Sulfur colloid composition, technetium-sulfur colloid as well as preparation method and application of technetium-sulfur colloid

Abstract

The invention belongs to the technical field of radiopharmaceutical preparation, and particularly relates to a sulfur colloid composition, technetium-sulfur colloid and a preparation method and application of the technetium-sulfur colloid. The technetium-sulfur colloid comprises a sulfur colloid composition and a pertechnetate solution, the sulfur colloid composition comprises sodium thiosulfate and a stabilizer, and the stabilizer comprises polyethylene glycol or carboxymethyl cellulose salt; the dispersing effect is good, and the technetium labeling rate of the technetium-sulfur colloid is high. The invention further provides a vulcanized colloid medicine box which comprises a first medicine box body and a second medicine box body. The first medicine box comprises freeze-dried sulfamic acid and a freeze-dried sulfur colloid composition; the second cartridge includes a buffer solution. The sulfamic acid, the sodium thiosulfate and the stabilizer mixture are integrated in the same medicine box, so that the medicine box is convenient to use.

Description

Technical Field

[0001] The invention belongs to the technical field of radiopharmaceutical preparation, and specifically relates to a sulfur colloid composition, technetium sulfur colloid, and a preparation method and application thereof. Background Art

[0002] Radiopharmaceutical diagnosis and treatment is now widely used in clinical practice. In this application, the radiochemical purity of radionuclide-labeled drugs has a direct impact on the effect of nuclear medicine imaging, so the determination of its radiochemical purity is particularly important. Technetium is the most commonly used tracer because it can label the most imaging agents and is the most widely used in the medical field. Among them, technetium sulfur colloid can be used in related detection of various cancers and other medical tests, such as: ① Sentinel lymph node imaging of breast cancer, lymph node drainage localization of breast cancer or malignant melanoma; ② Localization diagnosis of parathyroid hyperplasia and adenoma, localization of thyroid cancer (such as medullary carcinoma, lymphoma, Hurthle cell carcinoma); ③ Imaging of mononuclear-phagocytes (liver, spleen, bone marrow), evaluation of the patency of abdominal venous shunt; ④ Diagnosis and differential diagnosis of coronary artery disease (myocardial ischemia, myocardial infarction), understanding the effect of thrombolytic therapy, and comprehensive understanding of cardiac function; ⑤ Used for esophageal transit research, gastroesophageal reflux scintigraphy, and pulmonary aspiration puncture of gastric contents. However, the existing products have a low technetium labeling rate and low radiochemical purity. In addition, the existing preparations require a three-step method to prepare technetium sulfur colloids, which is to combine the sulfur colloid and the acid solution in two kits, add sodium pertechnetate to react, and then add the buffer solution in the third kit, which is cumbersome. Summary of the invention

[0003] Therefore, the technical problem to be solved by the present invention is to change the three-step method for preparing sulfur colloid into a two-step method, and overcome the defects of low technetium labeling rate and low chemical purity of technetium sulfur colloid in the prior art, thereby providing a sulfur colloid composition, technetium sulfur colloid and its preparation method and application.

[0004] To this end, the present invention provides the following technical solutions.

[0005] The invention provides a sulfur colloid composition, comprising sodium thiosulfate and a stabilizer; wherein the stabilizer comprises polyethylene glycol or carboxymethyl cellulose salt.

[0006] The sulfur colloid composition provided in the present invention can be prepared, typically but not limitedly, by mixing sodium thiosulfate and a stabilizer; specifically comprising the following steps: adding the stabilizer to deionized water from which oxygen has been removed, heating it to dissolve it, and cooling it to room temperature to obtain solution A; adding sodium thiosulfate to deionized water, dissolving it to obtain solution B; mixing solution A and solution B; further optionally, the method for removing oxygen from the deionized water is to boil the deionized water and then cool it.

[0007] The present invention provides a technetium-sulfur colloid, comprising the above-mentioned sulfur colloid composition and also comprising a pertechnetate solution; wherein the content of the sodium thiosulfate in the sulfur colloid composition is 1-11 mg / mL; when the stabilizer is polyethylene glycol, the content of the polyethylene glycol in the sulfur colloid composition is 7-20 mg / mL; when the stabilizer is carboxymethyl cellulose salt, the content of the carboxymethyl cellulose salt in the sulfur colloid composition is 0.5-3.5 mg / mL; the concentration of the pertechnetate solution is ≥0.1 mci / mL; optionally, the concentration of the pertechnetate solution is 0.5-1 mci / mL; the volume ratio of the sulfur colloid composition to the pertechnetate solution is 1:0.5-4; typically but not limitingly, the carboxymethyl cellulose salt comprises at least one of sodium carboxymethyl cellulose and potassium carboxymethyl cellulose.

