CN116920128A - Aqueous radiopharmaceutical solution and use thereof - Google Patents

Aqueous radiopharmaceutical solution and use thereof Download PDF

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CN116920128A
CN116920128A CN202210343626.7A CN202210343626A CN116920128A CN 116920128 A CN116920128 A CN 116920128A CN 202210343626 A CN202210343626 A CN 202210343626A CN 116920128 A CN116920128 A CN 116920128A
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solution
reaction
acid
stabilizer
gentisic acid
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郝晋
田佳乐
杜泽天
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Beijing Cotimes Biotech Co Ltd
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Abstract

The application relates to a radiopharmaceutical waterSolution and use thereof, said aqueous pharmaceutical solution comprising an active ingredient of [ 177 Lu]Radionuclide complexes and stabilizers for Lu-dottate.

Description

Aqueous radiopharmaceutical solution and use thereof
Technical Field
The application relates to a radionuclide complex solution with high chemical and radiochemical stability, in particular to a radionuclide complex solution with active component of [ 177 Lu]Radionuclide complexes of Lu-dottate.
Background
Neuroendocrine tumors (neuroendocrine tumor, NET) are a class of tumors that originate in stem cells and have neuroendocrine markers capable of producing bioactive amines and/or polypeptides. Among them, gastro-pancreatic neuroendocrine tumor (gastroenteropancreatic neuroendocrine neoplasms, GEP-NENs) is a tumor which is rare compared with adenocarcinoma, and the incidence rate is about 0.025 to 0.05 per mill. Gastrointestinal neuroendocrine tumors occur mainly in the digestive tract or pancreas and produce 5-hydroxytryptamine metabolites or polypeptide hormones, such as glucagon, insulin, gastrin or corticotropin. If the hormone secreted by the tumor can cause corresponding clinical symptoms, the hormone can be classified as functional NENs; if elevated levels of hormones such as pancreatic polypeptides (pancreatic polypeptide, PP) are detected in blood and urine, there is no associated symptoms (even if there is a tumor-pressed manifestation), usually categorized as nonfunctional NENs. For a long time, such diseases have often become "problematic" due to inadequate knowledge of the NENs by clinicians. The survival of NENs patients has not changed for many years in the past; however, in recent years, the current state of the art of NENs has been significantly altered with increased emphasis, in-depth research and advances in molecular targeted therapies.
The NET treatment means with wider clinical application comprise surgery, chemotherapy, somatostatin analogues (SSA such as octreotide and lanreotide), targeted treatment (such as sunitinib and everolimus), local interventional treatment and the like. With the deep knowledge of NET, the clinic increasingly finds that the treatment means have certain limitations: (1) The metastasis or primary focus of advanced NET patients cannot be resected by surgery; (2) Progression-free survival (PFS) of systemic chemotherapy is short; (3) Somatostatin analogues such as octreotide and lanreotide can relieve clinical symptoms caused by excessive secretion of hormone, but imaging and biological relief are difficult to realize: (4) Targeted therapy can prolong PFS in NET patients, but has lower overall efficacy. Radionuclide peptide receptor mediated therapy (peptide receptor radionuclide thera py, PRRT) is becoming increasingly interesting as a possible therapeutic approach for unresectable or metastatic NET.
PRRT is a somatostatin receptor (SSTR) that acts on the tumor surface using radionuclide-labeled SSA and is specific for itAnd the target treatment purpose is achieved by the specific binding. At present, more PRRT is studied including yttrium-90% 90 Y) and lutetium-177% 177 Lu) labeled SSTR. 90 Y is more advantageous for treating tumors of larger volume 177 Lu has better efficacy and less toxicity on small residual lesions. The study is carried out first 90 After Y 177 The Lu scheme treats NEN patients with tumor diameters more than 4cm, and achieves better curative effect. Some recent studies on combination therapy of PRRT with chemotherapeutic or targeted drugs have also shown promising prospects. PRRT is overall well tolerated, acute adverse reactions include nausea, vomiting, headache, etc., general symptoms are mild, and are transient reactions at the time of initial treatment. Long-term adverse reactions are mainly kidney injury and bone marrow suppression, and kidney function damage can be partially relieved by amino acid infusion. For patients with risk factors, the same therapeutic effect can be obtained and adverse reactions can be reduced by adopting a scheme of small-dose multiple treatments. As a novel therapeutic approach, PRRT may offer more options for metastatic NEN treatment in the progressive phase, with promising application prospects.
Lutetium [177Lu ] oxyoctreotide binds to somatostatin receptors, with highest affinity to receptor subtype 2 (SSRT 2). When bound to somatostatin receptor expressing cells (including somatostatin receptor positive malignancies), the compound is internalized. The beta rays emitted by 177Lu induce cell damage by forming free radicals in somatostatin receptor positive cells and neighboring cells. 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 the 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, also because of the sustained decay of radionuclides, which releases 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. Radiolysis 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, increase the noise signal of the diagnostic radiopharmaceutical, make the therapeutic efficacy of the therapeutic radiopharmaceutical insufficient, and cause unnecessary radiation damage to other normal tissues. This also makes the radiolysis problem a significant problem in the development of radiopharmaceuticals. 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.
