Compounding process and quality control method of gastrointestinal ultrasound and MRI (Magnetic Resonance Imaging) bifunctional contrast agent

Abstract

The invention belongs to the field of medical contrast agents, and particularly relates to a compounding process and a quality control method of a gastrointestinal ultrasound and MRI (Magnetic Resonance Imaging) bifunctional contrast agent. The gastrointestinal ultrasound and MRI bifunctional contrast agent comprises the following components in percentage by mass: 15%-18% of corn starch, 76%-82% of soybean protein, 0.3%-0.8% of coix seed polysaccharide, 1.5%-2.2% of xanthan gum and 0.05%-0.1% of manganese chloride. Wherein the manganese chloride and the coix seed polysaccharide form a paramagnetic compound with the particle size of 50-200 nm through coordination, and the corn starch and the soybean protein form a porous network structure with the pore diameter of 1-5 [mu] m. According to the method, gastrointestinal ultrasound and MRI clear development are achieved, quality standards are set from multiple dimensions, raw materials and the drying process are strictly monitored, it is guaranteed that the contrast agent is reliable in quality and small in batch-to-batch difference, and clinical use requirements are met.

Description

Technical Field

[0001] The invention belongs to the field of medical contrast agents, and in particular relates to a compounding process and a quality control method for a gastrointestinal ultrasound and MRI dual-function contrast agent. Background Art

[0002] In the field of medical imaging, gastrointestinal ultrasound and magnetic resonance imaging (MRI) are two important detection methods for accurate diagnosis of gastrointestinal diseases. However, the existing contrast agent technology has many shortcomings in meeting the clinical demand for efficient combination of the two examination methods.

[0003] Traditional gastrointestinal ultrasound contrast agents mostly rely on bubble-type microbubbles to achieve imaging. This type of contrast agent has poor stability. Under the influence of factors such as gastrointestinal peristalsis and chemical reactions of digestive juices, microbubbles are easy to rupture, resulting in a short duration of ultrasound imaging, generally only about 20min-30min, which is difficult to meet the doctor's needs for comprehensive and detailed observation of the gastrointestinal tract. In addition, bubble-type microbubble contrast agents cannot play a role in MRI examinations. If patients need to undergo MRI examinations at the same time, other contrast agents need to be used separately, which increases the burden on patients and the complexity of the examination process. On the other hand, existing MRI oral contrast agents, such as commonly used gadolinium agents, can enhance image contrast in MRI imaging, but have significant defects: first, their cost is high, which makes it economically unaffordable for many patients, limiting the widespread application of this contrast agent. Secondly, the biocompatibility of gadolinium agents is controversial. Some patients may experience adverse reactions such as allergic reactions and nephrogenic systemic fibrosis after use, posing a potential threat to patient health. Moreover, gadolinium cannot provide echo signals for ultrasound examinations and cannot meet the clinical expectation that a single contrast agent has the dual functions of gastrointestinal ultrasound and MRI.

[0004] In recent years, researchers have tried to develop plant-based compound contrast agents, hoping to combine the advantages of natural ingredients to achieve dual-function imaging. However, research in this field is still in its early stages. Existing plant-based compound contrast agents have the problem of poor component synergy, and each component has failed to fully exert its functional advantages, resulting in unsatisfactory effects in both ultrasound imaging and MRI enhancement. For example, in terms of ultrasound imaging, it is impossible to effectively enhance the difference in acoustic impedance, resulting in insufficient imaging clarity; in terms of MRI enhancement, T1 relaxation cannot be efficiently regulated, image contrast improvement is limited, and dual-modality imaging efficiency is low, which makes it difficult to meet the needs of actual clinical diagnosis.

[0005] Therefore, the development of a contrast agent and its supporting technology that can take into account the dual functions of gastrointestinal ultrasound and MRI imaging, with stable performance, safety, reliability, and reasonable cost has become an urgent problem to be solved in the field of medical imaging. Summary of the invention

[0006] The object of the present invention is to provide a compounding process and a quality control method for a gastrointestinal ultrasound and MRI dual-functional contrast agent.