[0008] The present invention provides a method for preparing the technetium sulfur colloid, comprising the following steps: mixing a sulfur colloid composition, a pertechnetate solution and an acid solution, heating the mixture and adding a buffer solution to obtain the technetium sulfur colloid.

[0009] Optionally, the acid solution includes at least one of hydrochloric acid and aminosulfonic acid; optionally, the concentration of the hydrochloric acid is 0.1 to 0.4 mol / L; optionally, the concentration of the aminosulfonic acid is 0.4 to 0.6 mol / L.

[0010] Optionally, the volume ratio of the acid solution to the pertechnetate solution is 1 to 5:1.

[0011] Optionally, the buffer solution is added to adjust the pH to 4-7.

[0012] Optionally, the heating time is 2 to 5 minutes, and the heating temperature is 95 to 105°C.

[0013] Optionally, the heating method includes hot bath heating; optionally, the hot bath heating includes at least one of water bath heating and oil bath heating.

[0014] The preparation method of technetium sulfur colloid provided in the present invention is typically but not limited to the following: the buffer solution uses a commonly used buffer solution, and optionally, the buffer solution includes at least one of a sodium dihydrogen phosphate solution and a disodium hydrogen phosphate solution; the pertechnetate is also a common pertechnetate, and optionally, the pertechnetate includes at least one of sodium pertechnetate and potassium pertechnetate; the sulfur colloid composition can be liquid, such as a mixed solution, or solid, such as a mixed freeze-dried solution.

[0015] The method for preparing the technetium sulfur colloid provided in the present invention is not limited to the mixing order of the raw materials. For example, the method may be to add a pertechnetate solution to a sulfur colloid composition, mix, add an acid solution, mix, heat, and add a buffer solution to obtain the technetium sulfur colloid; or the method may be to mix a pertechnetate solution and an acid solution, add the mixture to the sulfur colloid composition, heat, and add a buffer solution to obtain the technetium sulfur colloid.

[0016] The invention provides a sulphurized colloid medicine box, comprising a first medicine box and a second medicine box; the first medicine box comprises freeze-dried aminosulfonic acid and a freeze-dried sulphur colloid composition; the second medicine box comprises a buffer solution; wherein the stabilizing agent comprises polyethylene glycol or carboxymethyl cellulose salt.

[0017] Optionally, the volume of the freeze-dried sulfur colloid composition is less than or equal to the volume of the freeze-dried aminosulfonic acid; optionally, the volume ratio of the freeze-dried aminosulfonic acid to the freeze-dried sulfur colloid composition is 1 to 4:1; further optionally, the volume of the freeze-dried sulfur colloid composition is ≤1 mL, and the volume of the freeze-dried aminosulfonic acid is ≤1.5 mL.

[0018] The present invention provides a method for preparing the above-mentioned sulfurized colloid medicine box, wherein the preparation of the first medicine box comprises the following steps: pre-freezing: pre-freezing aminosulfonic acid at -35 to -40°C for 3 to 7 hours, adding a sulfur colloid composition and pre-freezing at -35 to -40°C for 2 to 4 hours; sublimating and removing water to obtain the first medicine box; the preparation of the second medicine box comprises the following steps: encapsulating the buffer solution. Typically, the positional relationship between aminosulfonic acid and the sulfur colloid composition is not limited, and it is sufficient to ensure that the two do not react during the preparation process. For example, aminosulfonic acid can be freeze-dried in a container first, and then the sulfur colloid composition can be directly added to the container and freeze-dried, so that the aminosulfonic acid and the sulfur colloid composition exist in the container in the form of upper and lower layers; aminosulfonic acid can also be freeze-dried in a smaller mold, and then the freeze-dried aminosulfonic acid is transferred to a larger mold, and the sulfur colloid composition is quickly added to continue freeze-drying, so that the freeze-dried sulfur colloid composition is wrapped outside the freeze-dried aminosulfonic acid.

