99mtc injection preparation and preparation method therefor

Abstract

A technetium [99mTc] injection preparation and a preparation method therefor and the use thereof. The preparation comprises component A and component B which are physically isolated from each other, wherein the component A comprises an active ingredient capable of being combined with a compound providing technetium [99mTc] to form a technetium [99mTc] drug, and the component B comprises a solvent capable of dissolving the technetium [99mTc] drug. The technetium [99mTc] injection preparation is suitable for single-photon emission computed tomography (SPECT) / CT imaging of prostate-specific membrane antigen (PSMA) positive lesions in prostate cancer patients.

Description

A sort of 99m Tc injection preparation and preparation method thereof

[0001] This application requests a Chinese patent application for "a 99m Tc injection preparation and preparation method thereof" (application number 202311154380.X, application date September 7, 2023). Technical Field

[0002] The present invention relates to the field of pharmaceutical preparations, and in particular to a technetium[ 99m Tc] injection preparation and its preparation method and application. Background Art

[0003] Nuclear medicine imaging technology is a very important diagnostic tool in medical imaging. By using radioactive isotopes as tracers, it can observe and evaluate the metabolic activity, physiological function, and pathological conditions of organs, tissues, or lesions in the human body. 99m Tc is also known as technetium[ 99m Tc] is one of the most commonly used radioactive isotopes because of its short half-life (about 6 hours) and suitable gamma ray energy, making it an ideal tracer widely used in nuclear medicine imaging diagnosis.

[0004] Currently, technetium [ 99m As a clinical radioactive diagnostic drug, [Tc] injection is primarily used to diagnose cardiovascular, oncology, orthopedic, neurological, and urological diseases. In the field of urological diseases, it is particularly suitable for single-photon emission computed tomography (SPECT / CT) imaging of prostate-specific membrane antigen (PSMA)-positive lesions in prostate cancer patients.

[0005] Specifically, because prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, it has become an important target for radiological diagnosis. Based on this target, in SPECT / CT imaging, patients first need to receive technetium [ 99m Tc] injection. 99m The [Tc]-labeled PSMA ligand is delivered to PSMA-positive lesions in the patient's body via the circulatory system. During the SPECT scan, a gamma-ray detector captures gamma rays emitted from the body and generates a corresponding image. CT scanning provides anatomical information corresponding to the SPECT image. Finally, by registering the SPECT and CT images, physicians can locate, evaluate, and analyze PSMA-positive lesions in prostate patients.

[0006] The applicant's earlier patents WO2021175338A1 and CN111777663B reported a PSMA binder HYNIC-PSMA that can be combined with technetium [ 99m Tc] to form a complex to avoid the adverse effects of physiological uptake on imaging results. However, the applicant found that HYNIC-PSMA and technetium [ 99m The complex formed by [Tc] is very unstable and its activity is significantly reduced in a short period of time (more than ten hours). Therefore, a new preparation is needed to meet the application of HYNIC-PSMA.

[0007] Summary of the Invention

[0008] In order to solve the problems raised in the above background technology, the present invention discloses a technetium [ 99m Technetium [ 99m Tc] injection and its preparation process.

[0009] The technetium in the present invention 99m Tc] injection preparation comprises: component A, component B, wherein component A includes a 99m Tc] compounds combined to form technetium [ 99m Tc] active ingredient of the drug, component B includes a 99m Tc] solvent for the drug; component A and component B are physically isolated from each other.

[0010] Preferably, the component B can also be used as component A to provide technetium [ 99m Tc] is a reaction solvent or dispersant for the reaction of the compound.

[0011] In a preferred embodiment, the binding can be achieved through one or more of ionic bonds, covalent bonds, hydrogen bonds, and van der Waals forces, such as technetium [ 99m Tc] forms a technetium [ 99m Tc] organic metal complex or coordination compound (or called ligand).

[0012] In a preferred embodiment, the covalent bond can be a disulfide bond, a peptide bond, an ester bond, a π bond, a single bond, or the like.

[0013] In a preferred embodiment, the component A may further include one or more of an excipient, an osmotic pressure regulator, an antioxidant, a pH regulator, a sustained-release agent, a solubilizer, a cosolvent, and a preservative.

[0014] More preferably, the component A can be a solution or a lyophilized powder, and is preferably a lyophilized powder. If it is a solution, component A may further include a solvent.

[0015] In a preferred embodiment, component B may further include a pH buffer. Preferably, the pH buffer may buffer and adjust the pH between component A and the 99m The pH of the reaction system when the compound of Tc] is reacted is preferably buffered and / or adjusted to 4-6, more preferably 4.2-5.8, more preferably 4.5-5.5, for example 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, or 5.4.

[0016] In a preferred embodiment, the technetium [ 99m Tc] injection preparation can also include component C, which is capable of providing technetium [ 99m Tc], and the component C can be combined with at least part of the active ingredient in the component A to form technetium [ 99m Tc] drug. Component C is physically isolated from components A and B.

