A room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent and its preparation method and application

Abstract

The present invention discloses a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent and its preparation method and application, which belongs to the technical field of ultrasound imaging agents. The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent includes: composite microcrystalline cellulose, the composite microcrystalline cellulose includes a microcrystalline cellulose matrix and carbon dots loaded on the microcrystalline cellulose matrix; the carbon dots are obtained by carbonization of amino acids. The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent of the present invention can be directly mixed and dispersed with room temperature water, and the dispersion stability meets the needs of clinical gastrointestinal ultrasound examination, and can maintain a stable state for a certain period of time during the examination without obvious stratification and particle sedimentation; at the same time, the preparation method of the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent product of the present invention has a simple process, low energy loss, low production cost, and is conducive to large-scale mass production and application, providing a necessary basis for the popularization of routine physical examination items of gastrointestinal ultrasound contrast, and has great practical value and economic value.

Description

Technical Field

[0001] The invention relates to a room-temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent and a preparation method and application thereof, belonging to the technical field of ultrasound imaging agents. Background Art

[0002] In recent years, the incidence of gastric cancer and colorectal cancer has gradually increased, and gastric cancer has gradually become younger. Gastrointestinal ultrasound angiography is of great significance in the early screening, early diagnosis and large-scale physical examination of gastric cancer.

[0003] Currently, most of the gastrointestinal ultrasound contrast agents available in clinical practice are granules made by mixing and grinding grains or medicinal and edible materials. Typical clinical products such as Xinzhang brand gastric window acoustic contrast agent and Tianxia brand gastrointestinal ultrasound contrast agent need to be mixed with boiling water and can only be used by patients after cooling. However, this will cause patients to wait for a long time, have a poor medical experience, have a low overall examination efficiency, and have a high cost of use. In addition, due to factors such as insufficient water temperature and incomplete stirring, the contrast agent is prone to stratification, which can easily lead to missed diagnoses during gastrointestinal ultrasound examinations.

[0004] With the development of gastrointestinal ultrasound contrast technology, the emergence of liquid ultrasound contrast agent products has provided great convenience for the clinical use of gastrointestinal ultrasound contrast. Typical products include a patent with publication number CN108939097A, which discloses a ready-to-use liquid oral gastric ultrasound contrast agent, which can not only ensure excellent ultrasound imaging quality, but also greatly simplify its preparation and use procedures, providing a convenient, liquid, ready-to-use oral gastric ultrasound contrast agent. However, due to the liquid form, the intrinsic factors of the product's own physical properties and the external factors of the transportation and storage environment will still have a potential impact on the storage stability of the liquid contrast agent, such as the destruction of the dispersion stability of ultrasound imaging particles, material sedimentation, flocculation and other problems, and the transportation and storage costs are higher than those of solid preparations.

[0005] Due to the above-mentioned problems of the existing technology, although gastrointestinal ultrasound examination has extremely strong application advantages in early screening and early diagnosis of diseases, it is difficult to popularize it as a routine physical examination item due to factors such as the efficiency, stability and cost of the contrast agent. Therefore, there is an urgent need for a solid gastrointestinal ultrasound contrast agent that can dissolve and disperse quickly at room temperature, has a long stability time and low examination cost. Summary of the invention

[0006] In order to solve the problems of gastrointestinal ultrasound contrast agent products in the above-mentioned prior art, such as solid preparations often need to be mixed with boiling water and have low efficiency, liquid preparations are insufficiently stable, and have high usage costs and are difficult to be popularized as routine physical examination items, the present invention provides a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent and a preparation method and application thereof. By adopting a solid preparation method, rapid dissolution and dispersion at room temperature can be achieved, the dispersion liquid is stable for a long time, and the cost is low, which is helpful to promote the popularization of gastrointestinal ultrasound contrast as a routine physical examination item.

[0007] The present invention adopts the following technical solutions:

[0008] According to a first aspect of the present invention, there is provided a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent, comprising:

[0009] Compound microcrystalline cellulose;

[0010] The composite microcrystalline cellulose comprises a microcrystalline cellulose matrix and carbon dots loaded on the microcrystalline cellulose matrix;

[0011] The carbon dots are obtained by carbonizing amino acids.

[0012] Optionally, the carbon dots are formed by in-situ carbonization of amino acids on microcrystalline cellulose in an aqueous solution.

[0013] After loading carbon dots on the surface of microcrystalline cellulose, it has a higher specific surface area and surface active sites, which changes the surface properties of microcrystalline cellulose particles, is beneficial to enhancing the interaction between microcrystalline cellulose particles and water, makes it easier for the surface of composite microcrystalline cellulose particles to form a hydration layer with water molecules, reduces the mutual attraction between composite microcrystalline cellulose particles, and thus slows down the aggregation and sedimentation of microcrystalline cellulose particles.