[0019] Optionally, the steps of sublimating and removing water include: pre-vacuuming: after pre-freezing is completed, pre-evacuate to a vacuum degree of 18 to 22 Pa; sublimate solid water: heat up and reduce pressure to -23 to -17°C, 10 to 13 Pa for 1.5 to 2.5 hours, heat up and reduce pressure to -13 to -7°C, <10 Pa for 2.5 to 3.5 hours; remove moisture: heat up to 8 to 12°C for 8 to 12 hours, keep warm for 1 to 2 hours, heat up to 20 to 28°C for 2.5 to 3.5 hours, and reduce pressure to 1 to 4 Pa ​​for 2 to 3 hours.

[0020] Optionally, the preparation of the second medicine kit further includes a step of freeze-drying the buffer solution.

[0021] The present invention provides the use of the above-mentioned sulfide colloid medicine box or the sulfide colloid medicine box prepared by the above-mentioned preparation method in obtaining technetium sulfide colloid.

[0022] Optionally, obtaining technetium sulfur colloid through the sulfurized colloid kit comprises the following steps: mixing the first kit with a pertechnetate solution, heating, and adding a buffer solution in the second kit to obtain the technetium sulfur colloid.

[0023] Optionally, the concentration of the pertechnetate solution is ≥ 0.1 mci / mL.

[0024] Optionally, the volume ratio of the sulfur colloid composition to the pertechnetate solution in the first medicine kit is 1:0.5-4.

[0025] Optionally, the heating time is 2 to 5 minutes, and the heating temperature is 95 to 105°C.

[0026] The present invention also provides a use of the above-mentioned sulfur colloid composition, or the above-mentioned technetium sulfur colloid, or the technetium sulfur colloid prepared by the above-mentioned preparation method, or the above-mentioned sulfurized colloid medicine box, or the sulfurized colloid medicine box prepared by the above-mentioned preparation method in the preparation of radioactive drugs.

[0027] The beneficial effects of the present invention are:

[0028] The sulfur colloid composition provided by the present invention comprises sodium thiosulfate and a stabilizer, wherein the stabilizer comprises polyethylene glycol or carboxymethyl cellulose salt. In the sulfur colloid composition, the use of polyethylene glycol or carboxymethyl cellulose salt as a stabilizer can achieve a better dispersion effect.

[0029] The technetium sulfur colloid provided by the present invention comprises the above-mentioned sulfur colloid composition and also comprises a pertechnetate solution; wherein the content of the sodium thiosulfate in the sulfur colloid composition is 1-11 mg / mL; when the stabilizer is polyethylene glycol, the content of the polyethylene glycol in the sulfur colloid composition is 7-20 mg / mL; when the stabilizer is carboxymethyl cellulose salt, the content of the carboxymethyl cellulose salt in the sulfur colloid composition is 0.5-3.5 mg / mL; the concentration of the pertechnetate solution is ≥0.1 mci / mL; optionally, the concentration of the pertechnetate solution is 0.5-1 mci / mL; the volume ratio of the sulfur colloid composition to the pertechnetate solution is 1:0.5-4. The technetium sulfur colloid has a very high technetium labeling rate and a better use effect.

[0030] The sulfide colloid medicine box provided by the present invention comprises a first medicine box and a second medicine box; the first medicine box comprises freeze-dried aminosulfonic acid and a freeze-dried sulfur colloid composition; the second medicine box comprises a buffer solution. The aminosulfonic acid and the sulfur colloid composition are integrated in the same medicine box, which makes the use of the medicine box more convenient, and the technetium labeling rate can reach about 95% during use, and even up to 99%.

[0031] The present invention provides the use of the above sulfur colloid composition, or the above technetium sulfur colloid, or the technetium sulfur colloid prepared by the above preparation method, or the above sulfurized colloid medicine box in the preparation of radioactive drugs. Due to the high technetium labeling rate, the radioactive drugs can be further exerted. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0033] Figure 1 This is a liver development image at 0.5h after the technetium sulfide colloid prepared in Example 3 of the present invention was injected into a mouse;

[0034] Figure 2 This is a liver development image 1 hour after the technetium sulfide colloid prepared in Example 3 of the present invention was injected into a mouse;