Furthermore, the addition of stabilizers to the formulation is also an effective way.
Gentisic acid is added into the reaction phase, and ethanol and amino acid are added as stabilizing agents after the reaction. The initial radiochemical purity (RCPs) obtained in these two protocols was 97.5% or more and very close to 98% (initial chemical purity means the radiochemical purity obtained immediately after the radiopharmaceutical has been prepared, i.e. at time 0 after preparation). The higher initial radiochemical purity necessarily extends the shelf life limit of the radiopharmaceutical, facilitating storage and transport of the radiopharmaceutical and facilitating availability of the radiopharmaceutical.
Disclosure of Invention
The object of the present application is to provide a pharmaceutical composition comprising [ active ingredient ] 177 Lu]Radionuclide complexes of Lu-DOTATATE,
in particular, the application relates to the following:
1. an aqueous radiopharmaceutical solution, wherein the aqueous radiopharmaceutical solution comprises: from radioactive metal species 177 Complexes of Lu and a chelating group-linked somatostatin receptor binding peptide, and stabilizers; wherein the radiometal nuclides are present at a concentration of 5-20mCi/mL radioactivity and the stabilizing agent is present at a total concentration of 20-400 mg/mL.
2. The aqueous pharmaceutical solution according to item 1, wherein the stabilizer is one or more selected from gentisic acid and salts thereof, ascorbic acid and salts thereof, histidine, cysteine and salts thereof, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably one or more selected from gentisic acid, ethanol, methionine.
3. The aqueous pharmaceutical solution according to item 2, wherein the stabilizer is added during the reaction to form the complex and after the end of the reaction, respectively.
4. The aqueous pharmaceutical solution according to item 3, wherein,
the stabilizer added during the reaction of forming the complex is selected from one or more than two of gentisic acid and salts thereof, ascorbic acid and salts thereof, histidine, cysteine and salts thereof, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, sea algae sugar, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid;
The stabilizer added after the reaction forming the complex is finished is selected from one or more of gentisic acid and its salt, ascorbic acid and its salt, histidine, cysteine and its salt, methionine, selenomethionine, thiosulphate, maltose, inositol, benzyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid, ethanol or methionine.
5. The aqueous pharmaceutical solution according to item 4, wherein the stabilizer added during the reaction to form the complex and after the end of the reaction is selected from gentisic acid, and the gentisic acid is present in the aqueous pharmaceutical solution at a total concentration of 0.1-10mg/mL, preferably 0.5-5mg/mL.
6. The aqueous pharmaceutical solution according to item 4, wherein the stabilizer added during the reaction to form the complex is gentisic acid, the stabilizer added after the end of the reaction to form the complex is ethanol, and gentisic acid is present in the aqueous pharmaceutical solution at a concentration of 0.1 to 10mg/mL, preferably 0.5 to 5mg/mL, and ethanol is present at a concentration of 0 to 400 mg/mL.
7. The aqueous pharmaceutical solution according to item 4, wherein the stabilizer added during the reaction to form the complex is gentisic acid, the stabilizer added after the end of the reaction to form the complex is methionine, and gentisic acid is present in the aqueous pharmaceutical solution at a concentration of 0.1 to 10mg/mL, preferably 0.5 to 5mg/mL, and methionine is present at a concentration of 0 to 50 mg/mL.
8. The aqueous pharmaceutical solution according to any one of claims 1 to 7, further comprising a buffer, which may be selected from acetate, citrate, phosphate or formate solutions, preferably acetate solutions, more preferably the buffer is a mixed solution of acetic acid and sodium acetate; the concentration of the buffer salt in the buffer solution in the aqueous solution of the drug is 0.005-0.5M.
9. The aqueous pharmaceutical solution according to any one of items 1 to 7, further comprising free 177 Lu chelating agent, the free 177 The Lu chelator is selected from pentetic acid and salts thereof, ethylenediamine tetraacetic acid and salts thereof, preferably pentetic acid; the free radical 177 The Lu chelator is present in the aqueous drug solution at a concentration of 0.005-0.1 mg/mL.
10. A kit, comprising:
a first agent comprising a somatostatin receptor binding peptide linked to a chelating group;
a second reagent which is a solution comprising a first stabilizer and a buffer salt
And a third reagent that is a solution including a second stabilizer and a chelating agent.
11. Use of the aqueous pharmaceutical solution of any one of items 1 to 9 or the kit of item 10 in the preparation of a medicament for treating neuroendocrine tumor.