[0017] In a preferred embodiment, the technetium [ 99m The injection solution may further comprise a component D, which is physically isolated from other components, wherein the component D comprises a component that can be used for technetium [ 99m diluent for Tc] injection.

[0018] In the above content of the present application, the active ingredient preferably includes a PSMA precursor, and the PSMA precursor has the following chemical structure:

[0019] in:

[0020] m is an integer from 0 to 5; such as 1, 2, 3, 4

[0021] n is an integer from 0 to 5, such as 1, 2, 3, or 4; but m and n are not both 0;

[0022] f, g are 0 or 1; preferably, f and g are not 0 at the same time;

[0023] Q1-Q3 are independently selected from -COOH, -SOOH, -SO3H, -SO4H, -POOH, -PO3H or -PO4H2;

[0024] X is an optionally substituted aryl or heteroaryl, wherein the substitution is substituted by at least one R group; Y is an optionally substituted aryl, an optionally substituted heterocyclic aryl, an optionally substituted cycloalkyl, or an optionally substituted heterocycloalkyl, wherein the substitution is substituted by at least one R group;

[0025] R, R 1 -R 8, R' are each independently selected from H, alkyl, halogen, -CN, -OH, -NH2, alkoxy or cycloalkyl;

[0026] AA1 is a natural or unnatural amino acid, a peptide composed of amino acids, or -CH2CH2-.

[0027] Furthermore, the PSMA precursor is the following compound:

[0028] Furthermore, the R, R 3 and R' are each independently selected from H, C1-C 10 Alkyl; said X is optionally substituted phenyl, naphthyl, biphenyl, indolyl, benzothiazolyl or quinolinyl; said optionally substituted heterocycloalkyl is selected from N-piperidinyl or N-methylated piperidinyl salt.

[0029] If not otherwise specified, in the present invention, the term "alkyl" by itself or as part of another molecule refers to a straight chain, branched chain or cyclic hydrocarbon group, or a combination thereof, which may be fully saturated, mono- or polyunsaturated, and may include divalent and polyvalent groups. The "alkyl" residue is preferably C1 to C 10 And can be unsubstituted or substituted (for example with halogen).Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl etc.This also applies to the corresponding cycloalkyl compounds preferably having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.Unsaturated alkyl is an alkyl with one or more double bonds or triple bonds.Examples of unsaturated alkyl include but are not limited to vinyl, 2-propenyl, 2-butenyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologues and isomers.Unless otherwise indicated, the term "alkyl" is also used to include those derivatives of alkyl, such as "heteroalkyl", "haloalkyl" and "high alkyl".

[0030] As used herein, the term "aryl" refers to a closed ring structure having at least one ring with a conjugated π electron system and includes carbocyclic aryl and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups. Carbocyclic or heterocyclic aromatic groups can contain 5 to 20 ring atoms. The above terms include covalently linked monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. Aromatic groups can be unsubstituted or substituted. Non-limiting examples of "aromatic" or "aryl" groups include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, anthracenyl, and phenanthrenyl. Substituents for each of the above-mentioned aryl and heteroaryl ring systems are selected from acceptable substituents described herein (e.g., alkyl, carbonyl, carboxyl, or halogen). When used together with other terms (including but not limited to aryloxy, arylthioxy, aralkyl), the term "aryl" includes aryl and heteroaryl rings. Thus, the term "aralkyl" or "alkaryl" is intended to include those groups in which an aryl group is attached to an alkyl group (including but not limited to benzyl, phenethyl, pyridylmethyl, etc.), including those alkyl groups in which carbon atoms (including but not limited to methylene) have been replaced by heteroatoms, such as, by way of example only, oxygen atoms. Examples of such aryl groups include but are not limited to phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like.

[0031] "Heteroaryl" refers to an aromatic radical containing at least one heteroatom selected from N, O, and S; wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heteroaryl radical may be substituted or unsubstituted. The heteroaryl radical may be attached to the remainder of the molecule via a heteroatom. Non-limiting examples of suitable radicals include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl , 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, purinyl, 2-benzimidazolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl.

[0032] The term "amino acid" refers to naturally occurring and unnatural amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Natural amino acids are the 20 common amino acids in their D- or L- forms (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine), as well as pyrrolysine and selenocysteine. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids, by way of example only, an ex-carbon attached to a hydrogen, a carboxyl group, an amino group, and an R group. Such analogs can have modified R groups (by way of example, norleucine) or can have a modified peptide backbone while still retaining the same basic chemical structure as naturally occurring amino acids. Non-limiting examples of amino acid analogs include homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. Amino acids may be referred to herein by their names, their commonly known three-letter symbols or by single-letter symbols (recommended by the IUPAC-IUB Biochemical Nomenclature Committee). "Non-natural amino acid" refers to an amino acid that is not one of the 20 common amino acids or pyrrolysine or selenocysteine. Other terms that may be used synonymously with the term "non-natural amino acid" are "non-naturally encoded amino acids," "non-natural amino acids," "non-naturally occurring amino acids," or "artificial amino acids." The term "non-natural amino acid" includes, but is not limited to, amino acids that occur by modification of naturally encoded amino acids in their backbones or side chains. In some embodiments, non-natural amino acids include carbonyl, acetyl, aminooxy, hydrazine groups, hydrazide groups, semicarbazide groups, azido groups, or alkynyl groups.