[0014] Optionally, the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent further comprises a polymer hydrophilic colloid powder;

[0015] The weight ratio of the composite microcrystalline cellulose to the high molecular weight hydrophilic colloid powder in the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent is 1:0.01-0.1.

[0016] Optionally, the weight ratio of composite microcrystalline cellulose to polymer hydrophilic colloid powder in the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent is selected from any value of 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1 or any range between two of them.

[0017] The polymer hydrophilic colloid is mainly a polymer hydrophilic polysaccharide, which is used for suspending and thickening. Excessive addition of the polymer hydrophilic colloid will form micelles due to its extremely strong hydrophilicity, and will not have enough time to fully diffuse during the mixing and stirring process with water during use. The outer layer absorbs water and expands into a gel shell, preventing water from entering the inner layer and affecting dispersion. The composite microcrystalline cellulose powder of the present invention itself has a stable dispersion time that meets the requirements of ultrasound angiography. Therefore, adding a small amount of polymer hydrophilic colloid powder in the present invention can be used for auxiliary suspension and thickening, further improving the dispersion stability and dispersion stability time of the composite microcrystalline cellulose powder, and will not form micelles due to insufficient dilution and insufficient time for full dispersion, which will affect dispersion in turn.

[0018] Optionally, the hydrophilic colloid is selected from at least one of xanthan gum, mannan, sodium alginate and sodium carboxymethyl cellulose.

[0019] It can be used alone or together with other drugs to act as a suspending agent.

[0020] Optionally, the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent further includes carbon dot powder; the carbon dot powder is obtained by carbonizing amino acids.

[0021] Carbon dots have good dispersibility in water and can form a colloidal system, which can increase the liquid viscosity to a certain extent and reduce the surface tension of water, which helps to further assist in slowing down the aggregation and sedimentation of the suspended composite microcrystalline cellulose particles and maintain their dispersed state.

[0022] The carbon dot powder is obtained after drying the carbon dots that are in the solution and not loaded on the microcrystalline cellulose during the preparation process of the composite microcrystalline cellulose. It can be removed by separation in the solution after the preparation of the composite microcrystalline cellulose or it can be retained. When retained, the powder obtained by drying the solution after the preparation of the composite microcrystalline cellulose includes the carbon dot powder. The amount of the carbon dot powder depends on the amount of raw materials and the reaction conditions in the preparation process of the composite microcrystalline cellulose. It is not specifically limited in the present invention, and those skilled in the art can adjust it according to needs.

[0023] Optionally, the content of carbon dots in the composite microcrystalline cellulose is 1-20wt%.

[0024] Optionally, the content of carbon dots in the composite microcrystalline cellulose is selected from any value among 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20wt%, or any range value therebetween.

[0025] Optionally, the size of the composite microcrystalline cellulose is 0.2-100 μm.

[0026] Optionally, the size of the composite microcrystalline cellulose is 30-70 μm.

[0027] Optionally, the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent further comprises at least one of a flavoring agent and a diluent.

[0028] Optionally, the diluent is selected from at least one of maltitol, xylitol, sorbitol, erythritol, trehalose and soluble starch.

[0029] The choice of flavoring agent in the present invention is not strictly limited, and is only used to improve the palatability of the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent. Those skilled in the art can choose from the existing technology according to their needs. Some flavoring agents can also replace the role of diluents, such as xylitol.

[0030] According to a second aspect of the present invention, there is provided a method for preparing the above-mentioned room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent, comprising the following steps:

[0031] A mixture of microcrystalline cellulose, amino acid and water is placed in a container, heated to form a water dispersion of composite microcrystalline cellulose, and then separated, dried and powdered to obtain the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0032] The separation and drying and powdering in the present invention are not strictly limited. Those skilled in the art can select existing technical methods or devices to dry and powder the formed aqueous dispersion of composite microcrystalline cellulose according to needs, or further configure the separated composite microcrystalline cellulose product into an aqueous dispersion for drying and then powdering.

[0033] Optionally, the dry powder making is selected from any one of vacuum drying, spray drying and freeze drying powder making.

[0034] Optionally, the amino acid is selected from at least one of lysine, arginine, histidine, serine, threonine, tyrosine, cysteine, asparagine, glutamine, selenocysteine, pyrrolysine, aspartic acid, glutamic acid, alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine and glycine.