[0035] Figure 3 This is a liver development image 2 hours after the technetium sulfide colloid prepared in Example 3 of the present invention was injected into a mouse;

[0036] Figure 4 This is a liver development image at 0.5h after the technetium sulfide colloid prepared in Example 7 of the present invention was injected into a mouse;

[0037] Figure 5 This is a liver development image 1 hour after the technetium sulfide colloid prepared in Example 7 of the present invention was injected into a mouse;

[0038] Figure 6 This is a liver development image 2 hours after the technetium sulfide colloid prepared in Example 7 of the present invention was injected into a mouse;

[0039] Figure 7 This is a liver development image at 0.5h after the technetium sulfide colloid prepared in Comparative Example 1 of the present invention was injected into a mouse;

[0040] Figure 8 This is a liver development image at 1 hour after the technetium sulfide colloid prepared in Comparative Example 1 of the present invention was injected into a mouse;

[0041] Fig. 9 This is a liver development image 2 hours after the technetium sulfide colloid prepared in Comparative Example 1 of the present invention was injected into a mouse. DETAILED DESCRIPTION

[0042] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0043] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0044] The present invention uses a homemade HCl solution, takes an appropriate amount of HCl and adds sterile injection water to dissolve, fixes the volume, and dispenses 1 mL into 10 mL vials. HCl solutions with concentrations of 0.1 mol / mL, 0.2 mol / mL, 0.3 mol / mL, and 0.4 mol / mL are prepared respectively.

[0045] Experimental drugs

[0046] Sodium pertechnetate: Shanghai Xinke Pharmaceutical Co., Ltd.;

[0047] Polyethylene glycol 1500: Sinopharm Group (Shanghai);

[0048] Sodium carboxymethyl cellulose: 800-1200, Jiangsu Yonghua Fine Chemicals Co., Ltd.;

[0049] Sodium thiosulfate pentahydrate: Sinopharm Group (Shanghai);

[0050] Sodium dihydrogen phosphate: Sinopharm Group (Shanghai);

[0051] Disodium hydrogen phosphate: Sinopharm Group (Shanghai);

[0052] Hydrochloric acid: Sinopharm Group (Shanghai);

[0053] Fish gelatin: Sigma;

[0054] Sterile water for injection: Shijiazhuang Pharmaceutical Group.

[0055] Example 1

[0056] This embodiment provides a method for preparing technetium sulfur colloid, comprising the following steps:

[0057] (1) Weigh 33.5 mg of sodium carboxymethyl cellulose and add it to 30 mL of deionized water, heat it to dissolve it, and cool it to room temperature to obtain solution A; add 0.5 g of sodium thiosulfate to 5 mL of deionized water and completely dissolve it to obtain solution B; mix solution A and solution B, adjust the volume to 50 mL, and obtain a mixed solution of sodium thiosulfate and stabilizer. After 0.5 mL is dispensed into 10 mL vials, half of the vials are filled with rubber stoppers and placed in a freeze dryer for freeze drying, specifically pre-freezing, vacuum drying, heating and drying again, and finally pressing the stopper under vacuum conditions and sealing the lid to obtain a freeze-dried powder. In the freeze-dried powder, the content of sodium carboxymethyl cellulose is 0.67 mg / mL, and the content of sodium thiosulfate is 10 mg / mL.

[0058] (2) Prepare the buffer solution by dissolving 6 g of sodium dihydrogen phosphate and 8 g of sodium dihydrogen phosphate in sterile water for injection, and make up to 50 mL. Dispense 1 mL into 10 mL vials.

[0059] (3) The lyophilized powder prepared in (1) is added to 0.5 mL of 0.7 mci / mL sodium pertechnetate solution, shaken to dissolve, and then 0.5 mL of 0.3 mol / mL hydrochloric acid is added. The mixture is sealed and placed in a boiling water bath for 3 min. The mixture is cooled and the buffer solution prepared in (2) is added to a pH of 6 to obtain a technetium sulfur colloidal suspension.

[0060] Example 2

[0061] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Embodiment 1 only in that, in step (1), 67 mg of sodium carboxymethyl cellulose is used, so that the concentration of sodium carboxymethyl cellulose in the lyophilized powder is 1.34 mg / mL.

[0062] Example 3

[0063] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Embodiment 1 only in that, in step (1), 100.5 mg of sodium carboxymethyl cellulose is used, so that the concentration of sodium carboxymethyl cellulose in the lyophilized powder is 2.01 mg / mL.