[0033] Some residues herein (including but not limited to non-natural amino acids) can exist in several tautomeric forms. All such tautomeric forms are considered to be part of the compounds described herein. In addition, all enol ketone forms of any compound herein are considered to be part of the compositions described herein.

[0034] AA1, i.e., natural and / or non-naturally occurring amino acids, can be bound within the molecule via peptide or amide bonds. However, in the case of acidic amino acids (e.g., glutamic acid, aspartic acid), binding may alternatively be via the α-, β-, or γ-position.

[0035] Although it is preferred that the Z group is -COOH, it can be readily replaced by biosteric alternatives such as -SO2H, -SO3H, -SO4H, -PO2H, -PO3H, -PO4H2, see, for example, "The Practice of Medicinal Chemistry" (Academic Press New York, 1996), page 203.

[0036] Within the meaning of the present invention, all residues are considered combinable unless otherwise indicated in the definition of a residue. All conceivable subgroups thereof are considered to be disclosed.

[0037] According to the invention, all chiral C atoms should have the D- and / or L-configuration; furthermore, combinations should be possible within one compound, ie some chiral C atoms may be in the D-configuration and others in the L-configuration.

[0038] In a preferred embodiment, AA1 has the following chemical formula:

[0039] in

[0040] and R″ is selected from H, COOH, CH2COOH, C2H4COOH, CH(COOH)2, CH(CH2COOH)2, CH(COOH)(CH2COOH), CH2CH(COOH)2, or SO3H;

[0041] i1 and i2 are independently selected from numbers 1-3; R 10 Selected from H, CH3.

[0042] Preferably, AA1 is an amino acid or peptide that brings a hydrophilic element into the PSMA precursor.

[0043] More preferably, the PSMA precursor is the following compound:

[0044] In a preferred embodiment, the A component or the active ingredient further comprises a co-ligand component tris(hydroxymethyl)methylglycine (TRICINE); more preferably, a second co-ligand is further included for reacting with the PSMA precursor together with the PSMA precursor. 99m Tc forms a complex, and the second co-ligand can be a polyamine, a polyacid, an organic phosphine compound, for example: one or more of ethylenediamine-N,N'-diacetic acid (EDDA), sodium 3-diphenylphosphinobenzenesulfonate (TPPMS), and sodium triphenylphosphine tris-metasulfonate (TPPTS).

[0045] In a preferred embodiment, the present invention is capable of providing technetium [ 99m Tc] is selected from the group consisting of 99m Tc-L, wherein L can be one or more selected from N-tris(hydroxymethyl)methylglycine, ethylenediamine-N,N'-diacetic acid, triphenylphosphine tris-metasulfonate, 3,3'-(phenylphosphinodiyl)di(benzene-1-sulfonic acid) disodium, diphenylphosphinobenzene-3-sulfonate sodium, nicotinic acid, glucoheptonic acid, glucosamine, mannitol, or diphenylphosphinobenzoic acid. Preferably, the technetium [ 99m Tc] compounds are high technetium [ 99m Tc] sodium bicarbonate, which can be an injection preparation or other preparations that can be used to prepare an injection.

[0046] Preferably, the excipient is selected from polyols, i.e., one or more of alcohols, ketols, and aldehydes having at least two hydroxy groups, such as one or more of mannitol, lactose, glucose, and dextran; and at least tetrahydric alcohols are particularly preferred.

[0047] Preferably, the solubilizer is selected from surfactants such as Tween-80, Tween-60, and poloxamer that reduce the surface tension of liquids.

[0048] Preferably, the cosolvent is selected from one or more of benzoic acid, sodium benzoate, salicylic acid, sodium salicylate, p-aminobenzoic acid, sodium p-aminobenzoate, malic acid, methionine, arginine, nicotinic acid, vitamin B6, sodium bicarbonate, urethane, glucose, meglumine, erucamide, and urea.

[0049] Preferably, the osmotic pressure regulator is one or more selected from sodium chloride, glucose, fructose, glycerol, sorbitol, xylitol, magnesium chloride, phosphate, sodium citrate, and mannitol.