Effects of the application
The technical scheme provided by the application has the following beneficial effects:
The stabilizer of the aqueous solution of the medicine can be selected from the combination of gentisic acid, ethanol and methionine, and the ethanol has good radiation decomposition resistance, and compared with the prior art, the initial radiochemical purity of the prepared radioactive medicine is not lower than 97%, preferably not lower than 98%. The radiochemical purity of the API of the aqueous pharmaceutical solution adopting the scheme of the application is kept to be not lower than 97% or close to 98% in 48 hours under the storage condition of 35 ℃ and 60% RH, preferably not lower than 97% in 72 hours, and the API has higher stability for the prior disclosed patent.
According to the characteristics of the radiopharmaceuticals and the physicochemical properties of the selected precursors and auxiliary materials, the application also provides a kit, the prescription composition of which is P1 bottle-DOTATATE powder; p2 bottle-gentisic acid, acetic acid, sodium acetate and water for injection; p3 bottle-sodium hydroxide, ethanol, vitamin C, pentetic acid (DTPA) water for injection; the kit is simple to use and convenient to operate, saves the time for preparing a sample specimen and increases the safety of clinical medication.
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 a 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 "comprise" and "comprise" 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 an aqueous radiopharmaceutical solution comprising a drug labelled with a radiometal nuclides and a stabilizer.
In a specific embodiment, the radiometal species is 177 Lu (lutetium-177).
In a specific embodiment, the radionuclide-labeled drug is a radionuclide 177 Complexes of Lu (lutetium-177) and a chelating group-linked somatostatin receptor binding peptide allow the molecule to form stable complexes with radionuclides. The chelating group may be selected from DOTA, NOTA, PCTA, DTPA, NTA, EDTA, DO3A, NOC. In a specific embodiment, the chelating group-linked somatostatin receptor binding peptide is dottate. Wherein the non-radioactive precursor dottate is a TFA salt of a somatostatin analogue, which is a peptide. The molecule undergoes cyclization by disulfide bonds between SH groups of cysteines.
Dottate is a white to off-white powder, readily soluble in water, and non-hygroscopic. Dottate has ten chiral centers and presents stereoisomers.
Wherein, DOTATATATE formula is represented by the following formula:
in a specific embodiment, the 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, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably one or more of gentisic acid, ethanol, methionine.
In a specific embodiment, the total concentration of the stabilizer in the aqueous drug solution is 20-400mg/mL, for example, 20, 30, 40, 50, 60, 70, 80, 100, 150, 200, 250, 300, 350, 400mg/mL, preferably 20-80mg/mL.
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 stabilizing agent and the solution of the radionuclide forming the complex and the solution of the somatostatin receptor binding peptide linked to the chelating group 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 formulation in a pure form upon 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, and 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, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid, ethanol or methionine.
In a preferred embodiment, the first and second stabilizing agents 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 thereof in the reaction system is in the range of 0.1-20.0mg/mL, preferably 0.1-10.0mg/mL, for example, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10mg/mL. Gentisic acid (i.e. the second stabilizer) is added continuously to the formulation after the reaction has ended. Gentisic acid is present in the total concentration of 0.1-10mg/mL, preferably 0.5-3mg/mL, for example 0.5, 1.0, 1.5, 2.0, 2.5, 3.0mg/mL, in the whole aqueous pharmaceutical solution.
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 30-80mg/mL, and may be, for example, 30, 40, 45, 50, 55, 60, 65, 70, 80mg/mL.
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 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 buffer added twice 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 (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 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 adoption of the aqueous solution of the medicine provided by the application can ensure that the radiochemical purity of the API is not lower than 98 percent in 48 hours, more preferably not lower than 97 percent in 72 hours under the storage condition of 35 ℃ and 60% RH, and the radiochemical purity is a value measured by HPLC.
The application also provides a kit of parts comprising a first reagent, a second reagent and a third reagent.
In a specific embodiment, the first agent comprises a somatostatin receptor binding peptide linked by a chelating group, preferably a dottate powder.
In a specific embodiment, the second agent is a solution comprising a first stabilizer, a buffer salt, preferably the second agent comprises gentisic acid, acetic acid, sodium acetate and water for injection.
In a specific embodiment, the third agent is a solution comprising a second stabilizer, a chelating agent, preferably, the third agent comprises sodium hydroxide, ethanol, vitamin C, pentetic acid (DTPA) water for injection.
In a specific embodiment, the first, second and third reagents of the kit may be placed in separate bottles.
In a specific embodiment, the kit may be used to prepare a sample of an aqueous pharmaceutical solution containing a nuclide complex. In a specific embodiment, the solution containing the radionuclide, the first reagent and the second reagent are mixed and then subjected to a complex reaction, and a third reagent is added after the reaction is finished, so that a drug aqueous solution sample is obtained.
In a preferred embodiment, the kit is used as follows: lutetium chloride [ 177 Lu]Adding the solution, the first reagent and the second reagent into a reaction bottle, heating (the reaction temperature is 85 ℃ and the reaction time is 20 minutes) to carry out marking reaction, cooling after the reaction is finished, adding the third reagent, conveying the third reagent into a split charging hot chamber, split charging, detecting and capping.
