Pharmaceutical composition containing [ 18f]flutemetamol, method for preparing same, and pharmaceutical use thereof

Abstract

A pharmaceutical composition containing [18F]flutemetamol, a method for preparing same, and pharmaceutical use thereof. Specifically, provided are a pharmaceutical composition containing [18F]flutemetamol and a polyoxyethylene castor oil derivative, a method for preparing same, and pharmaceutical use thereof.

Description

A type containing fluorine 18 F] Metapharmaceutical compositions, preparation methods and pharmaceutical uses thereof Technical Field

[0001] A type containing fluorine 18 The pharmaceutical composition of [F] Methafol, its preparation method and pharmaceutical use, belongs to the field of pharmaceutical preparations and radiopharmaceuticals. Background Technology

[0002] Alzheimer's disease (AD) is the most common form of dementia, and the global number of people with dementia is estimated to increase from 57.4 million in 2019 to 152.8 million in 2050. In China, surveys show that there are 15.07 million dementia patients in people over 60 years of age, including 9.83 million with AD; the prevalence of mild cognitive impairment (MCI) in people over 60 years of age is 15.5%, with 38.77 million patients. With the availability of Aβ-targeting therapies (aducanumab, lecanemab), there is an urgent clinical need for biomarker information (including but not limited to amyloid deposition, changes in cerebrospinal fluid tau protein levels, hyperphosphorylated tau protein (p-tau), or Aβ) for diagnosis, staging, and efficacy assessment. 1-42 Positron emission tomography (PET) is one of the most effective methods for diagnosing and guiding the treatment of tumors, coronary heart disease, and brain diseases because it can non-invasively, dynamically, and quantitatively evaluate molecular-level information such as metabolic activities and changes in biochemical indicators of living tissues or organs.

[0003] fluorine[ 18 F] Metformin, with the structure shown in formula (I):

[0004] It is a radioactive diagnostic agent used for positron emission tomography (PET) imaging of the brain, suitable for assessing β-amyloid plaque density in adult patients with cognitive impairment caused by Alzheimer's disease (AD) or other causes. WO2009027452A discloses fluorine [ 18 [F] Metaphenol has the problem of easily adhering to glass or plastic surfaces. This application solves this problem by using polysorbate 80 as a solubilizer. The search and use of other similar functional excipients also have important scientific research value and broad application prospects. Summary of the Invention

[0005] This disclosure provides a pharmaceutical composition comprising fluorine […]. 18F] Methanophenol and at least one surfactant, said surfactant being selected from polyoxyethylene castor oil derivatives or polyethylene glycol stearate or mixtures thereof, said fluorine [ 18 The structure of [F]methalin is shown below:

[0006] This disclosure provides a pharmaceutical composition comprising fluorine […]. 18 F] Methadol and polyoxyethylene castor oil derivatives.

[0007] In some embodiments, the polyoxyethylene castor oil derivative is selected from polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil or a mixture thereof.

[0008] In some embodiments, the polyoxyethylene castor oil derivative is polyoxyethylene castor oil.

[0009] In some embodiments, the polyoxyethylene castor oil derivative is polyoxyethylene hydrogenated castor oil.

[0010] In some embodiments, the polyoxyethylene castor oil derivative is a mixture of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil.

[0011] In some embodiments, the polyoxyethylene castor oil derivative is selected from polyoxyethylene (35) castor oil, polyoxyethylene (60) hydrogenated castor oil, or a mixture of both.

[0012] In some embodiments, the polyoxyethylene castor oil derivative is selected from a mixture of polyoxyethylene (35) castor oil and polyoxyethylene (60) hydrogenated castor oil.

[0013] In some embodiments, the polyoxyethylene castor oil derivative is polyoxyethylene (35) castor oil.

[0014] In some embodiments, the polyoxyethylene castor oil derivative is polyoxyethylene (60) hydrogenated castor oil.

[0015] In some embodiments, the pharmaceutical composition is a liquid pharmaceutical composition.

[0016] In some embodiments, the pharmaceutical composition is an injection solution.

[0017] In some embodiments, the concentration of the polyoxyethylene castor oil derivative (e.g., polyoxyethylene (35) castor oil) is selected from 0.1% to 10% (w / v).

[0018] In some embodiments, the concentration of the polyoxyethylene castor oil derivative (e.g., polyoxyethylene (35) castor oil) is selected from 0.5% to 5%.