[0050] Preferably, the antioxidant is selected from one or more of L-cysteine ​​hydrochloride, sodium sulfite, sodium bisulfite, propyl gallate, glutathione, sodium thiosulfate, thiourea, thioglycolic acid, sodium metabisulfite, potassium metabisulfite, vitamin E, sodium vitamin C, sodium phytate and ascorbyl palmitate.

[0051] Preferably, the pH regulator includes an acidic regulator and an alkaline regulator; wherein the acidic regulator is selected from one or more of hydrochloric acid, lactic acid, acetic acid, citric acid, malic acid, arginine and tartaric acid; and the alkaline regulator is selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate and disodium hydrogen phosphate.

[0052] In a preferred embodiment, the solvent is selected from one or more of water, soybean oil, safflower oil, sesame oil, cottonseed oil, and fish oil.

[0053] Preferably, the buffer is selected from one or more groups of disodium succinate and succinic acid, citric acid and sodium citrate, sodium acetate and acetic acid.

[0054] Preferably, the diluent is selected from one or more of sodium chloride injection, glucose injection and amino acid injection.

[0055] Preferably, the technetium [ 99m Tc] injection preparation composition includes, and preferably consists of:

[0056] Component A, comprising:

[0057] PSMA precursor: 20-50 μg, preferably 25-45 μg, such as 30 μg, 35 μg, 40 μg;

[0058] Second co-ligand: 2.5-4 mg, preferably 2.8-3.6 mg, such as 3.0 mg, 3.2 mg, 3.4 mg;

[0059] TRICINE: 5-8 mg, preferably 6-7 mg, such as 6.2 mg, 6.5 mg, 6.7 mg;

[0060] Component B, comprising:

[0061] Buffer: 40-55 mg, preferably 45-50 mg, such as 40 mg, 42 mg, 45 mg, 48 mg;

[0062] Solvent: Make up the total volume to 2-5 ml; preferably 2.5-4.5 ml, preferably 3-4 ml.

[0063] Or it may also include:

[0064] Component C: 99m The Tc content is ≥10 mCi, more preferably ≥15, and more preferably ≥20 mCi.

[0065] More preferably, component A may further include:

[0066] Antioxidant: 0.5-4 mg, preferably 1-3.5 mg, more preferably 1.5-3 mg, such as 2-2.5 mg;

[0067] Excipient: 0-50 mg, preferably 5-50 mg, more preferably 10-50 mg, such as 20-40 mg;

[0068] Osmotic pressure regulator: 0-50 mg, preferably 5-50 mg, more preferably 10-50 mg, such as 20-40 mg.

[0069] More preferably, in the above content of the present application, the components with different functions may be the same substance. For example, the excipient and the osmotic pressure regulator in component A may both be mannitol. In this case, the total amount of the excipient and the osmotic pressure regulator may be 0-50 mg, preferably 5-50 mg, more preferably 10-50 mg, such as 20-40 mg.

[0070] More preferably, in the above content of the present application, the components with the same function may be more than one substance, for example, the pH adjuster in component A may be a combination of hydrochloric acid and sodium hydroxide. For another example, the pH buffer in component B may be a combination of succinic acid and disodium succinate. In this case, the pH buffer includes:

[0071] Succinic acid: 10-15 mg, more preferably 11-14 mg, more preferably 12-13 mg, such as 12.2 mg, 12.5 mg, 12.7 mg

[0072] Disodium succinate: 30-45mg, such as 33mg, 35mg, 38mg, 40mg, 42mg.

[0073] In a second aspect, the present invention also provides a [99m The preparation method of the Tc] injection preparation comprises the following steps:

[0074] Dissolve the buffer in the solvent to prepare component B;

[0075] The active ingredient is dissolved in a second solvent, freeze-dried to prepare a lyophilized powder, and the second solvent is removed during the freeze-drying process to prepare the lyophilized powder, thereby obtaining component A;

[0076] Component A and component B are packaged in physical isolation from each other.

[0077] More preferably, the preparation method further comprises providing component C, and component C is packaged in a physically isolated manner from component A and component B.

[0078] In a preferred embodiment, the active ingredient is dissolved in the second solvent together with one or more of an excipient, an osmotic pressure regulator, an antioxidant, a pH regulator, a sustained-release agent, a solubilizer, a cosolvent, and a preservative.

[0079] In a preferred embodiment, the second solvent may be one or more of water, alcohol, organic acid, and ester solvent, such as water and glacial acetic acid.

[0080] In a preferred embodiment, the preparation method of component A comprises:

[0081] The active ingredient is dissolved in solvent A1, or an optional excipient is dissolved in solvent A2; and the two are then mixed;

[0082] If the pH value after mixing does not reach the expected value, a pH regulator is added to adjust the pH value. If the pH value reaches the expected value, no pH regulator is added.

[0083] Freeze-dry to obtain freeze-dried powder.

[0084] The solvents A1 and A2 can be independently water, organic acid, alcohol, ketone, aldehyde, ester solvents, such as water, acetic acid, ethanol, propylene glycol, volatile oil, etc.

