CN114947108A - Casein micelle accurate controlled-release composition and preparation method thereof - Google Patents
Casein micelle accurate controlled-release composition and preparation method thereof Download PDFInfo
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Images
Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/045—Organic compounds containing nitrogen as heteroatom
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention provides a casein micelle accurate controlled release composition and a preparation method thereof, wherein the composition comprises an active ingredient and a casein Micelle (MC) -Dextran Sulfate (DS) compound loading the active ingredient. The invention takes Colloidal Calcium Phosphate (CCP) in a casein micelle structure as a key breakthrough, controls the CCP content in the compound by adding DS, and then prepares a delivery system for loading small-molecule active substances by taking MC complexed with DS as a carrier. In the process of simulating gastrointestinal digestion, the accurate controlled release of the small molecular active substance in the stomach and the intestinal tract is simultaneously realized by changing the ratio of MC to DS to influence the digestion behavior of the composition, the accurate controlled release of a delivery system based on casein micelles in the process of simulating gastrointestinal digestion in vitro is simply and effectively realized, and new ideas and insights are provided for researching and developing novel processed foods, health care products, special medical application formula foods, drug carriers and the like related to casein.
Description
Technical Field
The present invention relates to the field of biology. In particular, the invention relates to a casein micelle accurate controlled release composition and a preparation method thereof.
Background
Casein is the major component of milk protein and accounts for about 80% of the total milk protein. Due to the advantages of wide sources, high nutritive value, good emulsifying property and the like, the natural casein has wide application in the fields of food, medicines, cosmetics and the like. Casein is composed primarily of four unstructured molecular entities, namely α s 1-casein, α s 2-casein, β -casein and κ -casein. Under the hydrophobic interaction and the connection of Colloidal Calcium Phosphate (CCP), the molecular entities can self-assemble to form a micelle structure of 50-500 nm. It is due to this unique micelle structure and the broad application advantages that casein micelles are often used as ideal carriers for the construction of delivery systems.
The gastrointestinal tract is the primary site of digestive absorption where the oral delivery system will undergo structural breakdown and rearrangement, then trigger the release of the loaded active ingredient. For casein-based delivery systems, however, the CCP-mediated tightness of the micelle structure generally results in a lower loading capacity of the active ingredient. In addition, the use of casein micelles to deliver active ingredients also suffers from easy hydrolysis and insufficient ability to target sustained release. Specifically, casein micelles inhibit the hydrolysis of pepsin during gastric digestion by forming a curd structure, but casein still exhibits a rapid breakdown of the curd structure in the small intestine, thereby allowing the loaded active ingredient to be degraded by rapid release in the intestinal tract. Since CCP is mainly responsible for maintaining the integrity of casein micelles, it is inferred that the micellar structure and digestion characteristics of casein can be changed by controlling CCP, thereby improving the loading capacity and controlled release capacity of casein micelles.
At present, many methods can be used to regulate CCP in the casein micelle structure, including organic acid acidification, inorganic acid acidification, and addition of calcium chelating salt. However, these methods typically introduce chemical agents into the native casein material, which is not in accordance with the requirements of food cleaning labels. Furthermore, these methods can only modulate the digestive behavior of casein micelles in the stomach, but casein still shows a rapid hydrolysis in the small intestine, which impairs the protective effect on the loaded active ingredient.
Therefore, how to realize accurate controlled release of casein micelles is a technical bottleneck to be solved urgently.
Disclosure of Invention
The present invention aims to solve at least to some extent at least one of the technical problems of the prior art.
In one aspect of the invention, a composition is provided. According to an embodiment of the invention, the composition comprises: an active ingredient, a casein micelle-dextran sulfate complex, the casein micelle-dextran sulfate complex supporting the active ingredient.
Dextran Sulfate (DS) as an anionic polysaccharide is capable of chelating Ca 2+ CCP in the casein micelle is dissociated, so that the content of CCP in the casein micelle is controlled, the load capacity of the CCP on active ingredients is accurately regulated and controlled, and the effect of accurate controlled release is achieved. Furthermore, dextran sulfate can also bind to proteins through covalent or non-covalent interactions, thereby also providing a structural barrier to the delivery system of casein micelles in the intestinal environment. Therefore, by controlling the gastrointestinal digestion of casein micelles by addition of DS, precise controlled release of the loaded active ingredient during digestion is expected.