[0007] To achieve the above object, the present invention provides the following technical solutions: A gastrointestinal ultrasound and MRI dual-functional contrast agent, comprising the following components in mass percentages: corn starch 15%-18%, soy protein 76%-82%, coix seed polysaccharide 0.3%-0.8%, xanthan gum 1.5-2.2%, manganese chloride 0.05-0.1%; wherein, the manganese chloride and the coix seed polysaccharide form a paramagnetic complex with a particle size of 50nm-200nm through coordination, and the corn starch and the soy protein form a porous network structure with pore sizes of 1μm-5μm.

[0008] Further, the corn starch is ultra-finely pulverized to D50 = 10μm-20μm, and the crystallinity ≤ 15%; the soy protein is subjected to heat and humidity modification treatment, and the treatment conditions are to maintain at 70°C-80°C and a relative humidity of 80-90% for 1h-3h.

[0009] Further, the xanthan gum and the paramagnetic complex form an ionic cross-linked gel network, and FTIR detection shows that the characteristic peak intensity ratio at 1635cm -1 and 1410cm -1 is 1.0-1.8, and the cross-linking degree is positively correlated with the gel strength.

[0010] A compounding process for a gastrointestinal ultrasound and MRI dual-functional contrast agent, comprising the following steps: (1) Add xanthan gum, coix seed polysaccharide, and manganese chloride to a mixer in sequence, and stir and mix at a speed of 300rpm-500rpm for 3min-5min to form a premix; (2) Add corn starch in 3-5 equal increments, and mix at the same speed for 3min-5min after each addition; (3) Add soy protein in 3-6 equal increments, and mix at the same speed for 3min-5min after each addition; (4) Add an ethanol solution with a mass concentration of 45%-55% to the mixed material for granulation, and pass through a 20-mesh sieve to obtain wet granules; (5) Dry the wet granules in two stages: the first stage: hot air drying at 50°C-60°C for 1h-2h; the second stage: fluidized bed drying at 35°C-45°C until the water content of the granules ≤ 6%; (6) Pass the dried granules through a 20-mesh sieve and pack them in portions.

[0011] Further, in step (4), the addition amount of the ethanol solution is 15%-25% of the total mass of the material, and the granulation pressure is 20MPa-50MPa.

[0012] Further, the equal incremental amount in each of steps (2) and (3) is 1 / 2 - 2 / 3 of the remaining material to be added.

[0013] A quality control method for a gastrointestinal ultrasound and MRI dual-functional contrast agent, comprising the following detection items: (a) Detection of imaging performance: The echo intensity is ≥20 dB under a 5 MHz ultrasonic probe, and the relaxation rate r1 value is ≥3.0 mM under a 1.5 T MRI field strength. -1 s -1 ; (b) Detection of physical properties: The passing rate through a 20-mesh sieve is ≥90%, the retention rate by a 40-mesh sieve is ≥75%, and the re-dissolution time in warm water at 37°C is ≤40 s; (c) Detection of chemical properties: The manganese ion release rate is ≤20% in simulated gastric juice for 2 h, and the manganese ion release rate is ≥75% in simulated intestinal juice for 4 h; The intensity ratio of the characteristic peaks at 1635 cm -1 and 1410 cm -1 in the FTIR spectrum is 1.0 - 1.8.

[0014] Further, a near-infrared spectroscopy method is used to establish a raw material fingerprint library with a matching similarity ≥95%; During the drying process, the area of the free water peak is monitored by low-field nuclear magnetic resonance T2 relaxation spectroscopy, and the drying is terminated when the area of the free water peak ≤10%.