The kit is simple to use and convenient to operate, saves the time for preparing a sample specimen, and increases the safety of clinical medication.
The kit is simple to use and convenient to operate, saves the time for preparing a sample specimen, and increases the safety of clinical medication.
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, preferably the given time is from 0.1 minutes to 20 minutes, more preferably from 3 minutes to 10 minutes, a solution containing a chelating group-linked somatostatin receptor binding peptide is added to the reaction vessel;
reacting the chelate group-linked somatostatin receptor binding peptide with a radionuclide to obtain the complex;
Adding a solution containing a second stabilizer to the reaction vessel after a given period of reaction;
recovering the resulting aqueous radiopharmaceutical solution.
In one embodiment of the application, the aqueous radiopharmaceutical solution comprises a radionuclide complex formed from a somatostatin receptor binding peptide having a radionuclide linked to a chelating group.
In a specific embodiment, the radionuclide-containing solution is added to the reaction container after being taken out from the raw material bottle, and after the radionuclide-containing solution is taken out, the raw material bottle is rinsed with a rinsing liquid to remove 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 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, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, sea algae sugar, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid.
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 the application, a toolIn an embodiment of the subject, the radionuclide-containing solution is a solution comprising 177 Solutions of Lu and hydrochloric acid, in particular, the radionuclides in the step of complexation of somatostatin receptor binding peptides linked to chelating groups 177 The specific activity of Lu is not less than 30Ci/mg, preferably not less than 60Ci/mg, and most preferably not less than 80Ci/mg. Too low a specific activity 177 Lu affects the radiolabeling efficiency.
In a specific embodiment of the present 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 chelating group-linked somatostatin receptor binding peptide 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 brought by the existing radiolysis in the first stabilizer, thereby protecting the somatostatin receptor binding peptide connected with the chelating group added into the reaction system from being attacked by active free radicals and being beneficial to improving the initial amplification purity of the final product.
In a specific embodiment, the given time is 0.1 to 20 minutes, more preferably 2 to 10 minutes, and may be, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 minutes. In a preferred embodiment, the given time is 5 minutes.
In a specific embodiment, the solution containing the chelating group-linked somatostatin receptor binding peptide is added to a reaction solution to react with a radionuclide to obtain the radionuclide complex.
In a specific embodiment, the chelating group-linked somatostatin receptor binding peptide (labeling precursor) solution is selected from the group consisting of aqueous solutions of compounds at a concentration of 0.5-5.0mg/mL by dissolving the powder of the labeling precursor in sterile injectable water.
In a preferred embodiment, the radionuclide complex is 177 Lu-DOTATATE。
In a specific embodiment, the chelating group-linked somatostatin receptor binding peptide is reacted with a radionuclide to give the radionuclide complex in the presence of gentisic acid as the first stabilizer at a concentration of 0.1-20.0mg/mL, preferably 0.1-10.0 mg/mL, more preferably 0.5-5mg/mL, for example 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5mg/mL in the reaction phase.
In a specific embodiment, the chelating group-linked somatostatin receptor binding peptide is reacted with the radionuclide in a reaction phase solution, wherein the molar ratio between the chelating group-linked somatostatin receptor binding peptide and the radionuclide is 1.5-50, preferably 5-20, for example 5, 8, 10, 12, 15, 18, 20. The molar ratio refers to the ratio of the molar amount of the chelating group-linked somatostatin receptor binding peptide (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 labeling rate, but unlabeled labeled 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 bound by other non-specific targets in the organism and is lost, 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 chelating group-linked somatostatin receptor binding peptide 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 chelate group-linked somatostatin receptor binding peptide and the radionuclide, the reaction temperature and the reaction time are controlled so as to control the reaction labeling 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 may be 50-95 ℃, for example 50, 55, 60, 65, 70, 72, 75, 78, 80, 85 ℃, preferably 60-85 ℃, and the reaction time may be 5-60 minutes, for example 5, 8, 10, 12, 14, 16, 18, 20, 25, 30, 40, 50, 60 minutes, preferably 10-30 minutes, most preferably 10-20 minutes.
In a specific embodiment, the second stabilizer is added after the completion of the reaction of the chelating group-linked somatostatin receptor binding peptide 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 stabilizer added in the post-reaction system is 0-400mg/mL, and may be, for example, 1, 3, 5, 10, 20, 40, 50, 60, 70, 80, 100, 150, 200, 250, 300, 400mg/mL. In some preferred embodiments, the second stabilizer added is gentisic acid or a salt thereof, preferably, it is added to the post-reaction system at a concentration of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 mg/mL; in other preferred embodiments, the second stabilizer added is ethanol, preferably, at a concentration of 10, 30, 40, 45, 50, 55, 60, 65, 70, 80, 100, 200, 300, or 400mg/mL to the post-reaction system; in other preferred embodiments, the second stabilizer added is L-methionine, preferably added to the post-reaction system at a concentration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30 or 50 mg/mL.