[0085] Among them, the expected pH value is ≤5, more preferably ≤4.5, more preferably 2-5, more preferably 3-4, such as 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, etc.

[0086] The third aspect of the present application is to provide a technetium [ 99m The method for using the Tc] injection preparation comprises the following steps:

[0087] Component A and component B are mixed and dissolved to obtain a mixed solution;

[0088] Component C is added to the mixture and heated to react;

[0089] After the reaction is completed, technetium [ 99m Tc] injection.

[0090] Component C can be diluted to a desired concentration using a diluent.

[0091] In a preferred embodiment, the heating reaction is carried out at a temperature of 80-150°C, preferably 90-130°C, and more preferably 100-120°C.

[0092] In a preferred embodiment, the heating reaction preferably has a reaction time of 5-60 min, more preferably 10-50 min, more preferably 15-40 min, more preferably 20-35 min, and more preferably 25-30 min.

[0093] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0094] The present invention discloses a technetium[ 99m Tc] injection preparation and its preparation method, wherein the components are classified and physically isolated, thereby improving the storage stability and providing convenience for the subsequent preparation of hot medicines, and the quality control method thereof can better achieve quantification and prepare technetium [ 99m The process of Tc] injection is safer, simpler and more efficient. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] The accompanying drawings, which constitute part of this application, are intended to provide a further understanding of this application. The exemplary embodiments and descriptions of this application are intended to explain this application and do not constitute an improper limitation on this application. In the accompanying drawings:

[0096] Figure 1-1 and Figure 1-2 are diagrams of the present invention. 99m Tc] injection preparation reaction route.

[0097] FIG2 is a technetium [ 99m Flow chart of the method of use of Tc injection preparation.

[0098] FIG3 is a technetium [ 99m Production flow chart of component A in Tc] injection preparation.

[0099] FIG4 is a technetium [ 99m Production flow chart of component B in Tc injection preparation. DETAILED DESCRIPTION

[0100] The following describes the embodiments of the present invention using specific examples and accompanying drawings. Those skilled in the art will readily understand the other advantages and benefits of the present invention from the disclosure herein. The present invention may also be implemented or applied through other different specific examples, and the details in this specification may be modified and altered based on different viewpoints and applications without departing from the spirit of the present invention.

[0101] The technetium in the present invention 99m Tc] injection preparation contains the following raw materials: component A, component B and component C;

[0102] Component A contains an active ingredient, which includes a PSMA precursor. In the following embodiments, the present application is introduced using the PSMA precursors (P1 and P2) with the following chemical structures as examples:

[0103] The synthesis methods of P1 and P2 can refer to WO2021175338A1 and CN111777663B.

[0104] The active ingredient also includes tris(hydroxymethyl)methylglycine (TRICINE, CAS No.: 5704-04-1), ethylenediamine-N,N'-diacetic acid (EDDA, ​​CAS No.: 5657-17-0), sodium 3-diphenylphosphinobenzenesulfonate (TPPMS, CAS No.: 63995-75-5), and sodium triphenylphosphine tris-metasulfonate (TPPTS, CAS No.: 63995-70-0).

[0105] In the present invention, component A may further include one or more of an excipient, an osmotic pressure regulator, an antioxidant, a pH regulator, a sustained-release agent, a solubilizer, a cosolvent, and a preservative.

[0106] Component C includes a component capable of providing technetium [ 99m Tc], and the compound is combined with at least part of the active ingredient to form technetium [ 99m Tc] drug, the following embodiments of this application are introduced using sodium pertechnetate as an example.

[0107] Component B includes a solvent and a buffer, and the solvent can [ 99m Tc] drug to dissolve.

[0108] 2 , when used, component A and component B are mixed, and then component C is added and heated for reaction. The reaction route is shown in FIG1 , and the mixture is cooled to room temperature after the reaction is completed.

[0109] Example:

[0110] 3 , the preparation method of component A is as follows:

[0111] S1: Dissolve the PSMA precursor and co-ligand in glacial acetic acid to prepare a 10% glacial acetic acid solution. Dissolve the antioxidant, excipient, and osmotic pressure regulator in water to obtain an aqueous solution.

[0112] S2: Mix the glacial acetic acid solution with the aqueous solution, add hydrochloric acid and / or sodium hydroxide as pH adjusters to adjust to the desired pH value, and add water to make up to volume.

[0113] S3: Pre-filtration to intercept any solid particles larger than 0.45 μm.

[0114] Filter to intercept any solid particles larger than 0.22 μm.

[0115] S4: Fill the filtered filtrate into cleaned and dried containers and sterilize them.

[0116] S5: Freeze-dry at -45°C for 6 hours, then freeze-dry at -10°C until the solvent content reaches the expected level, then maintain at 25°C for 14 hours to obtain freeze-dried powder, sterilize, and package to obtain freeze-dried powder bottle A.