[0064] Example 4

[0065] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Embodiment 1 only in that, in step (1), 134 mg of sodium carboxymethyl cellulose is used, so that the concentration of sodium carboxymethyl cellulose in the lyophilized powder is 2.68 mg / mL.

[0066] Example 5

[0067] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Embodiment 1 only in that, in step (1), 167.5 mg of sodium carboxymethyl cellulose is used, so that the concentration of sodium carboxymethyl cellulose in the lyophilized powder is 3.35 mg / mL.

[0068] Example 6

[0069] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Embodiment 1 only in that in step (1), instead of sodium carboxymethyl cellulose, 0.5 g of polyethylene glycol 1500 is used, so that the concentration of polyethylene glycol in the lyophilized powder is 10 mg / mL.

[0070] Example 7

[0071] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Example 6 only in that in step (1), 0.625 g of polyethylene glycol 1500 is used so that the concentration of polyethylene glycol in the lyophilized powder is 12.5 mg / mL.

[0072] Example 8

[0073] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Example 6 only in that in step (1), 0.75 g of polyethylene glycol 1500 is used so that the concentration of polyethylene glycol in the lyophilized powder is 15 mg / mL.

[0074] Example 9

[0075] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Example 6 only in that in step (1), 0.875 g of polyethylene glycol 1500 is used, so that the concentration of polyethylene glycol in the lyophilized powder is 17.5 mg / mL.

[0076] Example 10

[0077] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Embodiment 1 only in that, in step (3), a 0.1 mol / mL HCl solution is used.

[0078] Embodiment 11

[0079] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Embodiment 1 only in that, in step (3), a 0.2 mol / mL HCl solution is used.

[0080] Example 12

[0081] This embodiment provides a method for preparing technetium sulfide colloid, which is different from Embodiment 1 only in that, in step (3), a 0.4 mol / mL HCl solution is used.

[0082] Embodiments 13 to 15

[0083] This embodiment provides a method for preparing a sulphurized colloid medicine box, comprising the following steps:

[0084] Aminosulfonic acid solutions with concentrations of 0.4 mol / L, 0.6 mol / L, and 0.8 mol / L were prepared, corresponding to Examples 13, 14, and 15, respectively.

[0085] This embodiment provides a method for preparing technetium sulfur colloid, comprising the following steps:

[0086] (1) Weigh 100.5 mg of sodium carboxymethyl cellulose and add it to 30 mL of deionized water, heat it to dissolve it, and cool it to room temperature to obtain solution A; add 0.15 g of sodium thiosulfate to 5 mL of deionized water and completely dissolve it to obtain solution B; mix solution A and solution B, adjust the volume to 50 mL, and obtain a mixed solution of sodium thiosulfate and a stabilizer, i.e., a sulfur colloid composition, and dispense 1 mL into 10 mL vials for later use, wherein the content of sodium carboxymethyl cellulose is 2.01 mg / mL, and the content of sodium thiosulfate is 3 mg / mL.

[0087] (2) Take 1.5 mL of aminosulfonic acid solution and place it in a sample bottle, put it into a freeze dryer, pre-freeze it at -40°C for 5 hours, then quickly add 1 mL of sulfur colloid composition, and continue to pre-freeze it at -40°C for 2 hours. Pre-evacuate to a vacuum degree of 20Pa; heat and reduce pressure to -20°C and 12Pa for 2 hours, heat and reduce pressure to -10°C and 8Pa for 3 hours, so that solid water sublimates and escapes; heat and increase to 10°C for 10 hours, keep warm for 1 hour, heat and reduce pressure to 25°C for 3 hours, and reduce pressure to 3Pa for 2.5 hours, so that the residual water is completely exhausted; the first sulfide colloid medicine box is obtained.

[0088] (3) Prepare a buffer solution using the same method as in Example 1, and package to obtain a second medicine kit.

[0089] Embodiments 16 to 18

[0090] This embodiment provides a method for preparing technetium sulfur colloid, comprising the following steps:

[0091] The first sulfide colloid kit prepared in Examples 13 to 15 was added to 2.5 mL of a sodium pertechnetate solution with a concentration of 0.22 mci / mL, sealed and placed in a boiling water bath for 5 min, cooled, and the buffer solution in the second kit was added to a pH of 6 to obtain the corresponding technetium sulfur colloidal suspension. Examples 16 to 18 respectively used the sulfide colloid kits prepared in Examples 13 to 15.