In another aspect of the invention, the invention provides a method of making the composition described above. According to an embodiment of the invention, the method comprises: (1) preparing a first solution containing a casein micelle-dextran sulfate complex and a second solution containing an active ingredient, respectively; (2) mixing the first solution and the second solution to load the casein micelle-dextran sulfate complex with the active ingredient to obtain the composition.
In yet another aspect of the invention, a medicament, food or health product is provided. According to an embodiment of the present invention, the pharmaceutical, food or health product comprises: the composition as described hereinbefore.
In yet another aspect of the invention, the invention provides a non-diagnostic and non-therapeutic method for precise controlled release of an active ingredient. According to an embodiment of the invention, the method comprises: providing the active ingredient in the form of a preceding composition; applying the composition to an object to be treated.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 is a graph of Colloidal Calcium Phosphate (CCP) content, particle size, turbidity and potential results for MC solutions after addition of DS;
FIG. 2 is a microstructure of powder microparticles loaded with blueberry ACNs;
FIG. 3 is a graph of the cumulative release of microparticles in vitro to simulate gastrointestinal digestion;
FIG. 4 is a graph of the particle size change of microparticles in vitro simulating gastrointestinal digestion;
fig. 5 is a microscopic structural change of microparticles in vitro simulating the gastrointestinal digestion process.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are conventional products which are commercially available, and are not indicated by manufacturers.
The term "active ingredient" also called as active ingredient as used herein means an ingredient having medical or physiological effects, as long as it can have pharmacological or other direct actions or can affect the function or structure of the body, and the specific type can be flexibly selected according to the actual needs. Specifically, anthocyanin, resveratrol, curcumin, quercetin and the like can be mentioned.
Composition comprising a metal oxide and a metal oxide
In one aspect of the invention, a composition is provided. According to an embodiment of the invention, the composition comprises: an active ingredient, a casein micelle-dextran sulfate complex, the casein micelle-dextran sulfate complex supporting the active ingredient. Dextran Sulfate (DS) as an anionic polysaccharide is capable of chelating Ca 2+ The CCP in the casein micelle is dissociated, so that the CCP content in the casein micelle is controlled, the load capacity of the active ingredients is accurately regulated and controlled, and the effect of accurate controlled release is achieved. Furthermore, dextran sulfate can also bind to proteins by covalent or non-covalent interactions, thereby also providing a structural barrier to the delivery system of casein micelles in the intestinal environment. Thus, by controlling the gastrointestinal digestion of casein micelles by addition of DS, precise controlled release of the loaded active ingredient during digestion is expected.
According to the embodiment of the invention, the particle size of the casein micelle-dextran sulfate compound is 145-180 nm. Therefore, the casein micelle can realize secondary assembly after being opened, thereby being beneficial to combining active ingredients and preparing the compound with higher stability.
According to an embodiment of the invention, the casein micelle comprises casein and colloidal calcium phosphate, wherein the content of the colloidal calcium phosphate is 18-65 mass% of the mass of the casein micelle. Thereby, the active material can be effectively bound. If the content of the colloidal calcium phosphate is too low, the compound can be rapidly hydrolyzed in the gastric digestion process, so that the loaded active ingredients are released too quickly; if the colloidal calcium phosphate content is too high, the complex will over-aggregate during gastric digestion to form a larger curd, thereby causing dyspepsia problems.
According to an embodiment of the invention, the particle size of the composition is 5-9 μm, and the moisture content is less than 6.5 mass%. Thus, the composition has good storage stability.
According to the embodiment of the invention, the mass ratio of the casein micelles to the dextran sulfate in the casein micelle-dextran sulfate complex is (0.5-5): 1. by controlling the proportion of the casein micelle and the dextran sulfate, the loading capacity and the release rate of the active ingredient can be controlled, and after the proportion is adopted, the curding degree of the casein in the stomach and the release of the active ingredient in the stomach can be controlled, so that the aim of slow release in the intestinal tract is fulfilled. Specifically, the mass ratio of the casein micelle to the dextran sulfate can be (1-4): taking degradation of anthocyanin as an example, the release amount in the stomach can be accurately controlled to be 60-69 mass% within 2 hours, the slow release effect can be achieved in the intestinal tract for 2 hours, and the release amount is 19-35 mass% within 2 hours.
Method for preparing composition
In another aspect of the invention, the invention provides a method of making the composition described above. According to an embodiment of the invention, the method comprises: (1) preparing a first solution containing casein micelle-dextran sulfate complex and a second solution containing active ingredient, respectively; (2) mixing the first solution and the second solution to load the casein micelle-dextran sulfate complex with the active ingredient to obtain the composition. Thus, the method according to embodiments of the present invention may achieve precise controlled release of the active ingredient, and in particular may be expected to achieve precise controlled release of the loaded active ingredient during digestion.
