Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in the present invention, it is understood that the upper and lower limits of the ranges and each intermediate value therebetween are specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
Liquid gastrointestinal ultrasonic examination reagent
In one aspect of the present invention, there is provided a liquid agent for gastrointestinal ultrasound examination, comprising an aqueous medium and germinated barley powder capable of forming a homogeneous mixture with the aqueous medium, wherein the germinated barley powder is stably present in the aqueous medium in a particle size, and the stable presence means that the highland barley powder having a suitable particle size does not occur or does not substantially occur sedimentation in the aqueous medium.
In the present invention, "germinated highland barley" is a germinated product of highland barley seeds, wherein the germination operation can be performed by using a technique known in the art, and is not particularly limited. In a preferred embodiment, the highland barley seeds selected for germination are full, endosperm-lossless, mildew-free, worm-eaten-free highland barley seeds. Preferably, highland barley seeds are subjected to wet germination (kept at a proper humidity or soaked in water or nutrient solution) to obtain germinated highland barley germinated under a humid condition.
In the present invention, the "aqueous medium" includes, but is not limited to, distilled water, deionized water, mineral water, purified water, a buffer, or the like.
In a preferred embodiment, the germinated barley powder is the germinated barley powder which is dried, crushed to proper granularity, compounded and sterilized.
In a preferred embodiment, the liquid gastrointestinal diagnostic agent of the present invention further comprises at least one of granules, powders and pastes derived from plant seeds. In a specific embodiment, the liquid gastrointestinal ultrasound examination agent of the present invention further comprises black sesame paste.
In a preferred embodiment, the liquid gastrointestinal diagnostic agent of the present invention is a liquid ultrasound gastrointestinal diagnostic imaging agent.
In a preferred embodiment in which the liquid gastrointestinal diagnostic agent is a liquid ultrasonic gastrointestinal diagnostic auxiliary agent, the germinated barley powder has a particle size of 60 to 120 mesh, preferably 60 to 110 mesh, still preferably 60 to 100 mesh, still preferably 60 to 90 mesh, more preferably 60 to 80 mesh, for example 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 mesh.
In a preferred embodiment where the liquid gastrointestinal diagnostic agent is a liquid ultrasonic gastrointestinal diagnostic aid, the liquid gastrointestinal diagnostic agent of the present invention has a soluble solids content of the highland barley flour of 8-12%, for example 8%, 9%, 10%, 11%, 12%.
In a preferred embodiment wherein the liquid gastrointestinal diagnostic reagent is a liquid ultrasonic gastrointestinal diagnostic auxiliary reagent, the ratio of the germinated barley powder to the black sesame paste in the liquid gastrointestinal diagnostic reagent of the present invention is (1-5): 1, for example, 1:1, 2:1, 3:1, 4:1, 5:1.
The liquid gastrointestinal diagnostic agent of the present invention may further comprise an antifoaming agent, and when the antifoaming agent is included, the content of the antifoaming agent is not more than 5%, preferably not more than 4%, still preferably not more than 3%, for example not more than 2%, 1%, 0.01%. The specific type of the antifoaming agent is not particularly limited, and may be a conventional antifoaming agent used in the art, such as simethicone-based antifoaming agent.
When the product of the invention is a liquid ultrasound gastrointestinal tract examination developer, the characteristics of gastrointestinal tract such as digestion and absorption of food, irregular morphology, high acidity and high alkalinity of intracavity environment, gastrointestinal peristalsis and the like are considered, the dependence of gastric-intestinal ultrasound filling examination on the developer is very high, the qualified developer needs to be resistant to gastric acid and intestinal juice, the gastric juice is emptied under gastrointestinal peristalsis, the ultrasonic examination time window is given slowly, and the gastrointestinal digestive enzyme is not decomposed very quickly. Through researches, the auxiliary developer prepared from germinated highland barley has the advantages of longer stay time in the gastrointestinal cavity, slow evacuation, sufficient time for operators to operate and check, easy drinking, absorbability and digestion, no side effect and the like.
