formula is shown as formula II:
in a specific embodiment of the application, the compound of formula I is DOTA-EB-TATE, and the structural formula is shown in formula III:
in a specific embodiment of the application, the compound of formula I is EB-FAPI, and the structural formula is shown in formula IV:
in one embodiment of the application, the compound of formula I is NMEB-RGD, and the structural formula is shown as formula V:
in a specific embodiment of the present application, the radionuclide-containing solution is taken out from a raw material bottle and then added to the reaction container, and after the radionuclide-containing solution is taken out, the raw material bottle is rinsed with a rinsing liquid to extract the radionuclide solution remaining in the raw material bottle, and the rinsed solution is transferred into the reaction container and mixed with the radionuclide-containing solution.
In a specific embodiment, the rinse solution is an aqueous solution, preferably selected from the group consisting of a solution containing a first stabilizer, a solution containing a buffer salt, water or sodium chloride injection.
In a preferred embodiment, the rinse solution is selected from water for injection or sodium chloride injection.
In a preferred embodiment, the flushing is repeated one or more times with the flushing liquid.
In a specific embodiment of the present application, the first stabilizer is selected from one or more of gentisic acid and its salts, ascorbic acid and its salts, histidine, cysteine and its salts, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid.
In a specific embodiment of the application, the solution containing the first stabilizer and the solution containing the radionuclide are mixed in a reaction vessel, and after a given time, the solution containing the Evan's blue derivative molecule is added to the reaction vessel. The given time can enable the first stabilizer to be fully contacted with the nuclide solution, quench a large amount of free radicals caused by the radiation decomposition existing in the first stabilizer, thereby protecting the Evan blue derivative molecules added into a reaction system from being attacked by active free radicals, and being beneficial to improving the initial amplification purity of the final product.
In a preferred embodiment, the given time is 0.1 to 20 minutes, more preferably 3 to 10 minutes, and may be, for example, 3, 4, 5, 6, 7, 8, 9, 10 minutes.
In a specific embodiment, the solution containing the Evan's blue derivative molecule is added to a reaction phase solution to react with a radionuclide to obtain the radionuclide complex.
In a specific embodiment, the solution of Evan's blue derivative molecule (labeled precursor) is selected from a compound solution having a concentration of 0.05-10.0mg/mL, and is prepared by dissolving lyophilized powder of the labeled precursor in sterilized injectable water or ethanol.
In a preferred embodiment, the radionuclide complex is 177 Lu-DOTA-EB-TATE。
In a specific embodiment, during the reaction of the Evan's blue derivative molecule with a radionuclide to give the radionuclide complex, the first stabilizer is gentisic acid, which is present in the reaction phase at a concentration of 0.6-20.0mg/mL, preferably 2-10mg/mL, most preferably 3.0-5.0mg/mL, for example 3.0, 3.2, 3.5, 3.8, 4.0, 4.2, 4.5, 4.8, 5.0mg/mL. When the concentration of gentisic acid in a reaction phase system exceeds a control range, the reaction rate can be greatly slowed down, and the whole synthesis process is not facilitated; when the gentisic acid concentration is lower than the control concentration, the radiation-degradable impurities may increase due to insufficient stabilizer concentration.
In a specific embodiment, the molar ratio between the Evan's blue derivative molecule and the radionuclide in the reaction phase solution formed by the reaction of the Evan's blue derivative molecule and the radionuclide is 1.5-50, preferably 5-20, for example, may be 5, 8, 10, 12, 15, 18, 20. The molar ratio refers to the molar amount of the evans blue derivative molecule (labeled precursor) to the radionuclide in the reaction system. In the reaction phase solution, the increase in molar ratio facilitates complete reaction of the radionuclide, resulting in an increase in the labelling rate, but unlabeled labelling precursors compete with the API in vivo. However, too low a molar ratio results in a lack of carrier for the API, which is easily lost in the organism by binding to other non-specific targets, and thus the expected therapeutic or diagnostic effect is not achieved.