[0035] Optionally, the amino acid is selected from at least one of lysine, arginine, serine, threonine, cysteine, alanine, proline and glycine.

[0036] The preferred lysine, arginine, serine, threonine, cysteine, alanine, proline and glycine mentioned above are different from the other amino acid options mentioned above in that they have greater solubility in water, and a higher carbon dot loading amount or a shorter preparation time at the same loading amount can be obtained by controlling the concentration of the amino acid aqueous solution during the preparation process.

[0037] Optionally, the solid-liquid ratio of microcrystalline cellulose to water in the mixture is 1 g:10-200 mL;

[0038] The weight ratio of microcrystalline cellulose to amino acids in the mixture is 1:0.01-0.4.

[0039] Optionally, the solid-to-liquid ratio of microcrystalline cellulose to water in the mixture is selected from any value among 1g:10 mL, 1g:20 mL, 1g:30 mL, 1g:40 mL, 1g:50 mL, 1g:60 mL, 1g:70 mL, 1g:80 mL, 1g:90 mL, 1g:100 mL, 1g:110 mL, 1g:120 mL, 1g:130 mL, 1g:140 mL, 1g:150 mL, 1g:160 mL, 1g:170 mL, 1g:180 mL, 1g:190 mL, 1g:200 mL, or any range between two values.

[0040] The weight ratio of microcrystalline cellulose to amino acids in the mixture is selected from any value among 1:0.01, 1:0.02, 1:0.04, 1:0.06, 1:0.08, 1:0.1, 1:0.12, 1:0.14, 1:0.16, 1:0.18, 1:0.2, 1:0.22, 1:0.24, 1:0.26, 1:0.28, 1:0.3, 1:0.32, 1:0.34, 1:0.36, 1:0.38, 1:0.4 or any range value therebetween.

[0041] Optionally, the preparation method further comprises, after the drying and powdering step, uniformly mixing the powder with at least one of a polymer hydrophilic colloid powder, a flavoring agent and a diluent to obtain the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0042] Optionally, the heating condition is: heating at 160-220° C. for 0.5-6 h under stirring conditions of 200-1000 rpm.

[0043] Optionally, the stirring speed in the heating condition is selected from any value among 200 rpm, 400 rpm, 600 rpm, 800 rpm, 1000 rpm or any range therebetween.

[0044] Optionally, in the heating conditions, the heating temperature is selected from any value of 160°C, 170°C, 180°C, 190°C, 200°C, 210°C, 220°C, or any range therebetween.

[0045] Optionally, the heating temperature in the heating conditions is selected from any value among 0.5h, 1h, 2h, 3h, 4h, 5h, 6h or any range between two values.

[0046] Optionally, the container is a closed container;

[0047] When the container is a sealed container, the heating time is 0.5 to 3.

[0048] According to the third aspect of the present invention, there is also provided a use of the above-mentioned room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent or the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent prepared according to the above-mentioned preparation method in the preparation of gastric ultrasound contrast agent and / or intestinal ultrasound contrast agent.

[0049] Optionally, the method for using the ultrasound contrast agent is: adding it to an edible liquid and stirring to mix evenly;

[0050] The edible liquid is selected from at least one of purified water, mineral water, non-carbonated beverages and dairy drinks;

[0051] The solid-liquid ratio of the composite microcrystalline cellulose in the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent to the edible liquid is 1-100 g:1 L;

[0052] The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent is a powder and / or a disintegrating solid preparation.

[0053] The solid-to-liquid ratio of the composite microcrystalline cellulose to the edible liquid in the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent is selected from any value among 1g:1L, 5g:1L, 10g:1L, 20g:1L, 30g:1L, 40g:1L, 50g:1L, 601g:1L, 70g:1L, 80g:1L, 90g:1L, 100g:1L or any range value between two of them.

[0054] Although there are certain differences in the ultrasound sonogram quality effects of the composite microcrystalline cellulose in the above-mentioned room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent defined in the present invention and the dispersion liquid within the solid-to-liquid ratio range of the edible liquid, the echoes are uniform and can both be used for gastrointestinal ultrasound diagnosis. Those skilled in the art can select a specific ratio within the solid-to-liquid ratio range defined in the present invention for configuration as needed.

[0055] Optionally, the disintegrating solid preparation comprises a disintegrant.

[0056] The disintegrant in the present invention is not strictly limited, and those skilled in the art can make conventional selections in the prior art according to their needs, such as starch, modified starch, cellulose, microcrystalline cellulose, etc.