In an embodiment of the application, the method of preparation further comprises adding a buffer salt solution prior to reacting the chelating group-linked somatostatin receptor binding peptide with a 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. In a specific embodiment, 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 pH value of the reaction system can be adjusted by adding the buffer salt solution, the pH value of the reaction phase system is controlled to be in the range of 3.5-6.0, preferably the pH value is 3.5-5, and for example, the pH value can be 3.5, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8 and 5.0. In a specific embodiment, the pH of the final formulation solution is controlled to be in the range of 4.5 to 6, and may be, for example, pH4.5, 4.8, 5.0, 5.2, 5.4, 5.5, 5.8, 6.0.
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 adding sodium chloride injection for dilution and recovery, preferably adding sodium chloride injection for dilution and recovery. Considering that too high a concentration of radioactivity causes radiolysis problems, too low a concentration of radioactivity presents challenges for administration, and thus the final formulation has a specification of 5-20mCi/mL, preferably 8-15mCi/mL, which may be 8, 9, 10, 11, 12, 13, 14, 15mCi/mL, for example.
In a preferred embodiment, the filter sterilization and dilution are performed after the addition of the solution containing the second stabilizer. The application is not limited by the sequence of the steps of filtration sterilization and dilution, namely filtration sterilization and dilution can be performed first, or dilution can be performed first, filtration sterilization can be performed through a filter membrane, and recovery can be performed subsequently
In one embodiment, the present application provides a process for preparing in the following order 177 A method of preparing an aqueous Lu-dottate radiopharmaceutical solution:
a. will contain 300mCi 177 Transferring the nuclide solution of Lu and hydrochloric acid from the raw material bottle to the reaction bottle;
b. 0.3mL of a rinse solution containing 2M acetic acid-sodium acetate buffer and 100mg/mL gentisic acid was added to the above raw material bottle to rinse the residue 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 2mL 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. standing the reaction flask containing the above solution at room temperature for 5min4
g. Adding a solution containing 1mg of tagged precursor DOTATATATE to the reaction flask;
h. heating the reaction bottle to 90 ℃ for 20min;
i. after the reaction is finished, cooling a reaction bottle, and adding 3mL of a mixed solution containing 1mg/mL of pentetic acid, 300 mg/mL of ethanol and 1M of sodium hydroxide 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 23mL 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 chemical precursor LuCl used in the examples below 3 Available from ITG, DOTATATATE according to document Tetrahedron Letters (2003) 2393-2396.
Gentisic acid used in the following examples was purchased from Dou Purui technology development limited and ethanol was purchased from Hunan Xiangpikang pharmaceutical Co.
Other materials, reagents, etc., unless otherwise specified, are commercially available.
Example 1: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
mu.L DOTATATATE solution, 10mCi 177 LuCl 3 The solution (about 10. Mu.L) was mixed with 10. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 100mg/ml gentisic acid) and sterilized water for injection to a total volume of 100. Mu.L of the reaction phase solution, the reaction phase solution was heated to react sufficiently, cooled to room temperature, and then 30. Mu.L of an auxiliary material solution (containing 100mg/ml gentisic acid, 3.0mg/ml pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1ml.
Example 2: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
mu.L DOTATATATE solution, 10mCi 177 LuCl 3 The solution (about 10. Mu.L) was mixed with 10. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 100mg/ml gentisic acid) and sterilized water for injection to a total volume of 100. Mu.L of the reaction phase solution, the reaction phase solution was heated to react sufficiently, cooled to room temperature, and then 50. Mu.L of an auxiliary material solution (containing 100mg/ml gentisic acid, 3.0mg/ml pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1ml.
Example 3: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
mu.L DOTATATATE solution, 10mCi 177 LuCl 3 Mixing the solution (about 10 μl) with 10 μl of acetic acid-sodium acetate buffer salt solution (containing 100mg/ml gentisic acid) and sterilized injectable water to obtain a reaction phase solution with total volume of 100 μl, heating the reaction phase solution to react thoroughly, cooling to room temperature, adding 10 μl adjuvantThe total volume of the preparation was 1ml by mixing the solution (containing 100mg/ml gentisic acid, 3.0mg/ml pentetic acid) with physiological saline.
Example 4: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
mu.L DOTATATATE solution, 10mCi 177 LuCl 3 (about 10. Mu.L) of the solution was mixed with 10. Mu.L of an acetic acid-sodium acetate buffer salt solution (containing 100mg/ml gentisic acid) and sterile water for injection to a total volume of 50. Mu.L of a reaction phase solution, the reaction phase solution was heated to react sufficiently, cooled to room temperature, and 10. Mu.L of an auxiliary material solution (containing 100mg/ml gentisic acid, 3.0mg/ml pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1ml.