[0117] 4 , the preparation method of component B is as follows:

[0118] S1: Dissolve the buffer in 3.5 L of water and filter to remove any solid particles larger than 0.22 μm.

[0119] S2: The filtered filtrate is filled into a cleaned and dried container.

[0120] S3: Sterilize and seal the product; obtain the B solvent bottle.

[0121] Component C is high technetium [ 99m Tc] sodium salt injection (purchased from Senke (Nanjing) Pharmaceutical Technology Co., Ltd., the same below). 99m The Tc] injection preparation may contain or not contain component C. If component C is not contained in the preparation of the present application, the user shall prepare component C separately when using.

[0122] This application [ 99m [Tc] injection preparation, using the aforementioned components A, B, and C as starting materials, can be obtained through a one-step chelation reaction to obtain the final product. Referring to Figure 2, remove bottle A of lyophilized powder and bottle B of solvent. Open the plastic caps of bottles A and B. Remove the syringe needle, insert it through the rubber stopper into bottle A, and expel the protective nitrogen from bottle A.

[0123] Remove high technetium 99m Tc] sodium phosphate injection and penicillin bottle opener, remove high technetium [ 99m Remove the cap of sodium tc] acid injection bottle and take out 50 μL of pertechnetium [ 99m Tc] sodium salt injection into EP tube, put into activity meter, detect technetium [ 99m Tc] sodium salt injection radioactivity, calculate technetium [ 99m The activity concentration of sodium tc]ate injection, technetium [ 99m The activity concentration of sodium technetium[ 99m The activity of sodium tc[2-hydroxy-1-thiazolyl]ate injection is ≥20 mCi and ≥ the activity specified in the production specification. Take out the diluent saline solution and add the saline solution to the technetium[ 99m In the bottle of sodium tc-1-phosphate injection:

[0124] Use a syringe to extract 3.4 mL of the liquid from bottle B and add it to the lyophilized powder in bottle A to fully dissolve it. Then use a syringe to extract 1.6 mL of the diluted high-technetium [ 99m Add the dissolved lyophilized powder in bottle A.

[0125] Turn on the thermostatic mixer and set the heating temperature to 100℃. Keep the temperature at 100℃ for 5 minutes. 99m After the reaction is completed, take out bottle A and place it at room temperature for 30 minutes to obtain injectable technetium [ 99m Tc] injection, refer to Figures 1-1 and 1-2. Activity meter detects technetium [ 99m Tc] injection activity, record the detection time and 99mTc] injection sample production batch number.

[0126] technetium[ 99m The [Tc] injection solution was dispensed into sealed 10 mL brown vials. The activity of each 10 mL brown vial was measured using an activity meter. The measurement time was recorded, and the activity concentration was calculated based on the dispensed volume. Simultaneously, the activity of bottle A was measured, and the volume of bottle A was calculated.

[0127] The product can then be packaged into a stainless steel lead-clad container. This product is packaged in borosilicate glass vials, freeze-dried halogenated butyl rubber stoppers (brominated) for injection, and aluminum-plastic composite caps for antibiotic bottles. The packaged product is placed into a stainless steel lead-clad shielded container and labeled. An outer label is affixed to the product bottle and the outer wall of the shielded container, indicating the production date, batch number, activity, calibration time, and other information.

[0128] Table 1, components used in different examples

[0129] Table 2, performance test of bottle A obtained in this application

[0130] Table 3. Test results of direct mixing performance of components A and B

[0131] The freeze-dried powder in bottle A of the present application has a fast reconstitution speed. After 40 minutes of reconstitution, there is no significant change in the properties, pH value, solution clarity and color, visible foreign matter, osmotic pressure molar concentration, and active ingredients. Under 100°C conditions, the insoluble particles are significantly reduced, and there is no significant change in the properties, pH value, solution clarity and color, visible foreign matter, and active ingredients. This shows that the method of preparing bottles A and B of the present application can maintain the stability of the active ingredients, and the performance of the active ingredients is not affected after reconstitution.

[0132] The technetium obtained in the above examples [ 99m In the case of a Tc-based injection formulation, components A and B are packaged separately and can be stored for ≥2 years without compromising activity. In contrast, if components A and B are directly mixed to form a solution, chromatographic column analysis revealed a significant decrease in purity after just over 10 hours.