According to an embodiment of the present invention, the method for preparing the first solution containing the casein micelle-dextran sulfate complex comprises: dispersing casein micelles in water, adding dextran sulfate into the obtained solution, and mixing to obtain a suspension; adjusting the pH value of the suspension, and stirring the obtained solution to obtain the first solution; wherein the pH value is 7-8, the stirring temperature is 30-50 ℃, the rotating speed is 700-900 rpm, and the time is 10-14 hours.
The suspension containing casein micelles and dextran sulfate is adjusted to a pH value of 7-8, so that powder dispersion is facilitated and a casein micelle structure is maintained. Stirring is then carried out, with the stirring conditions described above being such as to ensure complete hydration of the powder.
According to an embodiment of the invention, the method of preparing the second solution comprises: dissolving the active ingredient in water to obtain the second solution. Thereby, a homogeneous solution of the active ingredient is obtained.
According to an embodiment of the present invention, the method of loading the casein micelle-dextran sulfate complex with the active ingredient comprises: (2-1) adjusting the pH value of the first solution to a first pH value, and stirring and mixing; (2-2) mixing the mixed solution obtained in the step (2-1) with the second solution, adjusting the pH value of the mixed solution to a second pH value, and stirring and mixing; (2-3) subjecting the mixed solution obtained in the step (2-2) to ultrahigh pressure microjet treatment so as to load the casein micelle-dextran sulfate complex with the active ingredient, thereby obtaining a solution containing the composition.
According to the embodiment of the invention, in the step (2-1), the first pH value is 10-12. Thereby, the casein micelle structure can be sufficiently developed at this pH. And after mixing the obtained mixed solution with the second solution, adjusting the second pH value to 5-7 again to ensure that the casein micelles are reaggregated, thereby being beneficial to the subsequent loading process.
According to the embodiment of the invention, in the step (2-1), the temperature for stirring and mixing is 22-28 ℃ and the time is 0.5-1.5 hours. This helps the dextran sulfate to fully capture the colloidal calcium phosphate in the casein micelle structure.
According to the embodiment of the invention, in the step (2-2), the mixing time is 20-30 seconds. This mixing process needs to be performed quickly to avoid irreversible degradation of the active ingredients.
According to the embodiment of the invention, in the step (2-2), the temperature for stirring and mixing is 22-28 ℃ and the time is 0.5-1.5 hours. Thereby, sufficient contact between the active ingredient and the protein-polysaccharide is facilitated, and loading of the active ingredient is facilitated.
According to the embodiment of the invention, in the step (2-3), the pressure of the ultrahigh-pressure micro-jet treatment is 150-250 MPa, the cycle time is 2-5 times, and the temperature of a cooling system is 20-30 ℃. Thus, the active ingredient can be stably supported on the casein micelle-dextran sulfate complex, and the entrapment rate is high.
According to an embodiment of the present invention, the method of loading the casein micelle-dextran sulfate complex with the active ingredient further comprises: and carrying out spray drying treatment on the solution containing the composition. Thereby facilitating drying of the composition and reducing active ingredient loss. Specifically, the inlet temperature of the spray drying treatment is 140-160 ℃, the outlet temperature is 70-90 ℃, the pump speed is 7-12 mL/min, and the suction rate is 100%.
It will be appreciated by those skilled in the art that the features and advantages previously described for the compositions apply equally to the method of preparing the compositions and will not be described in detail here.
Medicine, food or health product
In yet another aspect of the invention, a medicament, food or health product is provided. According to an embodiment of the present invention, the pharmaceutical, food or health product comprises: the composition as described hereinbefore. Therefore, the medicine, food or health product provided by the embodiment of the invention can realize precise controlled release effect, is expected to realize precise controlled release of the loaded active ingredient in the digestion process, and provides new ideas and insights for researching and developing novel processed food, health product, special medical application formula food, medicine carrier and the like related to casein.
It will be appreciated by those skilled in the art that the features and advantages described above in relation to the composition apply equally to the pharmaceutical, food or nutraceutical product and will not be described in any further detail herein.