[0019] In some embodiments, the concentration of the polyoxyethylene castor oil derivative (e.g., polyoxyethylene (35) castor oil) is selected from 0.5% to 2%.

[0020] In some embodiments, the concentration of the polyoxyethylene castor oil derivative (e.g., polyoxyethylene (35) castor oil) is selected from 0.5% to 1.5%.

[0021] In a specific implementation, the concentration of the polyoxyethylene castor oil derivative (e.g., polyoxyethylene (35) castor oil) is selected from 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, and 2%. 0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4 0.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5% 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, or the value between any two points.

[0022] This disclosure provides a pharmaceutical composition comprising fluorine […]. 18 F] Methadol and polyethylene glycol stearate.

[0023] In some embodiments, the polyethylene glycol stearate is polyethylene glycol monohydroxy stearate.

[0024] In some embodiments, the polyethylene glycol stearate is polyethylene glycol 15-hydroxy stearate.

[0025] In some embodiments, the concentration of the polyethylene glycol stearate (e.g., polyethylene glycol 15-hydroxystearate) is selected from 0.1% to 10%.

[0026] In some embodiments, the concentration of the polyethylene glycol stearate (e.g., polyethylene glycol 15-hydroxystearate) is selected from 0.5% to 4%.

[0027] In a specific implementation, the concentration of the polyethylene glycol stearate (e.g., polyethylene glycol 15-hydroxystearate) is selected from 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, and 2.0%. %, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4 0.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5% 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, or the value between any two points.

[0028] In some embodiments, the pharmaceutical composition comprises a pH adjuster with a pH value selected from 4.0 to 10.5.

[0029] In some embodiments, the pH value of the pharmaceutical composition is selected from 6.0 to 8.5.

[0030] In some embodiments, the pH value of the pharmaceutical composition is selected from 6.8 to 7.5.

[0031] In some embodiments, the pH value of the pharmaceutical composition is selected from 7.0 to 7.5.

[0032] In some embodiments, the pH adjuster in the pharmaceutical composition is a buffer.

[0033] In some implementations, the pH adjuster is a phosphate buffer (disodium hydrogen phosphate, sodium dihydrogen phosphate, and their hydrates).

[0034] In some embodiments, the pharmaceutical composition contains an isotonic modifier.

[0035] In some embodiments, the isotonic conditioner is sodium chloride at a concentration of 0.9%.

[0036] In some embodiments, the pharmaceutical composition provided in this disclosure, wherein the fluorine [ 18 The radioactivity of [F] methaquinol is selected from 50 MBq / mL to 1000 MBq / mL.

[0037] In some embodiments, the pharmaceutical composition provided in this disclosure, wherein the fluorine [ 18 The radioactivity of [F] methaqualone is selected from 150 MBq / mL to 850 MBq / mL.

[0038] In some embodiments, the pharmaceutical compositions provided in this disclosure have a chemical concentration of flumetazidine ≤ 2 μg / mL.

[0039] In some embodiments, the pharmaceutical compositions provided in this disclosure contain ethanol.

[0040] In some embodiments, the pharmaceutical compositions provided in this disclosure have an ethanol concentration selected from 20 mg / mL to 80 mg / mL.

[0041] In some embodiments, the pharmaceutical compositions provided in this disclosure have an ethanol concentration selected from 30 mg / mL to 70 mg / mL.

[0042] In some embodiments, the pharmaceutical compositions provided in this disclosure have an ethanol concentration selected from 50 mg / mL to 60 mg / mL.

[0043] In some embodiments, the pharmaceutical compositions provided in this disclosure contain water (e.g., water for injection).

[0044] In some embodiments, the pharmaceutical composition provided in this disclosure is an injectable preparation comprising the following components:

[0045] i) Polyoxyethylene (35) castor oil, concentration selected from 0.5%-1.5%;

[0046] ii) Phosphate buffer;

[0047] iii) Fluorine 18 F] The radioactivity of methotrexate was selected from 150 MBq / mL to 850 MBq / mL;

[0048] iv) Ethanol; concentration selected from 50 mg / mL to 60 mg / mL;

[0049] v) Sodium chloride, concentration 0.9%;

[0050] vi) Water for injection;

[0051] The pH value of the composition is selected from 6.0 to 8.5.