[0015] The beneficial effects of the present invention are as follows: 1. High-efficiency dual-functional imaging: Relying on the porous network structure formed by corn starch and soy protein to enhance the ultrasonic acoustic impedance difference, and cooperating with the paramagnetic complex formed by manganese chloride and coix seed polysaccharide to increase the MRI relaxation rate, clear imaging of gastrointestinal ultrasound and MRI is achieved, providing rich and accurate information for disease diagnosis.

[0016] 2. Optimization and synergy of raw materials: Ultrafine pulverization of corn starch and control of crystallinity, and hydrothermal modification of soy protein to optimize their respective properties, enhance the synergistic effect between components, and improve the overall quality and stability of the contrast agent.

[0017] 3. Precise process control: Through compound processes such as pre-gelation, ultrasonic treatment, equal incremental addition, temperature control, freeze-thaw cycle, and gradient drying, ensure the uniform dispersion and full interaction of each component, and guarantee the uniform and stable performance of the contrast agent.

[0018] 4. Strict quality assurance: Set quality standards from multiple dimensions of imaging performance, physical properties, and chemical properties, and strictly monitor the raw materials and drying process to ensure the reliable quality of the contrast agent, small differences between batches, and meet the clinical use requirements. Description of the Drawings

[0019] Figure 1Figure for comparing the structural characteristics of the examples and comparative examples. The paramagnetic particle sizes and the pore sizes of the porous network structures in Examples 1-3 are all within the normal specified ranges. In Comparative Example 1, aggregation occurred due to coordination imbalance, and finally the paramagnetic complex particle size was 280 nm, and the porous network structure was blocked (pore size not measured); in Comparative Example 2, the structure collapsed due to high-temperature gelatinization, and the paramagnetic complex particle size exceeded the normal specified range (pore size not measured), and the pore size of the porous network structure reached 0.5 μm - 10 μm; in Comparative Example 3, the network structure was damaged due to high-temperature deformation, the paramagnetic complex was damaged (particle size not measured), and the porous network structure collapsed (pore size not measured). It can be seen that slight deviations in temperature and component ratio can lead to cascading failure of the structure, verifying the necessity of strictly controlling the process of the present invention.

[0020] Figure 2 Figure for the release kinetics curves of the examples and comparative examples. Detailed implementation manners

[0021] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention; obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention. Example 1

[0022] 1. Raw materials and process Component ratio (mass percentage): Select the ratio of 17.5% corn starch, 79.925% soy protein, 0.5% coix seed polysaccharide, 2% xanthan gum, and 0.075% manganese chloride; Raw material treatment: Accurately weigh 8.4 g of corn starch, and through the ultrafine pulverization process, make its particle size reach D50 = 15 μm, and the crystallinity is measured to be 12% by X-ray diffraction (XRD). Weigh 38.4 g of soy protein and perform heat-moisture modification treatment at 75 °C and a relative humidity of 85% for 2 hours.

[0023] Compound process: (1) Preliminary mixing: Place xanthan gum, coix seed polysaccharide, and manganese chloride in a mixing device and stir at a speed of 400 rpm for 4 minutes.

[0024] (2) Addition of corn starch: Add the corn starch in 4 equal portions, 2.1 g each time, and stir at a speed of 400 rpm for 4 minutes after each addition.

[0025] (3) Addition of soy protein: Similarly, add the soy protein in 5 equal portions, 7.68 g each time, and stir at a speed of 400 rpm for 4 minutes after each addition.

[0026] (4) Granulation: 50% ethanol was used as the granulation medium, and granulation was carried out through a 20-mesh sieve under a pressure of 30 MPa.

[0027] (5) Drying: A two-stage drying process was adopted. First, it was dried in a hot air environment at 55 °C for 1.5 hours to initially remove a large amount of moisture, and then it was transferred to a fluidized bed at 40 °C for drying until the moisture content reached 5.8%.

[0028] 2. Performance Detection (1) Development performance: Detected using a 5 MHz probe, the ultrasonic echo intensity reached 23 dB, and under a magnetic field strength of 1.5 T, the r1 relaxation rate of MRI was 3.1 mM -1 s -1 .