In an embodiment of the present application, the concentration of the reaction phase in the reaction phase solution may also be controlled. Theoretically, the higher the concentration of the reaction phase, the faster the labeling reaction rate, but the stronger the radiolysis effect caused by the radionuclide at the same time, so the concentration of the reaction phase cannot be too high, while the too low concentration of the reaction phase makes the reaction volume larger, limiting the mass production of the nuclide complex. For the preparation method of the present application, the concentration of the Evan's blue derivative molecule in the reaction phase solution is in the range of 0.01-1.0mg/mL, preferably 0.05-0.5mg/mL, and may be, for example, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5mg/mL.
In the embodiment of the application, in the step of carrying out the complexation reaction between the Evan's blue derivative molecule and the radionuclide, the reaction temperature and the reaction time are controlled so as to control the reaction mark rate to be more than 90%, the chemical purity to be more than 90% and the radiochemical purity to be more than 90%. In a specific embodiment, the reaction temperature is 50-100 ℃, preferably 60-80 ℃, such as 60, 62, 65, 68, 70, 72, 75, 78, 80 ℃; the reaction time is 5 to 60 minutes, for example, 5, 10, 12, 15, 18, 20, 25, 30, 40, 50, 60 minutes, preferably 10 to 30 minutes, and most preferably 10 to 20 minutes.
In a specific embodiment, the second stabilizer is added after the reaction of the Evan's blue derivative molecule with the radionuclide for the reaction time described above to form a complex. Specifically, the second stabilizer is selected from one or more of gentisic acid and its salt, ascorbic acid and its salt, histidine, cysteine and its salt, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin and melatonin, preferably gentisic acid, ethanol or methionine.
In a specific embodiment, the concentration of the second stabilizing agent in the aqueous radiopharmaceutical solution is 0-400mg/mL, which may be, for example, 0, 50, 100, 150, 200, 250, 300, 350, 400mg/mL.
In an embodiment of the application, the method of preparation further comprises adding a buffer salt solution prior to the reaction of the evans blue derivative molecule with the radionuclide, preferably the buffer salt solution is present in the solution comprising the first stabilizer.
In a specific embodiment, the buffer salt solution is selected from acetate, citrate, phosphate or formate solutions, preferably acetic acid-sodium acetate buffer salt solution.
The pH of the reaction system can be adjusted by adding the buffer salt solution, and the pH of the reaction system is controlled within the range of 3.5-6.0, for example, 3.5, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.5 and 6, and the pH is preferably 3.5-5. In a specific embodiment, the pH of the final formulation solution is controlled to be 4-6, which may be, for example, 4, 4.2, 4.5, 4.8, 5, 5.2, 5.5, 5.8, 6.
In a specific embodiment, the step of adding a solution containing a second stabilizer to the reaction vessel after a given period of time of reaction further comprises adding a co-solvent to the reaction vessel.
In a specific embodiment, the cosolvent is selected from one or more of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer 188, polyoxyethylated castor oil, span, ethanol, propylene glycol, glycerol, polyethylene glycol (average molecular weight 200-8000), sorbitol, dimethyl sulfoxide, and sodium dodecyl sulfate, preferably polysorbate 80. In a specific embodiment, the co-solvent is added to a concentration of 0.01-10mg/mL, preferably 0.05-1.0mg/mL, for example, 0.05, 0.1, 0.3, 0.5, 0.6, 0.7, 0.8, 1.0mg/mL in the aqueous drug solution.
In a specific embodiment, the step of adding a solution containing a second stabilizer to the reaction vessel after a given period of reaction further comprises adding a free-nuclide chelating agent to the reaction vessel, the chelating agent being selected from pentetic acid and salts thereof, preferably pentetic acid. In a preferred embodiment, the chelating agent is added to a concentration of 0.005-0.1mg/mL in the aqueous drug solution, for example, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1mg/mL.
In a specific embodiment, the method of the present application further comprises filter sterilization of the aqueous radiopharmaceutical solution, and in a specific embodiment, filter sterilization of the aqueous radiopharmaceutical solution through a 0.22 μm filter.