Non-diagnostic and non-therapeutic methods for precise controlled release of active ingredients
In yet another aspect of the invention, the invention provides a non-diagnostic and non-therapeutic method for precise controlled release of an active ingredient. According to an embodiment of the invention, the method comprises: providing the active ingredient in the form of a preceding composition; applying the composition to an object to be treated. As mentioned previously, Dextran Sulfate (DS), an anionic polysaccharide, is capable of chelating Ca 2+ So that the CCP in the casein micelle is dissociated,thereby controlling the CCP content in the casein micelle, accurately regulating and controlling the load capacity of the active ingredients and achieving the effect of accurate controlled release. Furthermore, dextran sulfate can also bind to proteins through covalent or non-covalent interactions, thereby also providing a structural barrier to the delivery system of casein micelles in the intestinal environment. Thus, by controlling the gastrointestinal digestion of casein micelles by addition of DS, precise controlled release of the loaded active ingredient during digestion is expected.
According to an embodiment of the present invention, the object to be processed includes: simulated gastric and intestinal digestive fluids in vitro.
According to an embodiment of the invention, the release amount of the active ingredient in simulated gastric digestive fluid in vitro is 60-69 mass% within 2 hours, and the release amount of the active ingredient in simulated intestinal digestive fluid in vitro is 19-35 mass% within 2 hours. Therefore, the release amount of the active ingredients in the stomach is well controlled, and the slow release effect is realized in the intestinal tract.
It will be appreciated by those skilled in the art that the features and advantages previously described for the compositions apply equally to the non-diagnostic and non-therapeutic methods of precisely controlled release of active ingredients and will not be described in detail herein.
The invention has the beneficial effects that:
the invention starts from the structure of natural casein micelle, takes CCP in the micelle structure as a key breakthrough, and dissociates CCP by adding DS, so that the natural casein micelle is disintegrated into smaller sub-micelle. After loading small-molecule active substances, taking easily degradable anthocyanin molecules (ACNs) as an example, the embedding rate of corresponding powder microparticles can be improved from 52.76% +/-2.36% to 91.86% +/-0.87%.
Secondly, in the process of in vitro simulation of gastrointestinal digestion, taking easily degradable anthocyanin molecule ACNs as an example, the dissociation capability of DS on CCP and the compound action of DS can effectively control the dissolution, curd and structural disintegration conditions of the powder microparticles in the digestion process, thereby simultaneously realizing accurate controlled release of the loaded ACNs in the stomach and intestinal digestion stages.
Thirdly, the casein raw material used by the invention has wide sources, natural nutrition and lower cost. The implementation of the invention can further expand the utilization space of the casein, strengthen the nutritive value of the casein, and has great significance for the application of the casein in the fields of common food, health food, special medical application formula food, drug carriers and the like.
The scheme of the invention will be explained with reference to the following examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
In this example, the composition was prepared in the following manner:
preparing a casein micelle-sodium dextran sulfate (MC-DS) composite solution: 5g of casein micelle powder was slowly dispersed in 100mL of ultrapure water, and sodium Dextran Sulfate (DS) was added to make MC: DS 4:1, w/w. The pH was quickly adjusted to 7.6 using 1mol/L HCl and 1mol/L NaOH and stirred at 40 ℃ and 800rpm for 12h to ensure complete hydration of the powder.
② preparing blueberry Anthocyanin (ACNs) solution: 0.1g of blueberry ACNs extract powder was slowly dispersed in 5mL of ultrapure water and stirred at 800rpm for 10min to completely dissolve.
③ load of blueberry ACNs: adjusting the pH of the solution in the step (i) to 11.3 by using 1mol/L HCl and 1mol/L NaOH, stirring the solution at 25 ℃ for 1h, mixing the solution with the solution in the step (ii) for 20 to 30 seconds, adjusting the pH of the mixed solution to 6.0 by using 1mol/L HCl and 1mol/L NaOH, stirring the mixed solution at 25 ℃ for 1h, and performing high-pressure micro-jet treatment (200MPa, 3 cycles, and the temperature of a cooling system is 25 ℃).
Fourthly, preparing the composite powder micro-particles loaded with blueberry ACNs: and (4) carrying out spray drying treatment on the solution in the step (III) (the inlet temperature is 150 ℃, the outlet temperature is 78-80 ℃, the pump speed is 9mL/min, the suction rate is 100%), quickly collecting a dry powder sample in a tail end collector in an aluminum foil bag with good sealing performance, and storing the dry powder sample in a sealed dryer filled with allochroic silica gel for further use.
Example 2
This example differs from example 1 in that MC: DS is 2:1, w/w after addition of DS.
Example 3
This example differs from example 1 in that MC: DS is 1:1, w/w after addition of DS.
Comparative example 1
This comparative example differs from example 1 in that no DS is added.
Comparative example 2
This comparative example differs from example 1 in that no MC and DS are added.