[0029] (2) Physical properties: Determined by sieving analysis, the passing rate through a 20-mesh sieve was 93%, and in a warm water environment at 37 °C, the redissolution time was 38 s.

[0030] (3) Chemical properties: In a simulated gastric juice environment, the manganese ion release amount was 19% in 2 hours, and in a simulated intestinal juice environment, the manganese ion release amount reached 78% in 4 hours.

[0031] (4) Structural characteristics: Determined by electron microscopy and related analysis techniques, the particle size of the paramagnetic complex was 150 nm, and the pore size of the porous structure formed by corn starch and soy protein was between 2 - 4 μm.

[0032] 3. Quality Control Detected by Fourier transform infrared spectroscopy (FTIR), the intensity ratio of the characteristic peaks at 1635 cm -1 and 1410 cm -1 was 1.4; a near-infrared spectroscopy method was used to establish a fingerprint spectrum of the raw materials, and the matching degree with the standard spectrum reached 97%; detected by low-field nuclear magnetic resonance, the free water peak area was 8%. Example 2

[0033] 1. Raw Materials and Processes Component ratio (mass percentage): A formulation of 15% corn starch, 82% soy protein, 0.8% coix seed polysaccharide, 2.2% xanthan gum, and 0.1% manganese chloride was selected.

[0034] Raw material treatment: Accurately weigh 7.2 g of corn starch, and ultrasonically pulverize it to D50 = 20 μm, and the crystallinity measured by XRD was 14%. Weigh 39.36 g of soy protein and carry out hydrothermal modification treatment at 80 °C and a relative humidity of 90% for 1 hour.

[0035] Compound process: (1) Preliminary mixing: Place each raw material in a mixing device and stir at a speed of 500 rpm for 3 minutes.

[0036] (2) Corn starch addition: Add corn starch in 3 equal portions, 2.4 g each time, and keep stirring after each addition.

[0037] (3) Soybean protein addition: Add soybean protein in 3 equal portions, 13.12 g each time, and keep stirring after each addition.

[0038] (4) Granulation: Use 45% ethanol as the granulation medium, and granulate through a 20-mesh sieve under a pressure of 50 MPa.

[0039] (5) Drying: Adopt two-stage drying. First, dry in a hot air environment at 60 °C for 1 hour, and then transfer to a fluidized bed at 45 °C to dry until the moisture content is 5.5%.

[0040] 2. Performance detection (1) Imaging performance: The ultrasonic echo intensity detected by a 5 MHz probe is 21 dB, and the r1 relaxation rate of MRI under a magnetic field strength of 1.5 T is 3.0 mM -1 s -1 .

[0041] (2) Chemical properties: The release amount of manganese ions in simulated gastric juice is 20% in 2 hours, and the release amount in simulated intestinal juice is 75% in 4 hours.

[0042] (3) Structural characteristics: The particle size of the paramagnetic complex is 50 nm, and the pore size of the porous structure formed by corn starch and soybean protein is 1 μm. Example 3

[0043] 1. Raw materials and process Component ratio (mass percentage): Adopt the formula of 18% corn starch, 76% soybean protein, 0.3% coix seed polysaccharide, 1.5% xanthan gum, and 0.05% manganese chloride.

[0044] Raw material treatment: Accurately weigh 8.64 g of corn starch, ultrafinely pulverize it to D50 = 10 μm, and the crystallinity measured by XRD is 8%. Weigh 36.48 g of soybean protein and conduct hydrothermal modification treatment in an environment of 70 °C and relative humidity of 80% for 3 hours.

[0045] Compound process: (1) Preliminary mixing: Place each raw material in a mixing device and stir at a speed of 300 rpm for 5 minutes.

[0046] (2) Corn starch addition: Add corn starch in 5 equal portions, 1.728 g each time, and keep stirring after each addition.

[0047] (3) Soybean protein addition: Add soybean protein in 6 equal portions, 6.08 g each time, and keep stirring after each addition.