The ultrasonic contrast agent is characterized in that the ultrasonic contrast agent is a uniform high/equal echo interface on an acoustic image, has obvious contrast effect with a weak echo interface of a gastrointestinal wall, has better effect of eliminating mucus interference of a gastrointestinal cavity, does not generate acoustic artifacts, avoids the modulation step of the contrast agent, increases the quantity of ultrasonic filling examination of the gastrointestinal tract of an ultrasonic department, enlarges the range of examination crowds (including the aged, pregnant women, children and other special crowds), more clearly displays gastrointestinal related lesions by increasing the contrast between the contrast agent and the gastrointestinal wall, increases the diagnosis accuracy of gastrointestinal related diseases, performs primary screening work for clinical work and improves the detection positive rate of a digestive endoscope, and simultaneously can not increase the infection risk of high-risk patients by sterilizing the contrast agent.
The ultrasonic contrast agent has acoustic characteristics of ① longitudinal wave sound velocity value of 1500-1580 m/s, ② acoustic impedance of 1.58-1.70Z (106 Pa s/m), ③ acoustic attenuation coefficient=1, ④ acoustic attenuation coefficient slope of 0.7-1.3 dB/(cmMHz), ⑤ viscosity similar to digestive tract mucus, and ⑥ pH value of 7.3-7.4.
Preparation method
In one aspect of the present invention, there is provided a method of preparing a liquid agent for gastrointestinal ultrasound examination, comprising the steps of:
(1) Sprouting highland barley to obtain sprouted highland barley;
(2) Cleaning the germinated highland barley to obtain cleaned germinated highland barley;
(3) Mixing the cleaned germinated highland barley with a seasoning liquid to obtain a mixture;
(4) Curing the mixture at high temperature and high pressure to obtain cured germinated highland barley;
(5) Drying the germinated highland barley after curing to obtain dried germinated highland barley;
(6) Pulverizing the above baked germinated semen Avenae Nudae to obtain germinated semen Avenae Nudae powder, mixing with water medium and at least one of granule, powder and paste from plant seeds to form stable and homogeneous mixture, and
(7) Sterilizing the mixture.
In the present invention, the seasoning liquid is an aqueous solution including a seasoning, and examples of the seasoning include, but are not limited to, sodium chloride, glucose, sucrose, vitamins, essence, and the like. The volume ratio of the germinated barley to the flavoring liquid is 1 (1-5), such as 1:1, 1:2, 1:3, 1:4, and 1:5.
In the present invention, high temperature and high pressure curing includes treatment at 100 to 140 ℃, preferably 120 to 130 ℃, e.g., 120 ℃, 121 ℃, 122 ℃, 123 ℃, 124 ℃, 125 ℃, 126 ℃, 127 ℃, 128 ℃, 129 ℃, 130 ℃ for 5 to 30min, preferably 10 to 25 min, and still preferably 10 to 20min, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20min.
In the present invention, the drying and pulverizing operations may be performed using techniques known in the art, which are not particularly limited.
In a preferred embodiment of the preparation method, the present invention forms a stable, homogeneous mixture with an aqueous medium and at least one of granules, powders and pastes derived from plant seeds by controlling the particle size of the germinated barley powder. Wherein the particle size of the germinated barley powder is controlled to be 60-120 mesh, preferably 60-110 mesh, still preferably 60-100 mesh, further preferably 60-90 mesh, still more preferably 60-80 mesh, for example 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 mesh. In a specific embodiment, the invention controls the particle size of the germinated barley powder to form a stable, homogenous mixture with an aqueous medium and a black sesame paste.
In a preferred embodiment of the preparation method, the invention comprises the steps of drying and crushing the germinated highland barley, controlling the granularity of the germinated highland barley powder, mixing the obtained germinated highland barley powder with black sesame paste, and pregelatinizing to obtain a paste, wherein the ratio of the germinated highland barley powder obtained by drying and crushing to the black sesame paste is (1-5): 1, such as 1:1, 2:1, 3:1, 4:1 and 5:1, and the pregelatinizing comprises the steps of boiling in boiling water for 5-20 min, preferably 5-19 min, still preferably 5-18 min, further preferably 5-17 min, more preferably 5-16 min, more preferably 5-15 min, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 min.