Example 5: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
mu.L DOTATATATE solution, 10mCi 177 LuCl 3 (about 10. Mu.L) of the solution was mixed with 10. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 100mg/mL of gentisic acid) and sterile water for injection to a total volume of 100. Mu.L of the reaction phase solution, the reaction phase solution was heated to react sufficiently, and after cooling to room temperature, 200. Mu.L of an auxiliary material solution (containing 400mg/mL of ethanol, 0.5mg/mL of pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1mL.
Example 6: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
mu.L DOTATATATE solution, 10mCi 177 LuCl 3 (about 10. Mu.L) of the solution was mixed with 10. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 100mg/mL of gentisic acid) and sterile water for injection to a total volume of 100. Mu.L of the reaction phase solution, the reaction phase solution was heated to react sufficiently, and after cooling to room temperature, 200. Mu.L of an auxiliary material solution (containing 150mg/mL of ethanol, 0.5mg/mL of pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1mL.
Example 7: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
mu.L DOTATATATE solution, 10mCi 177 LuCl 3 (about 10. Mu.L) solution and 10. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 100mg/mL gentisic acid), sterilizingThe reaction phase solution was heated to react thoroughly by mixing the reaction phase solution with water for injection to a total volume of 100. Mu.L, and after cooling to room temperature, 400mg/mL of ethanol, 200. Mu.L of an auxiliary material solution (0.5 mg/mL of pentetic acid) and physiological saline were added thereto to make the total volume of the preparation about 1mL.
Example 8: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
mu.L DOTATATATE solution, 10mCi 177 LuCl 3 (about 10. Mu.L) of the solution was mixed with 10. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 100mg/mL of gentisic acid) and sterile water for injection to a total volume of 100. Mu.L of the reaction phase solution, the reaction phase solution was heated to react sufficiently, cooled to room temperature, and 200. Mu.L of an auxiliary material solution (containing 15mg/mL of methionine, 0.5mg/mL of pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1mL.
Example 9: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
About 10. Mu.L DOTATATE solution, 10mCi 177 LuCl 3 (about 10. Mu.L) of the solution was mixed with 10. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 100mg/mL of gentisic acid) and sterilized water for injection to a total volume of 100. Mu.L of the reaction phase solution, the reaction phase solution was heated to react sufficiently, and after cooling to room temperature, 200. Mu.L of an auxiliary material solution (containing 5mg/mL of methionine, 0.5mg/mL of pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1mL.
Example 10: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
mu.L DOTATATATE solution, 10mCi 177 LuCl 3 (about 10. Mu.L) of the solution was mixed with 10. Mu.L of an acetic acid-sodium acetate buffer salt solution (containing 100mg/mL of gentisic acid) and sterilized water for injection to a total volume of 100. Mu.L of the reaction phase solution, the reaction phase solution was heated to react sufficiently, cooled to room temperature, and 200. Mu.L of an auxiliary material solution (containing 25mg/mL of methionine, 0.5mg/mL of pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1mL.
Example 11: [ 177 Lu]Preparation of Lu-DOTATATATE pharmaceutical aqueous solution
mu.L DOTATATATE solution, 10mCi 177 LuCl 3 (about 10. Mu.L) of the solution was mixed with 10. Mu.L of an acetic acid-sodium acetate buffer salt solution (containing 100mg/mL of gentisic acid) and sterilized water for injection to a total volume of 100. Mu.L of the reaction phase solution, the reaction phase solution was heated to react sufficiently, cooled to room temperature, and 200. Mu.L of an auxiliary material solution (containing 250mg/mL of methionine, 0.5mg/mL of pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1mL.
Comparative example 1
Will 10mCi 177 LuCl 3 (about 10. Mu.L) of the solution, 10. Mu.L of DOTATATE solution and acetic acid-sodium acetate buffer salt solution (containing 100mg/mL gentisic acid), and sterile water for injection were mixed to a reaction phase solution having a total volume of 100. Mu.L, the reaction phase solution was heated to react sufficiently, cooled to room temperature, and 100. Mu.L of an auxiliary material solution (containing 28mg/mL ascorbic acid, 0.5mg/mL pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1mL.
Comparative example 2
Will 10mCi 177 LuCl 3 (about 10. Mu.L) of the solution, 10. Mu.L of DOTATATE solution and acetic acid-sodium acetate buffer salt solution (containing 50mg/mL gentisic acid), and sterile water for injection were mixed to a reaction phase solution having a total volume of 100. Mu.L, the reaction phase solution was heated to react sufficiently, cooled to room temperature, and 100. Mu.L of an auxiliary material solution (containing 5mg/mL gentisic acid) and physiological saline were added thereto to make the total volume of the preparation 1mL.
Comparative example 3
Will 10mCi 177 LuCl 3 (about 10. Mu.L) of the solution, 10. Mu.L of DOTATATE solution and acetic acid-sodium acetate buffer salt solution (containing 10mg/mL of gentisic acid), and sterile water for injection were mixed to a reaction phase solution having a total volume of 100. Mu.L, the reaction phase solution was heated to react sufficiently, cooled to room temperature, and 100. Mu.L of an auxiliary material solution (containing 28mg/mL of ascorbic acid, 0.5mg/mL of pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1mL.