[0052] In some embodiments, the pharmaceutical composition provided in this disclosure is an injectable preparation comprising the following components:

[0053] i) Polyoxyethylene (35) castor oil, concentration 1%;

[0054] ii) Phosphate buffer;

[0055] iii) Fluorine 18 F] The radioactivity of methotrexate was selected from 150 MBq / mL to 850 MBq / mL;

[0056] iv) Ethanol; concentration 55.2 mg / mL;

[0057] v) Sodium chloride, concentration 0.9%;

[0058] vi) Water for injection;

[0059] The pH value of the composition is selected from 6.0 to 8.5.

[0060] In some embodiments, the pharmaceutical composition provided in this disclosure is an injectable preparation comprising the following components:

[0061] i) Polyethylene glycol 15-hydroxystearate, with a concentration selected from 0.5% to 4%;

[0062] ii) Phosphate buffer;

[0063] iii) Fluorine 18 F] The radioactivity of methotrexate was selected from 150 MBq / mL to 850 MBq / mL;

[0064] iv) Ethanol; concentration selected from 50 mg / mL to 60 mg / mL;

[0065] v) Sodium chloride, concentration 0.9%;

[0066] vi) Water for injection;

[0067] The pH value of the composition is selected from 6.0 to 8.5.

[0068] In some embodiments, the pharmaceutical composition provided in this disclosure is an injectable preparation comprising the following components:

[0069] i) Polyethylene glycol 15-hydroxystearate, at a concentration of 1%;

[0070] ii) Phosphate buffer;

[0071] iii) Fluorine 18 F] The radioactivity of methotrexate was selected from 150 MBq / mL to 850 MBq / mL;

[0072] iv) Ethanol; concentration 55.2 mg / mL;

[0073] v) Sodium chloride, concentration 0.9%;

[0074] vi) Water for injection;

[0075] The pH value of the composition is selected from 6.0 to 8.5.

[0076] A method for preparing the aforementioned pharmaceutical composition provided in this disclosure includes fluorine [ 18 The step of mixing metformin and polyoxyethylene castor oil derivatives to obtain a drug mixture.

[0077] In some embodiments, the preparation method provided in this disclosure includes the step of filtering and sterilizing the drug mixture.

[0078] This disclosure further provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for determining the presence, location, and / or amount of one or more amyloid protein deposits in an organ or body region of a subject.

[0079] This disclosure further provides the use of detectable amounts of the aforementioned pharmaceutical composition in the preparation of a medicament for determining the presence, location, and / or amount of one or more amyloid protein deposits in an organ or body region of a subject, including: 1) allowing fluoride [ 18 F) Methafol binds to any amyloid deposits in the subject; and 2) the presence, location and / or amount of one or more amyloid deposits in the subject is determined by in vivo imaging.

[0080] In some embodiments, the amyloid deposit is a deposit of amyloid β, and the subject's organ or body region is the brain.

[0081] In some implementations, the in vivo imaging is performed via PET or SPECT.

[0082] In some implementations, in vivo imaging is performed at two or more different time points to monitor the progression or remission of amyloidosis in response to amyloidosis-specific treatment.

[0083] This disclosure also provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for identifying a subject as a precursor to amyloid deposition-related disease, the subject having clinical signs of dementia or mild cognitive impairment.

[0084] Terminology Definition

[0085] The term "polyoxyethylene castor oil derivatives" refers to a series of materials obtained by reacting different amounts of ethylene oxide with castor oil or hydrogenated castor oil.

[0086] The term "pH adjusting agent" refers to a compound or mixture of such compounds used to ensure that the pH of a radiopharmaceutical composition is maintained within acceptable limits (approximately pH 4.0 to 10.5) for administration to mammals. Attached Figure Description

[0087] Figure 1-A. Prescription 1 and Prescription 12 Fluorine [ 18 F] SUV levels in the mid-frontal cortex of SD.APP genetically engineered rats and normal SD rats were detected 30 minutes after injection of metoprolol. mean .

[0088] Figure 1-B. Prescription 1 and Prescription 12 Fluorine [ 18 F] SUV levels in the mid-frontal cortex of SD.APP genetically engineered rats and normal SD rats were detected 30 minutes after injection of metoprolol. max Intake value. Detailed Implementation

[0089] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0090] Example 1. Effect of different surfactants on the adsorption of fluorinated [19F]methalin

[0091] Polysorbate 80, polyoxyethylene (35) castor oil, 15-hydroxystearic acid polyethylene glycol ester (HS-15), polyoxyethylene (60) castor oil and poloxamer 188 were selected as surfactants to investigate the adsorption of flumethazone on the filter membrane in the flumethazone composition.