In the present invention, the sterilization temperature is 120 to 140 ℃, preferably 121 to 130 ℃, such as 121 ℃, 122 ℃, 123 ℃, 124 ℃, 125 ℃, 126 ℃, 127 ℃, 128 ℃, 129 ℃, 130 ℃ and the sterilization time is 5 to 30min, preferably 7 to 28 min, still preferably 9 to 26 min, still more preferably 12 to 25 min, still more preferably 15 to 25 min, such as 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 min.
Example 1
The following illustrates a method of preparing a liquid gastrointestinal ultrasound contrast agent.
Selecting full, non-destructive, mildew-free and worm-eaten highland barley seeds, washing away impurities and dust with tap water, spreading the washed seeds, placing the seeds in a spray type germination machine for germination, taking out the seeds after germination, washing the germinated highland barley, preparing according to a water-to-care ratio of 1:1, and sterilizing at 121 ℃ and 15 min. Drying the product, pulverizing, controlling the particle size to 60-120 meshes, mixing highland barley powder and black sesame paste according to a ratio of 7:3, preparing according to a feed liquid ratio of 1:12, pregelatinizing (boiling in boiling water of 10 min), packaging after pregelatinizing, sterilizing at 121 ℃ and 15 min, and obtaining the finished product which is the gastrointestinal contrast agent in liquid dosage form.
Example 2
The effect of different factors on the in vitro simulated gastric pouch sound image of the auxiliary developer is shown below.
1.1 Influence of different highland barley varieties on in-vitro simulation of auxiliary developer on sound image in gastric pouch
Based on the ingredient differences of dietary fibers, beta-glucan, amylose, proteins and the like of different highland barley varieties and the tolerance difference to gastric acid, the preparation method of germinated highland barley products and the preparation process of germinated highland barley products are adopted for three varieties of highland barley No.1, highland barley No. 2 and highland barley No.3 with the same soluble solid content, the preparation method of germinated highland barley products, and the acoustic characteristics of the three varieties in vitro simulated gastric bags are detected, so that the proper highland barley varieties are determined.
As shown in fig. 1, researches show that the acoustic characteristics of highland barley No.1, highland barley No. 2 and highland barley No.3 in the in-vitro simulated gastric bag are not obviously different, uniform isoechoic sound images can be obtained, and highland barley varieties have no obvious influence on the effect of the ultrasonic sound images.
1.2 Influence of different soluble solid contents on in-vitro simulation of sound image in gastric pouch by auxiliary developer
Detecting the acoustic characteristics of the germinated highland barley products with different soluble solid contents in an in-vitro simulated gastric bag, detecting whether precipitation occurs in the liquid stability of the germinated highland barley products, uniformly mixing the precipitated substances to influence the acoustic characteristics of the germinated highland barley products, and determining the content of the soluble solid contents of the germinated highland barley products which meet the acoustic characteristics of the auxiliary developer.
As shown in figure 2, the research shows that the different highland barley varieties have good liquid stability in the in-vitro simulated gastric bag with the content of 3% -8% of soluble solids, are not easy to precipitate, and the acoustic properties of the highland barley varieties are not obviously influenced by even mixing after precipitation.
1.3 Influence of different germination highland barley product preparation modes on in-vitro simulation of sound image in gastric pouch by auxiliary developer
The proper preparation mode of the germinated highland barley products is determined by detecting the acoustic characteristics of different preparation modes of the germinated highland barley products (including dried highland barley germination products and fresh/wet highland barley germination products) in a gastric pouch simulated in vitro.
As shown in fig. 3, researches show that the wet highland barley sprouting product has better homogeneity than the dry highland barley sprouting product in an in-vitro simulated gastric bag, and a more uniform isoechoic sound image can be obtained.
1.4 Influence of liquid auxiliary developer preparation process of highland barley products with different germination on in-vitro simulation of auxiliary developer on sound image in gastric pouch
The preparation process of the liquid auxiliary developer of the highland barley products suitable for germination is determined by detecting the acoustic characteristics of the liquid auxiliary developer of different highland barley products (including the processes of superfine grinding, filtering, shearing, homogenizing and the like) in the gastric bag simulated in vitro.