In a specific embodiment, the preparation method of the application further comprises diluting the radioactive aqueous solution, preferably adding sodium chloride injection for dilution for recovery.
In a preferred embodiment, the filter sterilization and dilution are performed after the addition of the solution containing the second stabilizer. The sequence of the filtration sterilization and dilution steps is not limited, and the filtration sterilization and dilution steps can be performed first, or the dilution can be performed first, the filtration sterilization can be performed through a filter membrane, and then the recovery can be performed.
In one embodiment, the present application provides a process for preparing in the following order 177 The method for preparing the Lu-DOTA-EB-TATE radiopharmaceutical aqueous solution comprises the following steps:
a. will contain 500mCi 177 Transferring the nuclide solution of Lu and hydrochloric acid from the raw material bottle to the reaction bottle;
b. 1mL of a rinse solution containing 2.0M formic acid-sodium formate buffer and 50mg/mL gentisic acid was added to the above raw material bottle to rinse the residual in the raw material bottle 177 A Lu solution;
c. transferring the mixed solution in the raw material bottle after washing into a reaction bottle;
d. adding 3mL of water for injection into the raw material bottle to flush the raw material bottle;
e. transferring the mixed solution in the raw material bottle after washing into a reaction bottle;
f. the reaction flask containing the above solution was allowed to stand at room temperature for 10 minutes;
g. 0.5mL DOTA-EB-TATE solution was added to the reaction flask;
h. the reaction flask was warmed to 90 ℃ and reacted for 15 minutes;
i. after the reaction is finished, cooling a reaction bottle, and adding 10mL of mixed solution containing 0.5mg/mL of pentetic acid, 45mg/mL of gentisic acid and 2.0mg/mL of polysorbate 80 into the reaction bottle;
j. filtering and sterilizing the obtained solution through a 0.22 mu m filter membrane;
k. diluting the resulting solution with 35mL of sodium chloride injection;
and I, recovering the obtained product.
Examples
The experimental methods used in the following examples are conventional methods, if no special requirements are imposed.
The precursor EB-PSMA used in the examples described below was synthesized according to literature methods (Bioconjugate chem.2018,29, 3213-3221).
The precursor DOTA-EB-TATE used in the examples below was synthesized according to literature methods (theranostics.2018; 8:735-745).
The precursor EB-FAPI used in the examples described below was synthesized according to literature methods (theranostics.2022; 12 (1): 422-433).
Gentisic acid used in the following examples was purchased from Dou Purui method technology development limited and pentetic acid was purchased from Jiangxi alpha high pharmaceutical Co.
Other materials, reagents, etc., unless otherwise specified, are commercially available.
Example 1: selection of stabilizers in aqueous pharmaceutical solutions
Prescription (1): [ 177 Lu]Preparation of Lu-DOTA-EB-TATE drug aqueous solution
Preparing a reaction phase solution: adding 10mCi of unsupported lutetium chloride into a reaction vessel 177 Lu]Solution (about 10. Mu.L), 20. Mu.L of formic acid-sodium formate buffer salt solution (containing 50mg/mL gentisic acid), 60. Mu.L of water for injection, and after mixing uniformly, the mixed solution was allowed to stand at room temperature for 3 minutes. Then, 10. Mu.L of DOTA-EB-TATE precursor solution was continuously added to the reaction vessel and mixed well, and the mixed solution was the reaction phase solution.
Heating reaction and cooling: the reaction phase solution was placed in a heater preheated to 90℃for 15 minutes, and after the reaction was completed, the reaction vessel was taken out and cooled for 15 minutes.
And (3) matching and diluting: after the reaction phase solution was cooled to room temperature, 200. Mu.L of a co-solution containing 45mg/mL gentisic acid, 0.5mg/mL pentetic acid and 2.0mg/mL polysorbate 80 was added to the reaction vessel. Finally, adding sodium chloride injection into the reaction vessel to dilute the total volume to 1.0mL, thus obtaining the final preparation solution.