[0092] Comparative Example 1

[0093] This comparative example provides a method for preparing technetium sulfide colloid, which is different from Example 1 in that in step (1), a freeze-dried powder having a fish gelatin content of 20 mg / mL and a sodium thiosulfate content of 3.0 mg / mL is obtained.

[0094] Comparative Example 2

[0095] This comparative example provides a method for preparing technetium sulfide colloid, which is prepared by imitating the existing medicine kit. The difference from Example 1 is that in step (1), a lyophilized powder with a sodium thiosulfate content of 2 mg / mL, a fish gelatin content of 18.1 mg / mL, and a disodium ethylenediaminetetraacetic acid content (as a chelating agent) of 2.3 mg / mL is obtained.

[0096] Test Example 1

[0097] The technetium labeling rate of the technetium sulfur colloid prepared in the embodiment and the comparative example was detected by ascending chromatography, and the specific operation was as follows:

[0098] To make your own chromatography paper, take Xinhua No. 1 chromatography paper and cut it into strips 10 cm long and 5 cm wide. Use a pencil to divide the long side into 12 grids. The first grid is 1.5 cm from the edge, the 12th grid is 1 cm from the other edge, and the remaining 10 grids are 0.75 cm each.

[0099] Spot a 0.5 cm diameter dot at 1.5 cm from the edge (the first grid line) of the above chromatography paper. After drying, place it vertically in a chromatography tube containing 0.5 ml of 85% methanol and seal it immediately. When the developing agent reaches the 11th grid line, take out the chromatography paper immediately, dry it, cut the 1st and 2nd grids with scissors and place them in a counting tube A. Cut the remaining 3 to 11 grids and place them in counting tubes B to J in order. Discard the 12th grid. Place the counting tubes in the gamma counter in order to detect the radioactivity of technetium. The technetium sulfur colloid in the developing agent remains at the origin of the spot. The formula for calculating the radiochemical purity is as follows:

[0100] Radiochemical purity = CPM value of counter tube A / sum of CPM of 10 counter tubes

[0101] The radiochemical purity is the labeling rate, and the obtained data are shown in Table 1.

[0102] The particle size and PDI (polymer dispersibility index) of the technetium sulfide colloids prepared in the examples and comparative examples were tested using a particle size analyzer (Malvern Instruments Ltd., UK). The obtained data are shown in Table 1.

[0103] Table 1

[0104]

[0105]

[0106] As can be seen from Table 1, when sodium carboxymethyl cellulose is used as a stabilizer, the technetium labeling rate of technetium sulfur colloid is the highest, and when the content of sodium carboxymethyl cellulose in the freeze-dried powder is 0.67-2.01 mg / mL, the technetium labeling rate can reach more than 98%, which is a good effect. When polyethylene glycol is used as a stabilizer, the technetium labeling rate is worse than that when sodium carboxymethyl cellulose is used as a stabilizer, but it is still better than that of gelatin as a stabilizer in Comparative Example 1, and when the content of polyethylene glycol in the freeze-dried powder is 12.5 mg / mL, the technetium labeling rate can reach more than 95%, which is a good effect. As can be seen from Examples 10 to 12, when the concentration of hydrochloric acid used is higher, the technetium labeling rate of the resulting technetium sulfur colloid will also be higher. It can be seen from Examples 16 to 18 that aminosulfonic acid can also achieve a good technetium labeling rate. When sodium carboxymethyl cellulose is used as a stabilizer, the technetium labeling rate is best when the aminosulfonic acid concentration is 0.6 mol / L, reaching 99.54%. It can be seen from Comparative Example 2 that when a chelating agent is added, the technetium labeling rate of the product is reduced.