[0092] To reduce the harm of radiation to the human body, research is being conducted using radioactive fluorine. 19 F] replaces fluorine [ 18 F] Preparation of fluorine [ 19 F] Metformin cold simulated drug solution.

[0093] The preparation process for flumetafenone cold-simulated solution is as follows (taking prescription 2 as an example):

[0094] 1) Preparation of raw material solution

[0095] Accurately weigh approximately 10 mg of the raw material and place it in a 250 ml volumetric flask. Add ethanol to the mark and shake to mix.

[0096] 2) Preparation of diluent

[0097] Weigh approximately 0.613 g of anhydrous sodium dihydrogen phosphate, approximately 1.946 g of anhydrous disodium hydrogen phosphate, and approximately 12.0 g of sodium chloride, and place them in 1000 g of water, stirring to dissolve. Take 100 ml of the above solution, add approximately 6.7 g of polyoxyethylene (35) castor oil, and stir to dissolve.

[0098] 3) Take 2.5 mL of the raw material solution (containing 100 μg of raw material and 2.5 mL of ethanol), add 1 mL of ethanol and 37.2 mL of diluent in sequence, add 9.3 g of water for injection, stir and mix well to obtain flumetafenol cold simulated drug solution.

[0099] Table 1. Composition of Prescriptions 1 to 5 Note: The table shows the concentration of water for injection diluted to 1 mL, with a batch size of 50 mL.

[0100] The molar mass of anhydrous disodium hydrogen phosphate is 141.96 g / mol, and the molar mass of anhydrous sodium dihydrogen phosphate is 119.98 g / mol, which means the molar concentration of disodium hydrogen phosphate is 10.20 mM and the molar concentration of sodium dihydrogen phosphate is 3.80 mM.

[0101] Evaluation of fluorine by high performance liquid chromatography (HPLC) 19 The percentage of loss of metformin on the PVDF filter membrane is shown in Table 2.

[0102] Table 2. Adsorption test results of filter membranes for formulations 1 to 5

[0103] The results showed that in the presence of poloxamer 188, the cold simulated drug solution fluoride [ 19 F] Flumethasone was almost completely lost on the filter membrane. In the presence of 5% polyoxyethylene (35) castor oil, 4% 15-hydroxystearic acid polyethylene glycol ester, and 5% polyoxyethylene (60) castor oil, the cold simulated drug solution flumethasone showed no significant adsorption on the filter membrane.

[0104] Example 2. Effect of reducing surfactant concentration on the adsorption of fluorinated [19F]methalin

[0105] Referring to the production process described in Example 1, Formula 1 and Formula 6-9 Fluorine were prepared according to Table 3. 19 F] Metformin cold simulated drug solution.

[0106] The surfactants are selected from: 1% polyoxyethylene (35) castor oil, 1% 15-hydroxystearic acid polyethylene glycol ester (HS-15), 1% polyoxyethylene (60) castor oil, and 20% polyethylene glycol 400.

[0107] Table 3. Composition of Prescription 1 and Prescriptions 6-9 Note: The table shows the concentration of water for injection diluted to 1 mL, with a batch size of 50 mL.

[0108] Take 2 mL of the intermediate drug solution filtered through the PES membrane each time, and collect the 1st, 2nd, and 5th portions of the filtered solution respectively. Evaluate the fluoride content based on appearance, content, and related substance indicators. 19 The percentage of loss of methotrexate on the filter membrane and the effects of different types and concentrations of surfactants on the quality of the drug solution are shown in Table 4.

[0109] Table 4. Results of surfactant adsorption on filter membrane and its effect on drug solution quality

[0110] The results showed that no impurities were detected in any of the drug solutions before or after filtration. Poloxamer 188 and polyethylene glycol 400 had almost no solubilizing ability, and the cold-simulated drug solution contained fluoride. 19 F] Metaphen is mainly adsorbed on the filter membrane; 1% polyoxyethylene (35) castor oil, polyoxyethylene (60) hydrogenated castor oil, and 15-hydroxystearic acid polyethylene glycol ester (HS-15) have similar solubilizing abilities, all superior to the comparative excipient 0.5% Tween-80 (polysorbate 80). Example 3. Surfactant concentration investigation

[0111] While ensuring that the types and amounts of other excipients remain unchanged, a cold-simulated drug solution of 0.5%-1.5% polyoxyethylene (35) castor oil is prepared. 19 F] Metformin injection, using appearance, content, and related substances as indicators, investigated the percentage loss on the filter membrane of samples containing different concentrations of surfactant. Furthermore, the fluoride content of a cold-simulated solution containing 1.0% polyoxyethylene (35) castor oil was investigated. 19 F] Percentage of loss of metformin injection in production components or packaging materials.