The final formulation solution contained 10mg/mL gentisic acid, 0.1mg/mL pentetic acid, 0.4mg/mL polysorbate 80, wherein API molecule [ 177 Lu]The activity concentration of Lu-DOTA-EB-TATE at the calibration time, which is the end of production time (T 0 ). The formulation solution was stored in a stability tank with a storage temperature set at 32 ℃ and a storage humidity set at 60% rh.
At T 0 The radiochemical purity of the preparation solution was 100% at time using Radio-HPLC, at T 0 The radiochemical purity of the formulation solution was 100% at time using ITLC detection.
At T 0 150. Mu.L of the formulation solution in the stabilization tank was taken out at time +48h for stability test. Radiochemical purity of the preparation solution was 94% by Radio-HPLC, using IThe radiochemical purity of the TLC detection formulation solution was 100%.
At T 0 150. Mu.L of the formulation solution in the stabilization tank was taken out at +72h for stability test. The radiochemical purity of the preparation solution was 92% by Radio-HPLC and 100% by ITLC.
Prescription (2): [ 177 Lu]Preparation of Lu-DOTA-EB-TATE drug aqueous solution
Preparing a reaction phase solution: adding 10mCi of unsupported lutetium chloride into a reaction vessel 177 Lu]Solution (about 10. Mu.L), 20. Mu.L of formic acid-sodium formate buffer salt solution (containing 50mg/mL gentisic acid), 160. Mu.L of water for injection, and after mixing uniformly, the mixed solution was allowed to stand at room temperature for 3 minutes. Then, 10. Mu.L of DOTA-EB-TATE precursor solution was continuously added to the reaction vessel and mixed well, and the mixed solution was the reaction phase solution.
Heating reaction and cooling: the reaction phase solution was placed in a heater preheated to 65℃and reacted for 40 minutes, and after the reaction was completed, the reaction vessel was taken out and cooled for 15 minutes.
And (3) matching and diluting: after the reaction phase solution was cooled to room temperature, 100. Mu.L of a co-solution containing 0.3mg/mL of pentetic acid and 1.0mg/mL of polysorbate 80 was added to the reaction vessel. And adding 50mg of absolute ethyl alcohol, and finally adding sodium chloride injection into a reaction container to dilute the total volume to 1.0mL to obtain a final preparation solution.
The final formulation solution contains 1mg/mL gentisic acid, 50mg/mL ethanol, 0.03mg/mL pentetic acid, 0.1mg/mL polysorbate 80, wherein the API molecule [ 177 Lu]The activity concentration of Lu-DOTA-EB-TATE at the calibration time, which is the end of production time (T 0 ). The formulation solution was stored in a stability tank with a storage temperature set at 32 ℃ and a storage humidity set at 60% rh.
At T 0 The radiochemical purity of the preparation solution was 100% at time using Radio-HPLC, at T 0 The radiochemical purity of the formulation solution was 100% at time using ITLC detection.
At T 0 Taking out the preparation in the stabilizing box at +48h150. Mu.L of the solution was used for stability test. The radiochemical purity of the preparation solution was 93% by Radio-HPLC and 100% by ITLC.
At T 0 150. Mu.L of the formulation solution in the stabilization tank was taken out at +72h for stability test. The radiochemical purity of the preparation solution was 92% by Radio-HPLC and 99% by ITLC.
Prescription (3): [ 177 Lu]Preparation of Lu-EB-FAPI medicine aqueous solution
Preparing a reaction phase solution: adding 20mCi of unsupported lutetium chloride into a reaction vessel 177 Lu]The solution (about 20. Mu.L), 20. Mu.L of ammonium acetate buffer salt solution (containing 50mg/mL gentisic acid) and 40. Mu.L of water for injection were mixed uniformly, and the mixed solution was allowed to stand at room temperature for 10 minutes. Then, 20. Mu.L of EB-FAPI precursor solution was continuously added to the reaction vessel and mixed well, and the mixed solution was the reaction phase solution. Wherein precursor EB-FAPI is a compound of formula iv, r=h.