[0057] According to a fourth aspect of the present invention, there is also provided a sealed packaged solid-liquid separation contrast agent product, comprising a solid storage portion and a liquid storage portion;

[0058] A film or sheet for isolating solid and liquid is included between the solid storage part and the liquid storage part;

[0059] The solid stored in the solid storage part is selected from at least one of the above-mentioned normal temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent or the normal temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent prepared according to the above-mentioned preparation method;

[0060] The liquid stored in the liquid storage portion is an edible liquid;

[0061] The edible liquid is selected from at least one of purified water, mineral water, non-carbonated beverages and dairy drinks;

[0062] The sealed packaging is selected from at least one of bottle packaging, bag packaging and box packaging;

[0063] When the sealed package is used, the film or sheet used to separate the solid and the liquid is broken to allow the solid to contact the liquid.

[0064] The structure of the sealed packaged solid-liquid separated contrast agent product including the solid storage part and the liquid storage part in the present invention is not strictly limited. Those skilled in the art can select from the existing technologies or design in combination with the existing technologies as needed. The solid and liquid can be stored separately through an isolation membrane or sheet, and when in use, the solid and liquid can be mixed by destroying the isolation membrane or sheet between the solid and liquid.

[0065] Optionally, the weight of the composite microcrystalline cellulose in the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent and the volume of the edible liquid are 1-100 g:1L.

[0066] Optionally, the weight of the composite microcrystalline cellulose in the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent and the volume of the edible liquid are selected from any value among 1g:1L, 5g:1L, 10g:1L, 20g:1L, 30g:1L, 40g:1L, 50g:1L, 601g:1L, 70g:1L, 80g:1L, 90g:1L, 100g:1L or any range value between two of them.

[0067] The beneficial effects produced by the present invention include:

[0068] (1) The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent provided by the present invention can be directly mixed and dispersed with room temperature or even low temperature water in clinical applications, and the dispersion stability time and stability meet the requirements of clinical gastrointestinal ultrasound examination. During the examination, it can maintain a stable state for a certain period of time without obvious stratification or particle sedimentation.

[0069] (2) The method for preparing the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent adopted by the present invention has a simple process, low energy loss, and a production cost that is conducive to large-scale mass production and application.

[0070] (3) The product of the present invention can be used in the form of powder and / or disintegrating solid preparation, which is convenient for transportation and storage and has good stability. Based on this characteristic, the product can also be prepared into a sealed package with solid-liquid separation for contrast agent product use, which can provide patients with a variety of options such as bottled, bagged, and boxed, greatly providing convenience for patients.

[0071] (4) The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent product provided by the present invention provides a necessary basis for the popularization of gastrointestinal ultrasound contrast as a routine physical examination item, and has great practical and economic value. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0073] Figure 1 A comparison of high-frequency ultrasonic sound and image between Application Example 11 (a) and Application Example 12 (b) of the present invention (detected using L12-5 linear vibration ultrasonic probe);

[0074] Figure 2 A comparison of high-frequency ultrasonic sound and image between Application Example 12 (a) and Application Example 8 (b) of the present invention (detected using L12-5 linear vibration ultrasonic probe);

[0075] Figure 3 The high-frequency ultrasonic sound image comparison diagram of application example 8 (a) and application example 13 (b) of the present invention (detected using L12-5 linear vibration ultrasonic probe);

[0076] Figure 4 The high-frequency ultrasonic sound image comparison diagram of application example 13 (a) of the present invention and comparative application example 5 (b) (detected using L12-5 linear vibration ultrasonic probe);

[0077] Figure 5 The low-frequency ultrasonic sound and image comparison diagram of Application Example 13 (a) of the present invention and Comparative Application Example 5 (b) (detected using C5-1 sudden vibration ultrasonic probe). DETAILED DESCRIPTION

[0078] The present invention is described in detail below in conjunction with embodiments, but the present invention is not limited to these embodiments.

[0079] The ultrasonic detection instrument of the ultrasonic sonogram in the present invention adopts Philips EPIQ 7 color ultrasonic diagnostic system. The present invention adopts transparent plastic bottle or transparent soft plastic cup as container test, and the thick white line at the boundary of the ultrasonic sonogram development area is the container wall.

[0080] The amino acids defined in the present invention can all be prepared into aqueous solutions and then directly heated or reacted by hydrothermal method to generate carbon dots, and can all meet the technical scheme of the present invention. In the specific implementation of the present invention, lysine and arginine, which have relatively large solubility in water, are used as typical examples for experiments and technical effect descriptions.