Experimental example 1 [ 177 Lu]Lu-DOTATATATE drug aqueous solution stability evaluation experiment
1.25 ℃ degradation pure detection experiment
The aqueous pharmaceutical solutions obtained in examples 1 to 11 and comparative examples 1 to 3 were stored at 25℃and 60% RH for 48 hours and 72 hours, and the API release purity was measured by HPLC, and the results are shown in Table 1.
2.35 ℃ degradation pure detection experiment
The aqueous pharmaceutical solutions obtained in examples 1 to 11 and comparative examples 1 to 3 were stored at 35℃and 60% RH for 48 hours and 72 hours, and the API release purity was measured by HPLC, and the results are shown in Table 1.
Table 1: experimental results of examples and comparative examples
Analysis of experimental results: the technical schemes of examples 1-4 (gentisic acid is added before and after the reaction), the technical schemes of examples 5-7 (gentisic acid is added before the reaction and ethanol is added after the reaction) and the technical schemes of examples 8-11 (gentisic acid is added before the reaction and methionine is added after the reaction) are adopted, the obtained aqueous pharmaceutical solution has higher release purity values, can reach more than 97% after 48 hours and 72 hours and can still be kept at a higher temperature of 35 ℃, and is obviously superior to the samples of the gentisic acid+vitamin C of the comparative example, the samples of the gentisic acid of the comparative example (0.5 mg/mL) and the samples of the gentisic acid of the comparative example (0.1 mg/mL), and the stabilizer selection and addition sequence of the stabilizing agent of the embodiment of the application have effective superposition effect on the product release purity, and can bring more excellent stability, wherein the gentisic acid concentration is in the range of 1mg/mL-5mg/mL, the ethanol concentration is in the range of 30mg/mL-80mg/mL, and the methionine concentration is more excellent in the range of 1 mg-50 mg/mL.
Experimental example 2 control of reaction temperature and time
To the reactor was added an aqueous precursor solution containing 10. Mu.g DOTATATE and 50mCi 177 LuCl 3 (about 50. Mu.L) of the solution, the pH of the solution was adjusted to 5 using a buffer solution containing 5. Mu.g of gentisic acid, water for injection was added thereto to make the volume of the reaction phase 1mL, and the reaction system was heated at a certain temperature for a certain period of time. From the point of view of the labeling rate (labeling rate = radioactivity chelated with precursor molecules +.total radioactivity), the labeling rate of the reaction can reach 90% when the reaction temperature is 50-95 ℃ and the reaction time is 5-60 minutes, preferably the reaction temperature is 60-80 ℃, preferably the reaction time is 10-30 minutes, and the labeling rate can reach more than 99%. From the standpoint of radiochemical purity, when the reaction temperature is 50 to 95℃and the reaction time is 5 to 60 minutes, the initial radiochemical purity of the resulting labeled compound is obtained>95%, preferably at a temperature of 60-80℃and for a time of 10-30 minutes, in which case the initial radiochemical purity of the labeled compound obtained is such that>98％。
Experimental example 3 control of pH value
To the reactor was added an aqueous precursor solution containing 10. Mu.g DOTATATE and 50mCi 177 LuCl 3 (about 50. Mu.L) of the solution, the solution was adjusted to a pH value (5. Mu.g of gentisic acid in the buffer solution) using various buffer solutions, water for injection was added thereto so that the volume of the reaction phase became 1mL, and the reaction system was heated at 65℃for 20 minutes. Reaction labeling Rate when the pH of the reaction phase solution is in the range of 4.5 to 6.0 >99％。
Experimental example 4 control of quenching time
(1) Preparation of aqueous pharmaceutical solutions without quenching time
Sequentially adding 10 mu L of DOTATATE aqueous solution and 10mCi into a reactor 177 LuCl 3 (about 10. Mu.L) of the solution was mixed with 10. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 100mg/ml gentisic acid) and sterilized water for injection to a total volume of 100. Mu.L of the reaction phase solution, the reaction phase solution was heated to react sufficiently, and after cooling to room temperature, 35. Mu.L of an auxiliary material solution (containing 100mg/ml gentisic acid, 3.0mg/ml pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1ml. The initial mark rate was 95% at this time.
(2) Preparation of aqueous drug solution under quenching for 5 minutes
To the reactor were successively added 70. Mu.L of sterilized water for injection, 10. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 100mg/ml gentisic acid), 10mCi 177 LuCl 3 (about 10. Mu.L) solution, and allowed to stand at room temperature for 5 minutes after being mixed uniformly. After standing, 10. Mu.L of DOTATATE aqueous solution was added, and mixed to form a reaction phase solution, the reaction phase solution was heated to allow the reaction phase solution to react sufficiently, and after cooling to room temperature, 30. Mu.L of an auxiliary material solution (containing 100mg/ml of gentisic acid, 3.0mg/ml of pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1ml. The initial mark rate was 99% at this time.