Heating reaction and cooling: the reaction phase solution was placed in a heater preheated to 95℃to react for 30 minutes, and after the reaction was completed, the reaction vessel was taken out and cooled for 15 minutes.
And (3) matching and diluting: after the reaction phase solution was cooled to room temperature, 500. Mu.L of a co-solution containing 20mg/mL methionine, 4.0mg/mL gentisic acid, 0.2mg/mL pentetic acid and 0.8mg/mL polysorbate 80 was added to the reaction vessel. Finally, adding sodium chloride injection into the reaction vessel to dilute the total volume to 1.0mL, thus obtaining the final preparation solution.
The final formulation solution contained 3.0mg/mL gentisic acid, 10mg/mL methionine, 0.1mg/mL pentetic acid, 0.4mg/mL polysorbate 80, wherein API molecule [ 177 Lu]The activity concentration of Lu-EB-FAPI was 20mCi/mL at the time of calibration, which means the end of production time (T 0 ). The formulation solution was stored in a stability tank with a storage temperature set at 32 ℃ and a storage humidity set at 60% rh.
At T 0 The radiochemical purity of the formulation solution was 98% at time using Radio-HPLC, at T 0 The radiochemical purity of the formulation solution was 100% at time using ITLC detection.
At T 0 150. Mu.L of the formulation solution in the stabilization tank was taken out at time +48h for stability test. The radiochemical purity of the preparation solution was 96% by Radio-HPLC and 100% by ITLC.
At T 0 150. Mu.L of the formulation solution in the stabilization tank was taken out at +72h for stability test. The radiochemical purity of the preparation solution was 93% by Radio-HPLC and 100% by ITLC.
Prescription (4): [ 177 Lu]Preparation of Lu-EB-PSMA drug aqueous solution
Preparing a reaction phase solution: adding 10mCi of unsupported lutetium chloride into a reaction vessel 177 Lu]Solution (about 10. Mu.L), 20. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 50mg/mL gentisic acid), 60. Mu.L of water for injection, and after mixing uniformly, the mixed solution was allowed to stand at room temperature for 3 minutes. Then, 10. Mu.L of EB-PSMA precursor solution was continuously added to the reaction vessel and mixed well, and the mixed solution was the reaction phase solution.
Heating reaction and cooling: the reaction phase solution was placed in a heater preheated to 80℃for 15 minutes, and after the reaction was completed, the reaction vessel was taken out and cooled for 15 minutes.
And (3) matching and diluting: after the reaction phase solution was cooled to room temperature, 100. Mu.L of a co-solution containing 30mg/mL ascorbic acid, 1.0mg/mL pentetic acid and 4.0mg/mL polysorbate 80 was added to the reaction vessel. Finally, adding sodium chloride injection into the reaction vessel to dilute the total volume to 1.0mL, thus obtaining the final preparation solution.
The final formulation solution contained 1.0mg/mL gentisic acid, 3.0mg/mL ascorbic acid, 0.1mg/mL pentetic acid, 0.4mg/mL polysorbate 80, wherein API molecule [ 177 Lu]The activity concentration of Lu-EB-PSMA was 10mCi/mL at the calibration time, which is the end of production time (T 0 ). The formulation solution was stored in a stability tank with a storage temperature set at 32 ℃ and a storage humidity set at 60% rh.
At T 0 The radiochemical purity of the formulation solution was 93% at time using Radio-HPLC.
At T 0 150. Mu.L of the preparation solution in the stabilizing tank was taken out at the time of +48 hours, and the radiochemical purity of the preparation solution was 81% by Radio-HPLC.
At T 0 150. Mu.L of the preparation solution in the stabilizing tank was taken out at +72 hours, and the radiochemical purity of the preparation solution was determined to be 66% by Radio-HPLC.
Analysis of experimental results: the aqueous solution of the medicine prepared by taking gentisic acid, gentisic acid and ethanol, gentisic acid and methionine as stabilizers in the prescriptions (1) to (3) can obtain more than 90% of API radiochemical purity in 48 hours and 72 hours, and is obviously superior to the stabilizer selection of ascorbic acid adopted in the prescriptions (4). This shows that the aqueous pharmaceutical solutions provided by the present disclosure can maintain better stability.