[0048] (4) Granulation: Using 55% ethanol as the granulation medium, granulate under a pressure of 20 MPa through a 20-mesh sieve.

[0049] (5) Drying: Adopt a two-stage drying process. First, dry in a hot air environment at 50 °C for 2 hours, and then dry in a fluidized bed at 35 °C until the moisture content reaches 6.0%.

[0050] 2. Performance Detection (1) Development performance: Detect using a 5 MHz probe. The ultrasonic echo intensity reaches 25 dB, and the r1 relaxation rate of MRI under a 1.5 T magnetic field strength is 3.3 mM -1 s -1 .

[0051] (2) Chemical properties: The manganese ion release amount is 15% in simulated gastric juice for 2 hours and 82% in simulated intestinal juice for 4 hours.

[0052] (3) Structural characteristics: The particle size of the paramagnetic complex is 200 nm, and the pore size of the porous structure formed by corn starch and soy protein is 5 μm.

[0053] Comparative Example 1 (1) Component ratio (mass percentage) Adopt components of 17.5% corn starch, 79.805% soy protein, 0.5% coix seed polysaccharide, 2% xanthan gum, and 0.12% manganese chloride.

[0054] (2) Result analysis After detection, the particle size of the paramagnetic complex reaches 280 nm, exceeding the normal range. In simulated gastric juice, the manganese ion release amount is 25% in 2 hours, higher than the normal range. The reconstitution time is extended to 52 s, which may be due to the change in particle size and the change in component ratio affecting the solubility of the contrast agent. Through FTIR detection, the intensity ratio is 1.9, exceeding the normal range, indicating that the cross-linked structure of xanthan gum and the paramagnetic complex is affected, thereby affecting the overall stability and performance of the contrast agent.

[0055] Comparative Example 2 (1) Component ratio (mass percentage) This comparative example is based on Example 1 to explore the influence of the mixing temperature deviating from 0 - 10 °C on the performance of the contrast agent. The components are the same as those in Example 1.

[0056] (2) Result analysis During the compounding process, when the mixing temperature in steps (2)-(3) reached 30 °C, caking of corn starch occurred. This is because the higher temperature may have accelerated the gelatinization process of corn starch, causing it to agglomerate and cake. At the same time, the porous structure collapsed, and the pore size became 0.5 μm - 10 μm, seriously damaging the originally designed structure and affecting the enhancement effect of the acoustic impedance difference. The redissolution time was greater than 120 s, significantly prolonged, because caking and structural collapse led to a sharp decrease in the dispersibility and solubility of the contrast agent in water.

[0057] Comparative Example 3 (1)Component ratio (mass percentage) This comparative example is based on the components of Example 1 to study the influence of deviation of the drying process from the claims on the performance of the contrast agent. In step (5), direct drying in an 80 °C oven until the moisture content ≤ 6% was adopted, abandoning the two-stage drying process.

[0058] (2)Result analysis Upon detection, the soybean protein was denatured because the high temperature of 80 °C exceeded the tolerance temperature of the soybean protein, causing irreversible changes in its structure and properties. Affected by this, the r1 relaxation rate of MRI decreased to 1.5 mM -1 s -1 , far lower than the normal level, indicating that the high temperature damaged the structure or components related to MRI imaging in the contrast agent, resulting in a significant decrease in the imaging performance. In simulated intestinal fluid, the manganese ion release rate was only 40% in 4 hours, significantly lower than the normal range.

[0059] The comparison diagram of the structural characteristics of the examples and comparative examples is shown in Figure 1 , and the release kinetic curve diagram is shown in Figure 2 .

[0060] The above is only the preferred specific implementation manner of the present invention; however, the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution of the present invention and its improved concept, makes equivalent substitutions or changes, and should be covered by the protection scope of the present invention.