[0081] Example 1

[0082] 50 g of microcrystalline cellulose (size 75 μm) and 10 g of lysine were added to 5 L of water and stirred to form a mixed liquid, which was then placed in a closed reactor. The mixed liquid was continuously stirred at a speed of 200 rpm and subjected to a hydrothermal reaction at a temperature of 165°C for 2 hours to obtain an aqueous dispersion of composite microcrystalline cellulose. The aqueous dispersion was separated after cooling, freeze-dried and powdered to obtain a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0083] Example 2

[0084] 50 g of microcrystalline cellulose (size 75 μm) and 10 g of lysine were added to 1 L of water and stirred to form a mixed liquid, which was then placed in a closed reactor. The mixed liquid was continuously stirred at a speed of 200 rpm and subjected to hydrothermal reaction at a temperature of 165°C for 2 hours to obtain an aqueous dispersion of composite microcrystalline cellulose. The aqueous dispersion was separated after cooling, freeze-dried and powdered to obtain a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0085] Example 3

[0086] 50 g of microcrystalline cellulose (size 75 μm) and 20 g of lysine were added to 5 L of water and stirred to form a mixed liquid, which was then placed in a closed reactor. The mixed liquid was continuously stirred at a speed of 200 rpm and subjected to a hydrothermal reaction at a temperature of 165°C for 2 hours to obtain an aqueous dispersion of composite microcrystalline cellulose. The aqueous dispersion was separated after cooling, freeze-dried and powdered to obtain a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0087] Example 4

[0088] 50 g of microcrystalline cellulose (size 75 μm) and 2 g of lysine were added to 5 L of water and stirred to form a mixed liquid, which was then placed in a closed reactor. The mixed liquid was continuously stirred at a speed of 200 rpm and subjected to a hydrothermal reaction at a temperature of 165°C for 2 hours to obtain an aqueous dispersion of composite microcrystalline cellulose. The aqueous dispersion was then cooled and freeze-dried to obtain a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0089] Example 5

[0090] 50 g of microcrystalline cellulose (size 75 μm) and 10 g of lysine were added to 5 L of water and stirred to form a mixed liquid, which was then placed in an open reactor. The mixed liquid was continuously stirred at a speed of 200 rpm and subjected to a hydrothermal reaction at a temperature of 165°C for 6 hours to obtain an aqueous dispersion of composite microcrystalline cellulose. The aqueous dispersion was separated after cooling, freeze-dried and powdered to obtain a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0091] Example 6

[0092] 50 g of microcrystalline cellulose (size 75 μm) and 10 g of arginine were added to 5 L of water and stirred to form a mixed liquid, which was then placed in a closed reactor. The mixed liquid was continuously stirred at a speed of 200 rpm and subjected to hydrothermal reaction at a temperature of 180°C for 2 hours to obtain an aqueous dispersion of composite microcrystalline cellulose. The aqueous dispersion was separated after cooling, freeze-dried and powdered to obtain a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0093] Example 7

[0094] The powder (composite microcrystalline cellulose powder) obtained by freeze-drying in Example 1 was weighed and evenly mixed with xanthan gum and mannan in a weight ratio of 1:0.05:0.05 to obtain a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0095] Example 8

[0096] The powder (composite microcrystalline cellulose powder) obtained by freeze-drying in Example 1 was weighed and evenly mixed with xanthan gum, mannan, xylitol and soluble starch in a weight ratio of 1:0.05:0.05:0.2:0.8 to obtain a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0097] Example 9

[0098] The powder (composite microcrystalline cellulose powder) obtained by freeze-drying in Example 1 was weighed and evenly mixed with xanthan gum, mannan, xylitol, soluble starch and flavoring agent (rice flower fragrance powder) in a weight ratio of 1:0.05:0.05:0.2:0.8:0.1 to obtain a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

[0099] Application Example 1

[0100] The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent is dispersed in water: based on the weight of the powder (composite microcrystalline cellulose powder) obtained by freeze-drying as 10 g, the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent of Example 1 is weighed and added into 500 mL of water, and stirred for 10 seconds to obtain a dispersion liquid, in which the content of the composite microcrystalline cellulose powder is 2 wt %.

[0101] Application Examples 2~9

[0102] The method for dispersing the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent in water is the same as that in Application Example 1, except that the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agents weighed are prepared from Example 2, Example 3, Example 4, Example 5, Example 6, Example 7, Example 8, and Example 9;

[0103] During the dispersion process, Examples 1 to 9 can all be dispersed quickly, and Example 7 produces a very small amount of tiny glue spots during the stirring process, which disappear after a slightly longer stirring time.