Example 2 control of reaction temperature and time
Preparing a reaction phase solution: the same as in the prescription (3).
Heating reaction and cooling: the reaction phase solution was placed in a heater at room temperature or preheated to a different temperature to react for 120 minutes. The temperatures examined included room temperature, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃, 95 ℃, 100 ℃.
And (3) detecting a mark rate: when the reaction is carried out to different time points, 5 mu Ci of reaction phase solution is taken out for ITLC detection, and the reaction phase solution is placed in a heater for reaction before and after sampling, namely the continuous reaction is not influenced in the sampling process. The labeling rate (ITLC) =activity sequestered with the precursor molecule/(total activity) was calculated and the time examined included 1, 5, 10, 30, 45, 60, 90, 120 minutes.
For the labeling rate, the reaction temperature and the reaction time are two complementary process conditions, and the "longer reaction time at lower temperature" or the "shorter reaction time at higher temperature" can both lead to the reaction labeling rate (ITLC) of 99% or more, and at this time we consider that the labeling reaction is completely carried out. However, considering that high temperature promotes the formation of chemical impurities and radiochemical impurities, and that a reaction time of more than 60 minutes is disadvantageous for the control of the process, it is selected to control the reaction temperature to 50-100 ℃, the reaction time to 5-60 minutes, preferably, the reaction temperature to 60-80 ℃ and the reaction time to 10-30 minutes.
Example 3 control of the feed ratio
Preparing a reaction phase solution: adding 10mCi of unsupported lutetium chloride into a reaction vessel 177 Lu]The solution (about 10. Mu.L) and 20. Mu.L of a formic acid-sodium formate buffer salt solution (containing 50mg/mL gentisic acid) were allowed to stand at room temperature for 3 minutes. Then continuously adding different volumes of water for injection and DOTA-EB-TATE precursor solution into the reaction container to make DOTA-EB-TATE and lutetium chloride in the reaction phase 177 Lu]The molar ratio of the materials is 1, 1.5, 2, 3, 5, 10, 15, 30 and 50 respectively, the total volume of the solution is 0.1mL, the solution is uniformly mixed, and the mixed solution is a reaction phase solution.
Heating reaction and cooling: the same as in the prescription (1).
And (3) matching and diluting: the same as in the prescription (1).
And (3) detecting a mark rate: ITLC detection was performed with 5 μci of the reaction phase solution, and the labeling rate (ITLC) =radioactivity sequestered with the precursor molecule +.total radioactivity was calculated.
When the feeding mole ratio of the precursor molecule and the nuclide is 1.5-50, the marking rate is more than or equal to 95 percent, and when the feeding mole ratio of the precursor molecule and the nuclide is 3-50, the marking rate is more than or equal to 99 percent, and at the moment, we consider that the marking reaction is completely carried out.
Example 4 control of quench time
Preparation of reaction phase solution A: sequentially adding 10mCi of unsupported lutetium chloride into a reaction vessel 177 Lu]The solution (about 10. Mu.L), 10. Mu.L of EB-FAPI precursor solution, 60. Mu.L of water for injection, 20. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 50mg/mL gentisic acid) were mixed well, and the mixed solution was reaction phase solution A. Wherein precursor EB-FAPI is a compound of formula iv, r=h.
Preparation of reaction phase solution B: adding 10mCi of unsupported lutetium chloride into a reaction vessel 177 Lu]Solution, 20. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 50mg/mL gentisic acid), 60. Mu.L of injectionAfter mixing with water, the mixed solution was allowed to stand at room temperature for 3 minutes (i.e., quenching time). Then, 10. Mu.L of EB-FAPI precursor solution was continuously added to the reaction vessel and mixed well, and the mixed solution was reaction phase solution B. Wherein precursor EB-FAPI is a compound of formula iv, r=h.