[0133] The freeze-dried powder in bottle A was dissolved in phosphoric acid and exposed to light at 25 and 40°C for 10 days or without light. The active ingredient content was determined by liquid chromatography, with the PSMA precursor content as the evaluation index. The freeze-dried powder in bottle A obtained in the present application has good stability. Among them, the PSMA content did not change significantly after being placed at 25°C and 40°C for 10 days, and remained at around 0.1μg / ml. The PSMA precursor content did not change significantly after being exposed to light at 25°C for 10 days, and only decreased by less than 0.01μg / ml after being exposed to light at 40°C for 10 days. In contrast, if the excipient, Tricine or second co-ligand of the present application is not contained, the PSMA content drops to below 0.04μg / ml, 0.05μg / ml and 0.04μg / ml respectively after being placed at 40°C for 10 days. In the case of containing the excipient, Tricine and second co-ligand of the present application, if the antioxidant of the present application is not present, the content drops to 0.05μg / ml after being exposed to light at 40°C for 10 days. If the excipient, Tricine, the second co-ligand, and the antioxidant are all absent, the concentration is reduced to below 0.02 μg / ml. This indicates that the combination of the specific components of the present application can synergistically stabilize bottle A under light and high temperature conditions.

[0134] The injections obtained after the chelation reaction were all clear and free of solid impurities. The injections are effective for up to ten hours, so the injections obtained after the chelation reaction can be used within a dozen hours, ensuring both storage durability and ease of use.

[0135] Liquid chromatography testing of the PSMA precursor and impurity content in the system after the chelation reaction revealed that temperature and humidity had a greater impact than light. After five days at 40°C, the radiochemical purity of bottle A, containing the tetraol excipient, tricine, a second co-ligand, and a vitamin antioxidant, decreased, but remained around 90%. After five days of exposure to light at room temperature, the prepared injection solution exhibited a radiochemical purity exceeding 90%. PSMA precursor levels were consistently above 6 μg / ml after five days, but dropped to well below 4 μg / ml in the absence of the tetraol excipient, tricine, or a second co-ligand.

[0136] This application also examined the effect of the pH value of the solution before freeze-dried powder preparation on the freeze-dried powder product in bottle A. When the pH value is ≤5, the purity of bottle A can reach >96%; however, when it exceeds 5, the purity drops significantly. Within the pH range of ≤5, the pH value ≤4 is even better, with the purity reaching above 98%, the total impurity content below 1.5%, and the maximum single impurity content below 0.5%. When the pH value exceeds 4, the single impurity content increases significantly.

[0137] While the specific embodiments of the present invention have been described in detail above, these are merely exemplary and the present invention is not limited thereto. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, any equivalent changes and modifications made without departing from the spirit and scope of the present invention are intended to be encompassed within the scope of the present invention.

Claims

1. A kind of technetium 99m Tc] injection preparation, characterized in that Comprising: component A and component B, wherein component A includes a component capable of providing technetium [ 99m Tc] compounds to form technetium [ 99m Tc] active ingredient of the drug, component B includes a 99m Tc] drug solvent, or B also as component A and provide technetium [ 99m Tc] compound to react with a reaction solvent or dispersant; component A and component B are physically isolated from each other; The active ingredient includes a PSMA precursor, and the PSMA precursor has the following chemical structure: in: m is an integer from 0 to 5; n is an integer from 0 to 5; but m and n are not both 0; f, g are 0 or 1; but f and g are not 0 at the same time; Q1-Q3 are independently selected from -COOH, -SOOH, -SO3H, -SO4H, -POOH, -PO3H or -PO4H2; X is an optionally substituted aryl or heteroaryl, wherein the substitution is substituted by at least one R group; Y is optionally substituted aryl, optionally substituted heterocyclic aryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl, wherein the substitution is substitution with at least one R group; R, R 1 -R 8 , R' are each independently selected from H, alkyl, halogen, -CN, -OH, -NH2, alkoxy or cycloalkyl; AA1 is a natural or unnatural amino acid, a peptide composed of amino acids, or -CH2CH2-.

2. Technetium according to claim 1 99m Tc] injection preparation, characterized in that The A component or the active ingredient further comprises a co-ligand component, tris(hydroxymethyl)methylglycine; or the A component or the active ingredient further comprises a second co-ligand for reacting with the PSMA precursor 99m Tc forms a complex, and the second co-ligand is selected from polyamines, polyacids, and organic phosphine compounds, such as: ethylenediamine-N,N'-diacetic acid (EDDA), sodium 3-diphenylphosphinobenzenesulfonate (TPPMS), sodium triphenylphosphine tris-metasulfonate (TPPTS), one or more thereof.