[0104] Comparative Application Example 1 Microcrystalline Cellulose

[0105] 10 g of microcrystalline cellulose (size 75 μm) was added to 500 mL of water and stirred for 10 s to obtain a dispersion. During the dispersion process, the microcrystalline cellulose could be dispersed quickly.

[0106] Comparative Application Example 2: Microcrystalline Cellulose + Xanthan Gum and Mannan

[0107] 10 g of microcrystalline cellulose (size 75 μm) was weighed, mixed evenly with xanthan gum and mannan in a weight ratio of 1:0.05:0.05, added to 500 mL of water, and stirred for 10 seconds to obtain a dispersion. During the dispersion process, a very small amount of fine gel spots were produced, which disappeared after a slightly longer stirring time.

[0108] Comparative Application Example 3: Microcrystalline Cellulose + Xanthan Gum and Mannan

[0109] 10 g of microcrystalline cellulose (size of 75 μm) was weighed, mixed evenly with xanthan gum and mannan in a weight ratio of 1:0.4:0.4, and added to 500 mL of water. The mixture was stirred for 10 seconds to obtain a dispersion. During the dispersion process, a small amount of block-like micelles appeared. This was due to the extremely strong hydrophilicity. During the manual stirring process, xanthan gum and mannan did not have time to fully diffuse and formed micelles. The outer layer absorbed water and expanded into a gel shell, preventing water from entering the inner layer.

[0110] Comparative Application Example 4: Microcrystalline Cellulose + Hydroxymethyl Cellulose

[0111] 2.5 g of microcrystalline cellulose (size 75 μm) and hydroxymethyl cellulose were weighed and mixed in a weight ratio of 1:0.4, and then added to 500 mL of water and stirred for 10 seconds to obtain a dispersion. During the dispersion process, the hydroxymethyl cellulose did not have time to fully diffuse and agglomerated, resulting in a small amount of block-like micelles.

[0112] Application Example 10 Sealed Package Solid-Liquid Separation Room Temperature Aqueous Self-Dispersible Gastrointestinal Ultrasound Contrast Agent

[0113] The bottle cap and the mixed beverage bottle having the bottle cap with publication number CN212126113U are used, wherein the containing tank is the solid storage portion of the present invention, 8g of the palatable room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent of Example 9 is stored in the containing tank, and the bottle body is the liquid storage portion of the present invention, which stores pure water inside;

[0114] When in use, tear off the easy-tear ring from the upper cover, and then apply external force to the upper cover so that the upper cover can move toward the bottom end of the lower cover when the external force acts on it, and the upper cover cutting assembly will be able to contact and cut the sealing piece to open the opening of the lower cover and connect with the interior of the bottle body, so that the palatable room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent can leak out from the opening of the accommodating groove and fall into the interior of the bottle body through the opening of the lower cover, even if the palatable room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent on the upper cover is mixed with the pure water inside the bottle body, manually shake the bottle body to make the palatable room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent evenly dispersed in the pure water, unscrew the lower cover, and drink it.

[0115] Test Example 1 Stability Comparison

[0116] The dispersions obtained in Application Examples 1 to 9 and Comparative Application Examples 1 to 4 were stirred for 30 seconds respectively, poured into a transparent reagent bottle and allowed to stand to observe the dispersion stability of the dispersions. The results are shown in Table 1.

[0117] Table 1 Dispersion stability comparison

[0118]

[0119] Test Example 2 Acid Stability Comparison

[0120] The dispersions obtained in Application Examples 1 to 9 were adjusted to pH 3.5 with hydrochloric acid, respectively, and poured into a transparent reagent bottle after stirring for 30 seconds, and allowed to stand to observe the dispersion stability of the dispersion. As a result, the dispersions in Application Examples 1 to 9 were stably dispersed and kept in a suspended state after standing for 30 minutes. After standing for 60 minutes, the dispersions were stably dispersed and kept in a good suspended state. The precipitation of particles at the bottom of the bottle was similar to that in Test Example 1. The acidic stability simulated the acidic environment after taking the contrast agent liquid on an empty stomach during a physical examination. It can be seen that the contrast agent of the present invention is stably dispersed under acidic conditions.

[0121] Application Example 11

[0122] Based on the weight of the powder (composite microcrystalline cellulose powder) obtained by freeze-drying as 2.5 g, the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent of Example 8 was weighed and added into 500 mL of water, and stirred for 10 seconds to obtain a dispersion liquid, in which the content of the composite microcrystalline cellulose powder in the dispersion liquid was 0.5 wt %.