[0112] Table 5. Composition of prescriptions 6, 10 and 11 Note: The table shows the concentration of water for injection diluted to 1 mL, with a batch size of 50 mL.

[0113] Table 6. Test Results for Prescriptions 6, 10, and 11

[0114] The results showed that after discarding 2 ml of the initial filtrate, the fluoride content of castor oil containing different concentrations (0.5%-1.5%) of polyoxyethylene (35) was […]. 19 [F] There were no significant differences in the appearance, content, and related substances of the cold-simulated metformin solution. The packaging materials and PTFE tubes showed no adsorption of the finished product containing 1% polyoxyethylene (35) castor oil, and no impurities were detected.

[0115] Example 4. Fluorine [ 18 Preparation of Metformin Injection (F)

[0116] Within the range of surfactant types and concentrations in Examples 1-3, Formulation 6 was selected as an example for thermal testing, as detailed below:

[0117] Table 7. Prescription 12 Note: * indicates fluorine [ 18 F] Methamphenicol and Fluoride 19 The sum of F] methaqualone.

[0118] **It is anhydrous disodium hydrogen phosphate or disodium hydrogen phosphate dodecahydrate, therefore it is measured using a molar concentration meter.

[0119] *** is anhydrous sodium dihydrogen phosphate or sodium dihydrogen phosphate dihydrate, therefore it is measured using a molar concentration meter.

[0120] fluorine[ 18 F] Metformin radioactive injection solution is derived from precursors Under the catalytic conditions of tetrabutylammonium bicarbonate, it reacts with fluorine [ 18 The F] ion undergoes a nucleophilic substitution reaction, followed by acid deprotection, base neutralization, column purification, and dilution to obtain the final product. Referring to patent application CN200680037139.7, fluorine […] was obtained. 18 F] Metformin, then fluoride [ 18 [F] Methafol was enriched on a C18 column, and the C18 column was washed with 3.5 mL of anhydrous ethanol and 9.3 mL of water for injection, respectively, to remove the active substance fluorine. 18 [F] Methanophene was eluted into a transfer bottle containing 37.2 mL of diluent and mixed by bubbling or shaking. The resulting 50 mL solution was then sterilely filtered through a 0.22 μm filter membrane and filled into vials. The filling volume per vial is 1-10 mL, depending on the usage requirements.

[0121] The results showed that the surfactant was effective against fluorine [ 18 The impact of methotrexate on membrane adsorption is similar to that of fluorine [F] 19 [F] Methamphenicol, the results of the cold test are also applicable to the hot test.

[0122] Test Example 1. Hemolysis Risk Test with Different Excipient Formulations

[0123] Fluorine was prepared according to Examples 1 and 2. 19 [F] Metaphenol injection was screened using in vitro hemolysis tests for different excipients and concentrations in the formulation. Different formulations were incubated with rabbit red blood cells at 37°C for 3 hours at a volume ratio of 2% to 10%, and the presence of hemolysis in the supernatant of each tube was observed. The results are shown in Table 8 below.

[0124] Table 8. Results of Prescription Hemolysis Risk Test

[0125] The results showed that formulations containing excipients 0.5% Tween 80, 4% HS-15, and 1% HS-15 caused hemolysis, while other excipients showed negative results for hemolysis.

[0126] Test Example 2. Vascular Stimulation Test with Different Excipient Formulations

[0127] Fluorine was prepared according to Examples 1 and 2. 19 F] Metformin injection was screened for vascular irritation by different excipients used in the prescription.

[0128] One New Zealand rabbit was selected, and 0.3 mL (undiluted solution) was administered via the marginal ear vein. The vascular irritation of the drug was observed, and the results are shown in Table 9.

[0129] Table 9. Results of Prescription Vascular Irritation Test

[0130] The results showed that none of the three prescriptions were vascular irritants, but prescription 9 caused transient discomfort in animals during injection.

[0131] Test Example 3. PET imaging of a rat model of Alzheimer's disease (AD)

[0132] Fluorine was prepared according to the process in Example 4. 18 [F] Metaphenol mimicking the original drug (Formula 1) and self-developed injection (Formula 12), the results were compared using PET imaging in normal and model rats. 18 [F] Uptake of metformin injection in rat brain tissue.