[0107] Test Example 2

[0108] Thirty-six ICR mice weighing about 20 g were randomly selected (Changzhou Cavens Experimental Animal Co., Ltd.) and randomly divided into three groups, with 12 mice in each group. The technetium sulfur colloid prepared in Examples 3, 7, and Comparative Example 1 (each corresponding to one of the three groups) was injected into each group of mice through the tail vein at a dose of 0.2 mL / mouse. Between 10 minutes, 30 minutes, 60 minutes, and 120 minutes, the mice were killed by dislocating the neck, and the heart, liver, spleen, lung, and kidney were removed. Each organ was wrapped with plastic paper, peeled, weighed, and placed in a radioactive counting tube. Three mice were made in each phase. The counting tube was placed on a γ counter to measure the radioactive count of each organ. The radioactive count of each organ was divided by the radioactive count of the total dose, and finally converted into the percentage of the count per gram of tissue to the total injection amount (%ID.g -1 ). The calculation formula is as follows:

[0109]

[0110] The total dose was determined in parallel from 99m Take 0.2 mL of Tc-sulfur colloid labeling solution and divide it equally into 4 counting tubes with about 0.05 mL in each tube. Place the counting tubes on a γ counter to measure the radioactive count. The sum of the total doses of the 4 counting tubes is the total dose. Measure the total doses of the 4 groups in parallel and calculate the average value.

[0111] Dynamic phenomena in mice: After injection of technetium sulfide colloid, the mice were anesthetized in an anesthesia machine for 5 minutes, and then placed on a SPECT-CT instrument for whole-body dynamic scanning of the mice at 0.5h, 1h, and 2h after drug injection.

[0112] After the technetium sulfide colloid prepared in Example 3 (the concentration of sodium carboxymethyl cellulose was 2.01 mg / mL) was injected into mice, the percentage of counts per gram of tissue to the total injected amount (% ID.g -1 ) See Table 2. At 0.5h, the radioactivity distribution of the liver and spleen of mice accounted for more than 80%, and there was a downward trend afterwards. Figures 1 to 3 , Figure 1 When it is 0.5h, Figure 2 When it is 1h, Figure 3 At 2h, it can be seen that the liver of the mouse is clearly visualized at 0.5h, with a very good effect, and then the color of the picture becomes dim.

[0113] After the technetium sulfide colloid prepared in Example 7 (polyethylene glycol concentration is 12.5 mg / mL) was injected into mice, the percentage of counts per gram of tissue to the total injected amount (% ID.g -1 ) See Table 3. The concentration in the liver is higher than that in the spleen. At 2 hours, the percentage of counts per gram of liver and spleen tissue to the total injected volume is as high as 89.77%±16.53% and 69.42%±7.11%. Mouse liver imaging images are shown in Figures 4 to 6 , Figure 4 When it is 0.5h, Figure 5 When it is 1h, Figure 6 When the imaging time is 2 hours, it can be seen that the mouse liver is clearly visualized at 2 hours, which provides more operability for clinical use. In actual use, the appropriate stabilizer can be selected by comprehensively considering the imaging time and imaging clarity.

[0114] After the technetium sulfide colloid prepared in Comparative Example 1 (using gelatin) was injected into mice, the percentage of counts per gram of tissue to the total injected amount (% ID.g -1 ) See Table 4. At 0.5h, 1h and 2h, the radioactivity counts in mouse liver and spleen ranged from 50% to 70% per gram. Mouse liver imaging images are shown in Figures 7 to 9 , Figure 7 When it is 0.5h, Figure 8 When it is 1h, Fig. 9 When the image is taken at 2 hours, it can be seen that the mouse liver imaging starts to become blurred at 0.5 hours, gradually becomes clear at 1 hour, and heterogeneous luminous spots appear after 2 hours. The overall effect is not as good as the mouse liver development image in the embodiment.

[0115] Table 2

[0116]

[0117]

[0118] Table 3

[0119]

[0120] Table 4

[0121]

[0122] Obviously, the above embodiments are merely examples for clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the protection scope of the invention.

Claims

1. A sulfur colloid composition, characterized in that: including sodium thiosulfate and a stabilizer; Wherein, the stabilizer includes polyethylene glycol or carboxymethyl cellulose salt.

2. A technetium sulfide colloid, characterized in that: The sulfur colloid composition of claim 1 further comprising a pertechnetate solution; Wherein, the content of sodium thiosulfate in the sulfur colloid composition is 1 to 11 mg / mL; When the stabilizer is polyethylene glycol, the content of the polyethylene glycol in the sulfur colloid composition is 7 to 20 mg / mL; When the stabilizer is carboxymethyl cellulose salt, the content of the carboxymethyl cellulose salt in the sulfur colloid composition is 0.5 to 3.5 mg / mL; The concentration of the pertechnetate solution is ≥ 0.1 mci / mL; optionally, the concentration of the pertechnetate solution is 0.5-1 mci / mL; The volume ratio of the sulfur colloid composition to the pertechnetate solution is 1:0.5-4.