[0123] Application Example 12

[0124] Based on the weight of the powder (composite microcrystalline cellulose powder) obtained by freeze-drying as 5 g, the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent of Example 8 was weighed and added into 500 mL of water, and stirred for 10 seconds to obtain a dispersion liquid, in which the content of the composite microcrystalline cellulose powder in the dispersion liquid was 1 wt %.

[0125] Application Example 13

[0126] Based on the weight of the powder (composite microcrystalline cellulose powder) obtained by freeze-drying as 25 g, the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent of Example 8 was weighed and added into 500 mL of water, and stirred for 10 seconds to obtain a dispersion liquid, in which the content of the composite microcrystalline cellulose powder in the dispersion liquid was 5 wt %.

[0127] Comparative Application Example 5

[0128] Taking the weight of the powder (composite microcrystalline cellulose powder) obtained by freeze-drying as 100 g, the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent of Example 8 was weighed and added into 500 mL of water, and stirred for 10 seconds to obtain a dispersion liquid, in which the content of the composite microcrystalline cellulose powder in the dispersion liquid was 20 wt %.

[0129] Comparative Application Example 6

[0130] Use Tianxia brand instant gastrointestinal ultrasound contrast agent as contrast developer. Pour about 450ml of boiling water into the original 600ml container (transparent soft plastic cup) of Tianxia brand instant gastrointestinal ultrasound contrast agent, then pour the contrast agent (1 bag / 50g) evenly into the container, stirring continuously to form a uniform paste. After it cools down, you can perform ultrasound examination.

[0131] Test Example 3 Ultrasonic imaging test

[0132] For the convenience of testing, the dispersions of Application Example 8, Application Examples 11-13, and Comparative Application Example 5 were poured into 500 mL cylindrical transparent plastic bottles, shaken and left to stand for 5 minutes. The dispersions of Application Examples 8 and Application Examples 11-13 remained in good dispersion state, while the dispersion of Comparative Application Example 5 had obvious particle sedimentation due to excessive content of composite microcrystalline cellulose powder in the dispersion, and the concentration of the dispersion in the bottle was obviously different, so it could not be used as a contrast agent.

[0133] The L12-5 linear vibration ultrasonic probe was used for detection (the probe direction was parallel to the length direction of the bottle cylinder, and the position in the middle of the bottle was detected), and the high-frequency ultrasonic sound image comparison of the dispersion liquid of Application Example 8 and Application Examples 11~13 was obtained. Figure 1~Figure 3As shown, comparisons were made when the composite microcrystalline cellulose powder content in the dispersion was 0.5wt% / 1.0wt%, 1wt% / 2wt%, and 2wt% / 5wt%. It can be seen from the figure that the dispersion echo uniformity of each content is good, and with the increase of the composite microcrystalline cellulose powder content in the dispersion, the ultrasonic echo uniformity of the dispersion is improved, and the quality of the high-frequency ultrasonic sound image is improved. After the composite microcrystalline cellulose powder content in the dispersion exceeds 2wt%, the quality of the high-frequency ultrasonic sound image of the dispersion is improved to a limited extent, that is, the quality of the high-frequency ultrasonic sound image of the 2wt% and 5wt% content cases is very similar, which also shows that the room temperature aqueous self-dispersible gastrointestinal ultrasonic contrast agent of the present invention can obtain good imaging effects in a larger range of configuration ratios with edible liquids when used, but when the configured composite microcrystalline cellulose powder content is too high, it will affect the stability of the dispersion, so the user can select a specific ratio as needed within the wider configuration ratio range defined by the present invention.

[0134] Further tests were conducted to compare the dispersion of Application Example 13 with the commonly used commercially available contrast agent in clinical application example 6. In order to facilitate comparison with prior art products, the original 600 ml container (transparent soft plastic cup) of Tianxia brand instant gastrointestinal ultrasound contrast agent product in comparative application example 6 was used as a container, and the dispersion of Application Example 13 was added thereto. After stirring and standing for 5 minutes, the dispersion was detected using an L12-5 linear vibration ultrasound probe to obtain a high-frequency ultrasound image of the dispersion of Application Example 13 as shown in FIG. Figure 4 b, and then the C5-1 sudden vibration ultrasonic probe is used to detect and obtain the low-frequency ultrasonic sound image of the dispersion liquid of Application Example 13 as shown in Figure 5 b; then the L12-5 linear vibration ultrasound probe is used to detect the Tianxia brand instant gastrointestinal ultrasound contrast agent in Comparative Application Example 6 when it is stirred into a paste and cooled to about 60°C, and the high-frequency ultrasound image of the Tianxia brand contrast agent in Comparative Application Example 6 is obtained as shown in Figure 4 As shown in a (the black shadow in the middle of the figure is caused by the stirring rod placed in the container), and then the C5-1 sudden vibration ultrasonic probe is used for detection to obtain the low-frequency ultrasonic image of the Tianxia brand instant gastrointestinal ultrasonic developer in comparative application example 6 when it is stirred into a paste and cooled to about 60°C. Figure 5 As shown in a; the probe direction of the linear vibration ultrasonic probe of the two is parallel to the cross-sectional direction of the transparent soft plastic cup, and the position in the middle of the bottle body is detected (because the container is a transparent soft plastic cup, the sudden vibration probe can be used to test the horizontal plane);