[0133] The stock solution was diluted to approximately 2 mCi / mL, and the dosage was 0.3-1.2 mCi / animal. Results showed that the self-developed and simulated original fluoride […]. 18 [F] Methafol injection showed significant uptake in the brains of SD.APP rats (AD model rats), while the signal was weaker in the brains of normal SD rats.

[0134] 30 minutes after injection, self-developed and simulated original fluorine [ 18 [F] Metaphenol injection showed almost complete brain deposition in the SD.APP model rats. As shown in Figures 1-A and 1-B, both the self-developed and simulated original drugs showed rapid uptake in the frontal cortex after injection, reaching peak concentration within 2 minutes, and SUV within 30 minutes. mean and SUV max The values ​​gradually decreased. Overall, the peak uptake of SD.APP rats was higher than that of SD rats, and there was no significant difference in uptake in the frontal cortex of the self-developed and original rat strains.

[0135] Test Example 4. Stimulus Test

[0136] Fluorine was prepared according to the formulation and production process of Example 4.18 F] Metformin mimics the original drug (Formula 1) and self-developed injection (Formula 12).

[0137] Vascular stimulation test: Sixteen New Zealand rabbits that passed quarantine were divided into a test sample group and a control group, with eight animals in each group (half male and half female). The test used a left-right side comparison method; fluoride was injected into the left ear vein of each animal. 18 F] Metaphen injection, with 0.9% sodium chloride injection as a control on the right. The clinical radioactivity concentration of the test sample was 3.42 mCi / ml, the dosage was 0.43 mCi / kg, the administration volume was 0.3 ml / animal, and it was administered as a single intravenous bolus injection. No vascular irritation reaction was observed.

[0138] Muscle stimulation test: Eight New Zealand rabbits, half male and half female, were selected and qualified for quarantine. The test used a left-right side comparison method. Fluoride was injected into the quadriceps femoris muscle of the left thigh of each animal. 18 F] Metformin injection, with 0.9% sodium chloride injection as a control on the right. The clinical radioactivity concentration of the test sample was 4.615 mCi / mL, the dosage was 0.17 mCi / kg, the administration volume was 0.1 ml / animal, and it was administered by single intramuscular injection. No muscle irritation reaction was observed.

[0139] Test Example 5. In vitro hemolysis test

[0140] Fluorine in prescription 12 18 F] The hemolytic activity test of metformin injection was conducted at the clinically intended radioactive concentration—that is, the original solution concentration of 4.78 mCi / mL.

[0141] Rabbit blood was collected from the heart to prepare a 2% rabbit erythrocyte suspension. The experiment included negative control, positive control, and test sample tubes, with one replicate per tube. The 2% erythrocyte suspension, sodium chloride injection, purified water, and test sample solution were added sequentially as required, mixed thoroughly, and incubated at 37°C. Observations were taken at 15 min, 30 min, 45 min, 1 h, 2 h, and 3 h. After 3 h of incubation, 1 mL of supernatant from each tube was centrifuged at 2000 r / min for 5 min. 200 μL of the supernatant from each tube was measured at 545 nm using an ELISA reader, and the hemolysis rate was calculated for each tube. No hemolysis or erythrocyte aggregation was observed.

[0142] Test Example 6. Active Systemic Allergy Test

[0143] Fluorine in prescription 12 18 F] Metformin Injection.

[0144] Thirty-two guinea pigs (half male and half female) that passed quarantine were randomly divided into four groups according to body weight: a negative control group (sodium chloride injection), a positive control group (1% ovalbumin), a low-dose group, and a high-dose group, with eight guinea pigs (half male and half female) in each group. Experimental setup: The low-dose group used radioactive fluorine at a concentration of 1.35 mCi / mL. 18 [F] Methamidophenol injection: In the high-dose group, the undiluted solution (4.05 mCi / mL) was administered to guinea pigs via intraperitoneal injection at 0.5 mL / animal on days 1, 3, and 5 of the experiment to sensitize them. On days 14 and 21 after the last sensitization, 1.0 mL / animal was administered intravenously to challenge the animals. Animal reactions were observed after challenge for at least 30 minutes. No allergic reactions were observed in the guinea pigs.