3. The technetium according to claim 1 99m Tc] injection preparation, characterized in that Component B also includes a pH buffer; the pH buffer can buffer and adjust the pH of component A and provide technetium [ 99m Tc], preferably, the pH value is buffered or / or adjusted to 4-6, more preferably 4.2-5.8, more preferably 4.5-5.5, such as 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4; the buffer is preferably selected from one or more groups of disodium succinate and succinic acid, citric acid and sodium citrate, sodium acetate and acetic acid; The component A also includes one or more of an excipient, an osmotic pressure regulator, an antioxidant, a pH regulator, a sustained-release agent, a solubilizer, a cosolvent, and a preservative; The excipient is selected from one or more of mannitol, lactose, glucose and dextran; the solubilizer is selected from surfactants such as Tween-80, Tween-60, poloxamer, etc. that reduce the surface tension of the liquid; the cosolvent is selected from one or more of benzoic acid, sodium benzoate, salicylic acid, sodium salicylate, p-aminobenzoic acid, sodium p-aminobenzoate, malic acid, methionine, arginine, nicotinic acid, vitamin B6, sodium bicarbonate, urethane, glucose, meglumine, erucamide, and urea; the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, fructose, glycerol, sorbitol, xylitol, magnesium chloride, phosphate, sodium citrate, and mannitol; the antioxidant is selected from L- One or more of cysteine ​​hydrochloride, sodium sulfite, sodium bisulfite, propyl gallate, glutathione, sodium thiosulfate, thiourea, thioglycolic acid, sodium pyrosulfite, potassium pyrosulfite, vitamin E, sodium vitamin C, sodium phytate and ascorbyl palmitate; the pH regulator includes an acidic regulator and / or an alkaline regulator, wherein the acidic regulator is selected from one or more of hydrochloric acid, lactic acid, acetic acid, citric acid, malic acid, arginine and tartaric acid; the alkaline regulator is selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate and disodium hydrogen phosphate; the solvent is selected from one or more of water, soybean oil, safflower oil, sesame oil, cottonseed oil and fish oil.

4. The technetium according to claim 1 99m Tc] injection preparation, characterized in that The technetium [ 99m Tc] injection preparation also includes component C, which is capable of providing technetium [ 99m Tc], and the component C can be combined with at least part of the active ingredient in the component A to form technetium [ 99m Tc] drug; component C is physically isolated from component A and component B.

5. Technetium according to claim 1 or 4 [ 99m Tc] injection preparation, characterized in that The technetium [ 99m The composition of the Tc injection preparation includes: Component A, comprising: PSMA precursor: 20-50 μg, preferably 25-45 μg, such as 30 μg, 35 μg, 40 μg; Second co-ligand: 2.5-4 mg, preferably 2.8-3.6 mg, such as 3.0 mg, 3.2 mg, 3.4 mg; TRICINE: 5-8 mg, preferably 6-7 mg, such as 6.2 mg, 6.5 mg, 6.7 mg; Alternatively, component A also includes: Antioxidant: 0.5-4 mg, preferably 1-3.5 mg, more preferably 1.5-3 mg, such as 2-2.5 mg; Excipient: 0-50 mg, preferably 5-50 mg, more preferably 10-50 mg, such as 20-40 mg; Osmotic pressure regulator: 0-50 mg, preferably 5-50 mg, more preferably 10-50 mg, such as 20-40 mg; Component B, comprising: Succinic acid: 10-15 mg, more preferably 11-14 mg, more preferably 12-13 mg, such as 12.2 mg, 12.5 mg, 12.7 mg Disodium succinate: 30-45 mg, such as 33 mg, 35 mg, 38 mg, 40 mg, 42 mg; Solvent: make up the total volume to 2-5 ml; preferably 2.5-4.5 ml, more preferably 3-4 ml; Alternatively, the technetium [ 99m Tc] injection preparations also include: Component C: 99m The Tc content is ≥10 mCi, more preferably ≥15, more preferably ≥20 mCi.

6. Technetium according to claim 1 99m Tc] injection preparation, characterized in that The PSMA precursor is the following compound:

7. A method for preparing the technetium [ 99m Tc] injection preparation method, characterized in that the steps include: Dissolving the buffer in the solvent to prepare component B; The active ingredient is dissolved in a second solvent, freeze-dried to prepare a lyophilized powder, and the second solvent is removed during the freeze-drying process to prepare the lyophilized powder, thereby obtaining component A; Wherein, component A and component B are packaged in physical isolation from each other.

8. The method according to claim 7, characterized in that The preparation method of component A comprises: dissolving the active ingredient in solvent A1, dissolving the available auxiliary materials in solvent A2, and then mixing them. If the pH value does not reach the expected value, a pH adjuster is added to adjust the pH value. If the pH value reaches the expected value, no pH adjuster is needed. Preferably, the expected pH value is ≤5, more preferably ≤4.

5. Freeze-dry to obtain freeze-dried powder.

9. A technetium as claimed in claim 1 99m Tc] The method for using the injection preparation is characterized by the steps of: include: Component A and component B are mixed and dissolved to obtain a mixed solution; Component C is added to the mixed solution and heated to react; After the reaction is completed, technetium [ 99m Tc] injection.

10. The method according to claim 9, characterized in that The heating reaction has a heating temperature of 80-150°C, preferably 90-130°C, and more preferably 100-120°C; the heating reaction has a reaction time of preferably 5-60min, more preferably 10-50min, more preferably 15-40min, more preferably 20-35min, and more preferably 25-30min.

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