Preparation of reaction phase solution C: the rest was the same as the reaction phase solution B except that the quenching time was 15 minutes.
Heating reaction and cooling: the same as in the prescription (1).
And (3) matching and diluting: the same as in the prescription (1).
Radiochemical purity detection: immediately after the completion of the co-dilution, 150. Mu.L of the reaction phase solution was subjected to HPLC detection, and the radiochemical purity (HPLC) =peak area of the labeled compound/(total peak area) was calculated.
The radiochemical purity of the reaction phase solution A, B, C was 93%, 99% and 99%, respectively. Experimental results show that before the precursor solution is added, the mixed solution containing the nuclide solution, the buffer salt and the first stabilizer is kept stand for a short period of time (quenching time), and then the precursor molecule is added for reaction, so that the initial radiochemical purity of the API can be obviously improved. Because the first stabilizer is in sufficient contact with the nuclide solution over a quenching period of time, a significant amount of the free radicals in the solution due to the high radioactivity are quenched by the first stabilizer to reduce the damage of the free radicals to the labeled precursor molecules upon subsequent addition of the precursor molecules. The quenching time depends on the species of the nuclide and the initial activity, and in general, the quenching time is controlled to be 0.1 to 20 minutes, preferably 3 to 10 minutes.
Example 5[ 68 Ga]Marking of Ga-EB-FAPI
Preparing a reaction phase solution: rinsing the commercial gallium germanium generator with 0.1M hydrochloric acid to obtain 68 Ga hydrochloric acid solution 68 Ga hydrochloric acid solution 5mCi into a reaction vessel, adding 20 mu L of sodium acetate solution (containing 50mg/mL gentisic acid) and 150 mu L of water for injection, mixing uniformly, standing the mixed solution at room temperature for 6 minutes, then adding 5 mu L of EB-FAPI precursor solution into the reaction vessel, adding water for injection to make the total volume of the solution be 0.3mL, and mixing uniformly, wherein The mixed solution is a reaction phase solution. Wherein precursor EB-FAPI is a compound of formula iv, r=h.
Heating reaction and cooling: the reaction phase solution was placed in a heater preheated to 95℃to react for 30 minutes, and after the reaction was completed, the reaction vessel was taken out and cooled for 5 minutes.
Purifying: the reaction phase solution was purified using a C18 column, followed by rinsing the labeled complex with 0.4mL of absolute ethanol into a product bottle.
And (3) matching and diluting: 200. Mu.L of a co-solution containing 45mg/mL gentisic acid, 0.5mg/mL pentetic acid and 2.0mg/mL polysorbate 80 was continuously added to the product bottle. Finally, adding sodium chloride injection into the product bottle to dilute the total volume to 1.0mL, thus obtaining the final preparation solution.
The final formulation solution contained 9mg/mL gentisic acid, 40% ethanol (i.e., 315.6 mg/mL) by volume fraction, 0.1mg/mL pentetic acid, 0.4mg/mL polysorbate 80, wherein API molecule [ 177 Lu]The activity concentration of Lu-EB-FAPI was 5mCi/mL at the time of calibration, which means the end of production time (T 0 ). The formulation solution was stored in a stability tank with a storage temperature set at 25 ℃ and a storage humidity set at 60% rh.
At T 0 The radiochemical purity of the preparation solution was 99% at time using Radio-HPLC, at T 0 The radiochemical purity of the formulation solution was 100% at time using ITLC detection.
At T 0 150. Mu.L of the preparation solution in the stabilizing tank was taken out at +5 hours, and the radiochemical purity of the preparation solution was 93% by Radio-HPLC and 100% by ITLC.