Claims

1. A pharmaceutical composition comprising fluorine [ 18 F] Methanophenol and at least one surfactant, said surfactant being selected from polyoxyethylene castor oil derivatives or polyethylene glycol stearate or mixtures thereof, said fluorine [ 18 The structure of [F]methalin is shown below:

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises fluorine [ 18 F] Methadol and polyoxyethylene castor oil derivatives.

3. The pharmaceutical composition of claim 2, wherein the polyoxyethylene castor oil derivative is selected from polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil or a mixture thereof; Preferably, the polyoxyethylene castor oil derivative is selected from polyoxyethylene (35) castor oil, polyoxyethylene (60) hydrogenated castor oil, or a mixture of the two; Most preferably, the polyoxyethylene castor oil derivative is polyoxyethylene (35) castor oil.

4. The pharmaceutical composition according to any one of claims 2 to 3, wherein the pharmaceutical composition is a liquid pharmaceutical composition; preferably an injection solution.

5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the concentration of the polyoxyethylene castor oil derivative is selected from 0.1% to 10%; Preferably, the concentration of the polyoxyethylene castor oil derivative is selected from 0.5% to 5%; Most preferably, the concentration of the polyoxyethylene castor oil derivative is selected from 0.5% to 2%; Specifically, the concentration of the polyoxyethylene castor oil derivative is selected from 0.5% to 1.5%.

6. The pharmaceutical composition according to any one of claims 2 to 5, wherein the pharmaceutical composition comprises a pH adjuster having a pH value selected from 4.0 to 10.5; Preferably, the pH value is selected from 6.0 to 8.

5.

7. The pharmaceutical composition of claim 6, wherein the pH adjuster is a buffer; preferably, the pH adjuster is a phosphate buffer.

8. The pharmaceutical composition according to any one of claims 2 to 7, wherein the pharmaceutical composition contains an isotonic regulator; preferably, the isotonic regulator is sodium chloride at a concentration of 0.9%.

9. The pharmaceutical composition according to any one of claims 2 to 8, wherein the fluorine [ 18 The radioactivity of [F] methaqualone was selected from 50 MBq / mL to 1000 MBq / mL; Preferably, the fluorine [ 18 The radioactivity of [F] methaqualone is selected from 150 MBq / mL to 850 MBq / mL.

10. The pharmaceutical composition according to claims 2 to 9, wherein the pharmaceutical composition contains ethanol.

11. The pharmaceutical composition of claim 10, wherein the concentration of ethanol is selected from 20 mg / mL to 80 mg / mL; Preferably, the concentration of the ethanol is selected from 30 mg / mL to 70 mg / mL; Most preferably, the concentration of the ethanol is selected from 50 mg / mL to 60 mg / mL.

12. The pharmaceutical composition according to any one of claims 2 to 11, wherein the pharmaceutical composition contains water; preferably, the water is water for injection.

13. The pharmaceutical composition according to claims 2 to 12, wherein it is an injectable preparation comprising the following components: i) Polyoxyethylene (35) castor oil, concentration selected from 0.5%-1.5%; ii) Phosphate buffer; iii) Fluorine 18 F] The radioactivity of methotrexate was selected from 150 MBq / mL to 850 MBq / mL; iv) Ethanol; concentration selected from 50 mg to 60 mg / mL; v) Sodium chloride, concentration 0.9%; vi) Water for injection; the pH of the composition is selected from 6.0 to 8.

5.

14. The pharmaceutical composition according to claim 13, comprising the following components: i) Polyoxyethylene (35) castor oil, concentration 1%; ii) Phosphate buffer; iii) Fluorine 18 The radioactivity concentration of methaquinol was selected from 150 MBq / mL to 850 MBq / mL; iv) Ethanol; concentration 55.2 mg / mL; v) Sodium chloride, concentration 0.9%; vi) Water for injection; the pH of the composition is selected from 6.0 to 8.

5.

15. A method for preparing a pharmaceutical composition according to any one of claims 2 to 14, comprising fluorine [ 18 The step of mixing metformin and polyoxyethylene castor oil derivatives to obtain a drug mixture.

16. The preparation method according to claim 15, comprising the step of filtering and sterilizing the drug mixture.

17. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises fluorine [ 18 F] Methanophenol and polyethylene glycol stearate; preferably, the polyethylene glycol stearate is polyethylene glycol monohydroxy stearate; more preferably, the polyethylene glycol stearate is polyethylene glycol 15-hydroxy stearate.

18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a liquid pharmaceutical composition; preferably an injection solution.