[0135] from Figure 4 , Figure 5It can be seen that the quality of high-frequency and low-frequency ultrasound images of the dispersion in Application Example 13 of the present invention is similar to that of the ultrasound image of the Tianxia brand contrast agent commonly used in clinical practice in Comparative Application Example 6, and the echo is more uniform, indicating that the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent prepared by the present invention can reach the imaging level of contrast agent products commonly used in clinical practice in the prior art;

[0136] from Figures 1 to 5 From the comparison, when the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent of the present invention is used, the imaging quality when the content of composite microcrystalline cellulose powder in the dispersion is below 2wt% is compared with that of comparative application example 6. Due to the good echo uniformity, the difference in imaging quality is also relatively weak from the perspective of clinical application. Therefore, the configuration ratio of the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent of the present invention and the edible liquid when used is not very strict, and it can be within the range defined by the present invention. Compared with products such as the Tianxia brand contrast agent commonly used in clinical practice in comparative application example 6, which require strict dilution configuration ratios and conditions, the product prepared by the present invention has the advantages of being more flexible and convenient in use, and the efficiency of pre-diagnosis preparation and diagnosis process of ultrasonic examination can also be significantly improved, which will be conducive to the large-scale promotion and application of gastrointestinal ultrasound contrast as a routine item of physical examination.

[0137] The above are only several embodiments of the present invention and are not intended to limit the present invention in any form. Although the present invention is disclosed as above in the form of a preferred embodiment, it is not intended to limit the present invention. Any technician familiar with the profession, without departing from the scope of the technical solution of the present invention, using the above disclosed technical content to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent, characterized in that: include: Compound microcrystalline cellulose; The composite microcrystalline cellulose comprises a microcrystalline cellulose matrix and carbon dots loaded on the microcrystalline cellulose matrix; the carbon dots are formed by in-situ carbonization of amino acids on the microcrystalline cellulose in an aqueous solution; The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent is a powder and / or a disintegrating solid preparation.

2. The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent according to claim 1, characterized in that: The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent also includes polymer hydrophilic colloid powder; The weight ratio of the composite microcrystalline cellulose to the polymer hydrophilic colloid powder is 1:0.01-0.

1.

3. The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent according to claim 1, characterized in that: The content of carbon dots in the composite microcrystalline cellulose is 1-20wt%.

4. The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent according to claim 1, characterized in that: The room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent further comprises at least one of a flavoring agent and a diluent.

5. The method for preparing a room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent according to any one of claims 1 to 4, characterized in that: The steps include: A mixture of microcrystalline cellulose, amino acid and water is placed in a container, heated to form a water dispersion of composite microcrystalline cellulose, and then separated, dried and powdered to obtain the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

6. The preparation method according to claim 5, characterized in that: The solid-to-liquid ratio of microcrystalline cellulose to water in the mixture is 1 g:10-200 mL.

7. The preparation method according to claim 5, characterized in that: The preparation method further comprises, after the drying and powdering step, uniformly mixing the powder with at least one of a polymer hydrophilic colloid powder, a flavoring agent and a diluent to obtain the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent.

8. The preparation method according to claim 5, characterized in that: The heating conditions are: heating at 160-220° C. for 0.5-6 h under stirring conditions of 200-1000 rpm.

9. Use of the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent according to any one of claims 1 to 4 or the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent prepared according to the preparation method according to any one of claims 5 to 8 in the preparation of gastric ultrasound contrast agents and / or intestinal ultrasound contrast agents.

10. A sealed packaged solid-liquid separation contrast agent product, characterized in that: comprising a solid storage portion and a liquid storage portion; A film or sheet for isolating solid and liquid is included between the solid storage part and the liquid storage part; The solid stored in the solid storage part is the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent according to any one of claims 1 to 4 or the room temperature aqueous self-dispersible gastrointestinal ultrasound contrast agent prepared by the preparation method according to any one of claims 5 to 8; The liquid stored in the liquid storage portion is edible liquid.

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