As shown in fig. 4, researches show that the wet highland barley sprouting product obtained through superfine grinding, 200-mesh filtering, shearing and homogenizing has better homogeneity in an in-vitro simulated gastric bag, and a more uniform isoechoic sound image can be obtained.
Example 3
The effect of different factors on the intragastric sound image of the auxiliary display agent is shown below.
1.1 Complete the preparation and the debugging of the in vivo gastrointestinal ultrasound auxiliary display agent
Based on the primary screening of the in-vitro gastrointestinal ultrasonic auxiliary developer, an auxiliary developer sample of a wet highland barley germination product which is subjected to superfine grinding, 200-mesh filtering, shearing and homogenizing is obtained, and further screening and debugging in vivo are carried out. The ultrasound-assisted ability of the contrast agent in the stomach was tested by oral administration of the contrast agent samples 500-1000 ml.
As shown in fig. 5, the research shows that the contrast agent with more uniform acoustic image in the in-vitro simulated gastric pouch has uneven echo in the stomach, more point and linear strong echoes are visible, the phenomenon of floating and layering of the small blocky strong echoes can occur along with the extension of the time in the stomach, part of the stomach wall of the contrast agent is not clearly displayed, and the change of the backward echo exists. Thus, debugging is performed according to the above problems.
The following study was conducted in this example on the assumption that the dotted-line-like hyperechoic effect in the intragastric agent might be bubbles, short fibers of highland barley rhizome, or protein clots generated after exposure to gastric acid.
1.2 Effect of defoamer on the visualization-aid in-gastric sound image
By detecting the acoustic properties of different defoamers and defoamer contents on the auxiliary developer in the stomach, whether the uneven strong echo is caused by small bubbles or not is determined.
As shown in fig. 6 a, the influence of different antifoaming agents on the acoustic image in the stomach of the auxiliary developer was first examined, and simethicone antifoaming agents were found to have the best antifoaming effect.
Subsequently, the effect of different simethicone antifoam content on the intragastric sound image of the contrast agent was examined, as shown in FIG. 6B, and it was found that exceeding 5% simethicone antifoam content resulted in increased viscosity of the contrast agent, increased and uneven intragastric echo. Therefore, the simethicone defoamer should not exceed 5%.
As shown in FIG. 7A, the addition of high temperature resistant alpha-amylase to the co-developer had no significant effect on the short-line-like hyperechoic effects in the co-developer's stomach. As shown in fig. 7B, the short line-like hyperechoic effects of the auxiliary agent in the stomach were significantly reduced after removal of the root of the germination product. Therefore, the stub-like strong echo of the auxiliary developer in the stomach is caused by root fibers of sprouting products, the fibers are fine, the 200-mesh filtering can be adopted to cause the sound image representation of the stub-like strong echo in the stomach, the stub-like strong echo can be effectively reduced by removing the root, and the sound image uniformity of the auxiliary developer is increased.
1.3 Influence of particle size of solid matters in highland barley germination products on intragastric sound image of contrast agent
The layering and the increase of the back echo of the contrast agent occur after half an hour in the stomach, probably because the particle size of soluble solids in the contrast agent is too small, and the highland barley sprouting products with small particle size can be quickly decomposed by gastric acid, so that the liquid stability of the contrast agent is reduced. Therefore, the particle size of highland barley germination products is adjusted in the embodiment. As shown in fig. 8, the contrast agent with particle size between 60-80 mesh is most uniform in intragastric echo.
1.4 In vitro and in vivo sonogram comparison of the display-aid product of this example with the control group
The result is shown in figure 9, and the novel auxiliary developer with uniform in-vivo and in-vitro sound image is finally obtained through twice repeated double-blind experiments, and has no obvious difference from the competitive products.
In this example, the control group was a contrast agent for acoustic contrast of stomach window (production lot number: 230804) manufactured by Hangzhou Wang Yingzhi medical technology Co., ltd.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same, and although the present invention has been described in detail with reference to the above embodiments, it should be understood by those skilled in the art that the technical solution described in the above embodiments may be modified or some of the technical features may be equivalently replaced. Such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.