Claims

1. A gastrointestinal ultrasound and MRI dual-functional contrast agent, characterized in that, The components contain the following mass percentages: corn starch 15%-18%, soy protein 76%-82%, coix seed polysaccharide 0.3%-0.8%, xanthan gum 1.5-2.2%, manganese chloride 0.05-0.1%; wherein, the manganese chloride and the coix seed polysaccharide form a paramagnetic complex with a particle size of 50nm-200nm through coordination, and the corn starch and the soy protein form a porous network structure with a pore size of 1μm-5μm.

2. The gastrointestinal ultrasound and MRI dual-functional contrast agent according to claim 1, wherein: The corn starch is ultra-finely pulverized to D50 = 10μm-20μm, and the crystallinity ≤ 15%; the soy protein is subjected to heat-moisture modification treatment, and the treatment conditions are to maintain at 70°C-80°C and a relative humidity of 80-90% for 1h-3h.

3. The gastrointestinal ultrasound and MRI dual-functional contrast agent according to claim 1, wherein : The xanthan gum forms an ionic cross-linked gel network with the paramagnetic complex, and the FTIR detection shows that the intensity ratio of the characteristic peaks at 1635 cm -1 and 1410 cm -1 is 1.0 - 1.8, and the cross-linking degree is positively correlated with the gel strength.

4. The compounding process of the gastrointestinal ultrasound and MRI dual-functional contrast agent according to any one of claims 1-3, characterized in that: It includes the following steps: (1) Add xanthan gum, coix seed polysaccharide, and manganese chloride to a mixer in sequence, and stir and mix at a speed of 300rpm-500rpm for 3min-5min to form a premix; (2) Add corn starch in 3-5 equal increments, and mix at the same speed for 3min-5min after each addition; (3) Add soy protein in 3-6 equal increments, and mix at the same speed for 3min-5min after each addition; (4) Add an ethanol solution with a mass concentration of 45%-55% to the mixed material for granulation, and pass through a 20-mesh sieve to obtain wet granules; (5) Dry the wet granules in two stages: The first stage: hot air drying at 50°C-60°C for 1h-2h: The second stage: fluidized bed drying at 35°C-45°C until the water content of the granules ≤ 6%; (6) Pass the dried granules through a 20-mesh sieve and package them.

5. The compounding process of the gastrointestinal ultrasound and MRI dual-functional contrast agent according to claim 4, characterized in that: In step (4), the addition amount of the ethanol solution is 15%-25% of the total mass of the material, and the granulation pressure is 20MPa-50MPa.

6. The compounding process of the gastrointestinal ultrasound and MRI dual-functional contrast agent according to claim 4, characterized in that: In steps (2) and (3), the equal addition amount each time is 1 / 2-2 / 3 of the remaining material to be added.

7. A quality control method for the gastrointestinal ultrasound and MRI dual-functional contrast agent according to any one of claims 1-3, characterized in that: It includes the following detection items: (a)Detection of development performance: Echo intensity ≥ 20 dB under a 5 MHz ultrasonic probe, and relaxation rate r1 value ≥ 3.0 mM under a 1.5 T MR field strength -1 s -1 ; (b) Physical property detection: the passing rate through a 20-mesh sieve ≥ 90%, the retention rate through a 40-mesh sieve ≥ 75%, and the re-dissolution time in warm water at 37°C ≤ 40s; (c)Chemical property detection: The manganese ion release rate ≤ 20% in simulated gastric juice for 2 h and ≥ 75% in simulated intestinal juice for 4 h; the intensity ratio of characteristic peaks at 1635 cm -1 and 1410 cm -1 is 1.0 - 1.

8.

8. The quality control method of the gastrointestinal ultrasound and MRI dual-functional contrast agent according to claim 7, characterized in that: Establish a raw material fingerprint library by near-infrared spectroscopy, and the matching similarity ≥ 95%; monitor the free water peak area by low-field nuclear magnetic resonance T2 relaxation spectrum during the drying process, and terminate the drying when the free water peak area ≤ 10%.

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