3. A method for preparing technetium sulfide colloid as claimed in claim 2, characterized in that: The steps include: The sulfur colloid composition, pertechnetate solution and acid solution are mixed, heated, and a buffer solution is added to obtain the technetium sulfur colloid.

4. The preparation method according to claim 3, characterized in that: The acid solution includes at least one of hydrochloric acid and aminosulfonic acid; optionally, the concentration of the hydrochloric acid is 0.1 to 0.4 mol / L; optionally, the concentration of the aminosulfonic acid is 0.4 to 0.6 mol / L; and / or, the volume ratio of the acid solution to the pertechnetate solution is 1 to 5:1; and / or, adding the buffer solution to adjust the pH to 4 to 7; And / or, the heating time is 2 to 5 minutes, and the heating temperature is 95 to 105°C; And / or, the heating method includes hot bath heating; optionally, the hot bath heating includes at least one of water bath heating and oil bath heating.

5. A sulphurized colloid medicine box, characterized in that: comprising a first medicine box and a second medicine box; The first kit includes lyophilized aminosulfonic acid and lyophilized sulfur colloid composition; The second kit includes a buffer solution; Wherein, the stabilizer includes polyethylene glycol or carboxymethyl cellulose salt.

6. The sulphurized colloid medicine box according to claim 5, characterized in that: The volume of the freeze-dried sulfur colloid composition is less than or equal to the volume of the freeze-dried aminosulfonic acid; optionally, the volume ratio of the freeze-dried aminosulfonic acid to the freeze-dried sulfur colloid composition is 1 to 4:1; further optionally, the volume of the freeze-dried sulfur colloid composition is ≤1 mL, and the volume of the freeze-dried aminosulfonic acid is ≤1.5 mL.

7. A method for preparing a sulphurized colloid medicine box as claimed in claim 5 or 6, characterized in that: The preparation of the first medicine box includes the following steps: pre-freezing: pre-freezing aminosulfonic acid at -35 to -40°C for 3 to 7 hours, adding the sulfur colloid composition and pre-freezing at -35 to -40°C for 2 to 4 hours; sublimating and removing water to obtain the first medicine box; the preparation of the second medicine box includes the following steps: encapsulating the buffer solution; Optionally, the step of sublimating and removing water includes: pre-vacuuming: after pre-freezing, pre-evacuate to a vacuum degree of 18-22 Pa; sublimate solid water: heat up and reduce pressure to -23--17°C, 10-13 Pa for 1.5-2.5 hours, heat up and reduce pressure to -13--7°C, <10 Pa for 2.5-3.5 hours; remove moisture: heat up to 8-12°C for 8-12 hours, keep warm for 1-2 hours, heat up to 20-28°C for 2.5-3.5 hours, and reduce pressure to 1-4 Pa for 2-3 hours; Optionally, the preparation of the second medicine kit further includes a step of freeze-drying the buffer solution.

8. Use of the sulfide colloid kit as claimed in claim 5 or 6 or the sulfide colloid kit prepared by the preparation method as claimed in claim 7 in obtaining technetium sulfide colloid.

9. The use according to claim 8, characterized in that: The method of obtaining technetium sulfide colloid by using the sulfide colloid kit comprises the following steps: mixing the first kit with a pertechnetate solution, heating, and adding a buffer solution in the second kit to obtain the technetium sulfide colloid; Optionally, the concentration of the pertechnetate solution is ≥ 0.1 mci / mL; Optionally, the volume ratio of the sulfur colloid composition to the pertechnetate solution in the first kit is 1:0.5-4; Optionally, the heating time is 2 to 5 minutes, and the heating temperature is 95 to 105°C.

10. Use of the sulfur colloid composition according to claim 1, or the technetium sulfide colloid according to claim 2, or the technetium sulfide colloid prepared by the preparation method according to claim 3 or 4, or the sulfurized colloid medicine box according to claim 5 or 6, or the sulfurized colloid medicine box prepared by the preparation method according to claim 7 in the preparation of radioactive drugs.

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