Although the present invention has been described with reference to the above embodiments, it should be understood that the invention is not limited thereto, but rather by one skilled in the art, and that various changes and modifications can be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (10)

1. A method of preparing an aqueous radiopharmaceutical solution comprising a complex of a radionuclide and an evans blue derivative molecule, comprising the steps of:
mixing a solution containing a first stabilizer with a solution containing a radionuclide in a reaction container;
after a given time, adding a solution containing the evans blue derivative molecules to the reaction vessel, preferably the given time is 0.1 minutes to 20 minutes, more preferably 3 minutes to 10 minutes;
the Evan blue derivative molecule reacts with a radionuclide to obtain a radionuclide complex;
Adding a solution containing a second stabilizer to the reaction vessel after a given period of reaction;
recovering the resulting aqueous radiopharmaceutical solution;
wherein the Evan's blue derivative molecule is a compound shown in a formula I or pharmaceutically acceptable ester, amide, solvate, salt thereof, or salt of a compound shown in a formula I or pharmaceutically acceptable ester thereof, or salt of a compound shown in a formula I or pharmaceutically acceptable amide thereof, or solvate of a compound shown in a formula I or pharmaceutically acceptable ester thereof, or solvate of a compound shown in a formula I or pharmaceutically acceptable amide thereof, or solvate of a compound shown in a formula I or pharmaceutically acceptable salt thereof,
wherein,
L 1 is- (CH) 2 ) m Wherein m is an integer from 0 to 12, wherein each CH 2 Can be independently used as-O-, -NH (CO), -or- (CO) NH-substitution, provided that there are no two adjacent CH 2 The groups are replaced;
L 2 is C 1 -C 60 A linking group, a group attached to the base, optionally comprising-O-, -S-, S S (O) -S (O) 2 —、—N(R)—、—C(＝O)—、—C(＝O)O—、—OC(＝O)—、—N(R)C(＝O)—、—C(＝O)N(R)—、—OC(＝O)O—、—N(R)C(＝O)O—、—OC(＝O)N(R)—、Wherein each R is H or C 1 -C 6 An alkyl group;
L 3 is- (CH) 2 ) n Wherein n is an integer from 0 to 12, wherein each CH 2 Can be independently used as-O-, -NH (CO), -or- (CO) NH-substitution, provided that there are no two adjacent CH 2 The groups are replaced;
ch is a chelating group;
tg is a targeting group.
2. The method of claim 1, wherein the radionuclide is selected from the group consisting of 177 Lu、 99m Tc、 68 Ga、 64 Cu、 67 Cu、 111 In、 86 Y、 90 Y、 89 Zr、 186 Re、 188 Re、 15 3Sm、 8 2Rb、 166 Ho、 225 Ac、 212 Pb、 213 Bi. 212Bi or 227 Th。
3. The method of claim 1 wherein Ch in formula I is selected from Preferably +.>
4. The method of claim 1, wherein Tg in formula i is selected from a group of compounds capable of targeting somatostatin receptors (SSTR), prostate Specific Membrane Antigen (PSMA), fibroblast Activation Protein (FAP), folate Receptor (FR), epidermal growth factor receptor or integrins.
5. The method of claim 1, wherein the Evan's blue derivative molecule is selected from the group consisting of compounds of formula II, formula III, formula IV, and formula V,
6. the method of any one of claims 1-5, wherein the radionuclide-containing solution is added to the reaction container after being removed from a source bottle, the method further comprising:
and flushing the raw material bottle with flushing liquid, and transferring the flushed solution into the reaction container to be mixed with the solution containing the radionuclide.
7. The method according to claim 1, wherein in the step of reacting the evans blue derivative molecule with a radionuclide, the reaction temperature is 50-100 ℃, preferably 60-80 ℃, and the reaction time is 5-60 minutes, preferably 10-30 minutes.
8. The method according to claim 1, wherein the first stabilizer is selected from one or more of gentisic acid and salts thereof, ascorbic acid and salts thereof, histidine, cysteine and salts thereof, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid.
9. The method according to claim 1, wherein the second stabilizer is selected from one or more of gentisic acid and its salts, ascorbic acid and its salts, histidine, cysteine and its salts, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid, ethanol or methionine.
10. An aqueous radiopharmaceutical solution prepared by the method of any one of claims 1 to 9.
CN202311356940.XA 2022-04-20 2022-04-20 Preparation method and application of radiolabeled Evansi blue derivative drug Pending CN117159753A (en)

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