19. The pharmaceutical composition according to any one of claims 17 to 18, wherein the concentration of the polyethylene glycol stearate is selected from 0.1% to 10%; Preferably, the concentration of the polyethylene glycol stearate is selected from 0.5% to 4%.

20. The pharmaceutical composition according to any one of claims 17 to 19, wherein the pharmaceutical composition comprises a pH adjuster having a pH value selected from 4.0 to 10.5; Preferably, the pH value is selected from 6.0 to 8.

5.

21. The pharmaceutical composition of claim 20, wherein the pH adjuster is a buffer; preferably, the pH adjuster is a phosphate buffer.

22. The pharmaceutical composition according to any one of claims 17 to 21, wherein the pharmaceutical composition contains an isotonic regulator; preferably, the isotonic regulator is sodium chloride at a concentration of 0.9%.

23. The pharmaceutical composition according to any one of claims 17 to 22, wherein the fluorine [ 18 The radioactivity of [F] methaqualone was selected from 50 MBq / mL to 1000 MBq / mL; Preferably, the fluorine [ 18 The radioactivity of [F] methaqualone is selected from 150 MBq / mL to 850 MBq / mL.

24. The pharmaceutical composition according to claims 17 to 23, wherein the pharmaceutical composition contains ethanol.

25. The pharmaceutical composition of claim 24, wherein the concentration of ethanol is selected from 20 mg / mL to 80 mg / mL; Preferably, the concentration of the ethanol is selected from 30 mg / mL to 70 mg / mL; Most preferably, the concentration of the ethanol is selected from 50 mg / mL to 60 mg / mL.

26. The pharmaceutical composition according to any one of claims 17 to 25, wherein the pharmaceutical composition contains water; preferably, the water is water for injection.

27. The pharmaceutical composition according to claims 17 to 26, wherein it is an injectable preparation comprising the following components: i) Polyethylene glycol 15-hydroxystearate, with a concentration selected from 0.5% to 4%; ii) Phosphate buffer; iii) Fluorine 18 F] The radioactivity of methotrexate was selected from 150 MBq / mL to 850 MBq / mL; iv) Ethanol; concentration selected from 50 mg / mL to 60 mg / mL; v) Sodium chloride, concentration 0.9%; vi) Water for injection; the pH of the composition is selected from 6.0 to 8.

5.

28. The pharmaceutical composition according to claim 27, comprising the following components: i) Polyethylene glycol 15-hydroxystearate, at a concentration of 1%; ii) Phosphate buffer; iii) Fluorine 18 The radioactivity concentration of methaquinol was selected from 150 MBq / mL to 850 MBq / mL; iv) Ethanol; concentration 55.2 mg / mL; v) Sodium chloride, concentration 0.9%; vi) Water for injection; the pH of the composition is selected from 6.0 to 8.

5.

29. A method for preparing a pharmaceutical composition according to any one of claims 17 to 28, comprising fluorine [ 18 The step of mixing metformin and polyoxyethylene castor oil derivatives to obtain a drug mixture.

30. The preparation method according to claim 29, comprising the step of filtering and sterilizing the drug mixture.

31. Use of the pharmaceutical composition according to any one of claims 1 to 14, 17 to 28 in the preparation of a medicament for determining the presence, location and / or amount of one or more amyloid protein deposits in an organ or body region of a subject.

32. Use of a detectable amount of the pharmaceutical composition of any one of claims 1 to 14, 17 to 28 in the preparation of a medicament for determining the presence, location, and / or amount of one or more amyloid protein deposits in an organ or body region of a subject, including: 1) Let fluorine [ 18 F] Metformin binds to any amyloid protein deposits in the subject's body; 2) Determine the presence, location, and / or amount of one or more amyloid protein deposits in a subject by in vivo imaging.

33. The use according to claim 32, wherein the amyloid protein deposit is a deposit of amyloid protein β, and the organ or body region of the subject is the brain.

34. The use of claim 32 or 33, wherein the in vivo imaging is performed by PET or SPECT.

35. The use of any one of claims 32 or 33, wherein imaging is performed at two or more different time points for monitoring the progression or remission of amyloidosis in response to amyloidosis-specific treatment.

36. Use of the pharmaceutical composition according to any one of claims 1 to 14, 17 to 28 in the preparation of a medicament for identifying a subject as a precursor of amyloid deposition-related disease, the subject having clinical signs of dementia or mild cognitive impairment.

Images