(3) Preparation of aqueous drug solution quenched for 15 min
To the reactor were successively added 70. Mu.L of sterilized water for injection, 10. Mu.L of acetic acid-sodium acetate buffer salt solution (containing 100mg/ml gentisic acid), 10mCi 177 LuCl 3 (about 10. Mu.L) solution, and allowed to stand at room temperature for 10 minutes after being mixed uniformly. After standing, 10. Mu.L of DOTATATE solution was added, and mixed to form a reaction phase solution, the reaction phase solution was heated to allow the reaction phase solution to react sufficiently, and after cooling to room temperature, 30. Mu.L of an auxiliary material solution (containing 100mg/ml gentisic acid, 3.0mg/ml pentetic acid) and physiological saline were added thereto to make the total volume of the preparation 1ml. The initial mark rate was 99% at this time.
Analysis of experimental results: before adding the labeling precursor solution, the mixed solution of 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 compound is added for reaction, so that the initial amplification purity of the API can be obviously improved. The quenching time is sufficient to allow the first stabilizer to contact the nuclide solution and allow a substantial amount of the free radicals in the solution generated by the high radioactivity to be quenched by the first stabilizer, thereby reducing the damage of the free radicals to the labeled precursor molecules during subsequent addition of the labeled precursor. The standing time is controlled to be 2-20min, preferably 2-10min, and most preferably about 5min.
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 is capable of modification in detail without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims (11)

1. An aqueous radiopharmaceutical solution, wherein the aqueous radiopharmaceutical solution comprises: from radiometallic nuclides 177 Complexes of Lu and a chelating group-linked somatostatin receptor binding peptide, and stabilizers; wherein the radiometal nuclides are present at a concentration of 5-20mCi/mL radioactivity and the stabilizing agent is present at a total concentration of 20-400 mg/mL.
2. The aqueous pharmaceutical solution according to claim 1, wherein the 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, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably one or more of gentisic acid, ethanol, methionine.
3. The aqueous pharmaceutical solution according to claim 2, wherein the stabilizer is added during the reaction to form the complex and after the end of the reaction, respectively.
4. The aqueous pharmaceutical solution according to claim 3, wherein,
the stabilizer added during the reaction of forming the complex 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, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, trehalose, povidone, nicotinamide, ethanol, curcumin, melatonin, preferably gentisic acid;
the stabilizer added after the reaction forming the complex is finished is selected from one or more than two 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 and melatonin, preferably gentisic acid, ethanol or methionine.
5. The aqueous pharmaceutical solution according to claim 4, wherein the stabilizer added during and after the reaction forming the complex is selected from gentisic acid and the gentisic acid is present in the aqueous pharmaceutical solution in a total concentration of 0.1-10mg/mL, preferably 0.5-5mg/mL.
6. The aqueous pharmaceutical solution according to claim 4, wherein the stabilizer added during the reaction forming the complex is gentisic acid, the stabilizer added after the end of the reaction forming the complex is ethanol, and gentisic acid is present in the aqueous pharmaceutical solution at a concentration of 0.1-10mg/mL, preferably 0.5-5mg/mL, ethanol is present at a concentration of 0-400 mg/mL.
7. The aqueous pharmaceutical solution according to claim 4, wherein the stabilizer added during the reaction to form the complex is gentisic acid, the stabilizer added after the end of the reaction to form the complex is methionine, and gentisic acid is present in the aqueous pharmaceutical solution at a concentration of 0.1-10mg/mL, preferably 0.5-5mg/mL, methionine is present at a concentration of 0-50 mg/mL.
8. The aqueous pharmaceutical solution according to any one of claims 1 to 7, further comprising a buffer, which may be selected from acetate, citrate, phosphate or formate solutions, preferably acetate solutions, more preferably the buffer is a mixed solution of acetic acid and sodium acetate; the concentration of the buffer salt in the buffer solution in the aqueous drug solution is 0.005-0.5M.
9. The aqueous pharmaceutical solution according to any one of claims 1 to 7, further comprising free 177 Lu chelator, the free 177 Lu chelators may beSelected from pentetic acid and its salts, ethylenediamine tetraacetic acid and its salts, preferably pentetic acid; the free radical 177 The Lu chelator is present in the aqueous drug solution at a concentration of 0.005-0.1 mg/mL.
10. A kit, comprising:
a first agent comprising a somatostatin receptor binding peptide linked to a chelating group;
a second reagent that is a solution comprising a first stabilizer, a buffer salt;
and a third reagent that is a solution including a second stabilizer and a chelating agent.
11. Use of an aqueous pharmaceutical solution according to any one of claims 1 to 9 or a kit according to claim 10 for the preparation of a medicament for the treatment of neuroendocrine neoplasia.
CN202210343626.7A 2022-04-02 2022-04-02 Aqueous radiopharmaceutical solution and use thereof Pending CN116920128A (en)

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