Examples of effects
The CCP content, basic physical properties, and microstructure before and after loading ACNs and before and after spray drying were characterized for the examples and comparative examples; in-vitro simulated gastrointestinal digestion experiments are carried out on the powder microparticles in the examples and the comparative examples, and the cumulative release amount, the particle size and the microstructure change of the ACNs in the digestion process are represented.
As shown in FIG. 1A, the addition of DS can dissociate the CCP. By adjusting the ratio of MC to DS, the CCP content is controlled to be in the range of 18.29% + -0.48% to 65.40% + -0.07%. The particle size (FIG. 1B) and turbidity (FIG. 1C) of the MC-DS composite solution were significantly reduced after the addition of DS. The particle size of the MC-DS composite nano-particles is controlled within the range of 90nm to 151 nm. While the turbidity remained in the range of 232 NTU-583 NTU. The absolute value of the potential results (FIG. 1D) show that complexation of MC by DS increases the surface negative charge of the nanoparticle from 14.93. + -. 0.79mV to 28.30. + -. 1.30 mV. Therefore, the results of fig. 1 indicate that the ratio of MC to DS affects the CCP content and the basic physical properties of the composite nanoparticle, thereby effectively controlling the dispersibility and stability of the MC-DS composite nanoparticle.
Table 1 shows the physicochemical properties of blueberry ACNs-loaded microparticles before and after spray drying
Note: the letters in the upper right corner indicate the degree of difference, with different letters indicating significant differences between different samples in the same column (p <0.05)
As shown in table 1, the ACNs-loaded microparticles can be controlled to be in the range of about 150nm to 176nm by adjusting the ratio of MC to DS before spray drying. After spray drying, the particle size of the powder samples was around 7 μm and the moisture content was less than 6.5%, indicating that the spray dried products had higher quality and storage stability. In addition, by adjusting the ratio of MC to DS, the embedding rate of the powder microparticles is greatly increased from 52.76% + -2.36% to 91.86% + -0.87%. It is shown that different DS content promotes binding to ACNs by opening up the micellar structure of MC to different degrees.
Fig. 2 shows the microstructure of the powder microparticles. As can be seen from the scanning electron microscope images, all the powder particles present the typical shape of spray-dried particles, and are represented by irregular spherical shapes with wrinkles and depressions on the surface.
Figure 3 shows the cumulative release of microparticles in vitro to simulate gastrointestinal digestion. First, unencapsulated ACNs are rapidly released during gastrointestinal digestion and then degrade continuously. When MC is used as the wall material, the MC microparticles loaded with the ACNs release about 33% of the ACNs after 30min of gastric digestion, and the release amount of the ACNs is not greatly changed in the stomach period. After entering the intestine, MC microparticles release all ACNs explosively within 30 min. By adding DS and adjusting the ratio of MC to DS, the release of microparticles in the stomach and intestinal tract is effectively controlled. Specifically, under gastric conditions, the ratio of MC to DS is changed to control the content of CCP in the range of 18% -65%, so that the release of ACNs in the corresponding powder micro-particles is accurately controlled in the range of 60% -69% within 2 hours. While in the small intestine, the addition of DS causes the ACNs-loaded composite particles to exhibit a relatively sustained release process. And by continuously increasing the proportion of DS, the release amount of ACNs can be reduced. In this case, microparticles show the greatest potential to protect ACNs from degradation during digestion when MC: DS ═ 1: 1.
As shown in fig. 4, it is clear that the change in particle size of the composite microparticles during digestion, especially during gastric digestion, is closely related to the proportion of DS. Wherein the MC microparticles loaded with ACNs have a particle size distribution in stomach of up to 1.8mm, but after 30min of intestinal digestion, its average particle size is reduced to 41.78 μm. In contrast, an increase in the DS ratio gradually decreases the particle size of these composite microparticles during gastric digestion. When MC: DS is 1:1, the particle size distribution of almost all composite microparticles during the stomach shifts to 300 μm or less. After 30min of intestinal digestion, the average particle size of the MC-DS microparticles loaded with the ACNs is shifted to below 25 mu m.
Fig. 5 shows the change in microstructure of the microparticles during digestion. Because MC is constantly hydrolyzed during the gastric digestion process, the outer shell of the powder microparticles is corroded to different degrees. After gastric digestion for 30min, MC microparticles with intact powder structure could be observed. And until the end of the gastric digestion, curd particles with a diameter of more than 1mm can still be observed. For MC-DS composite microparticles loaded with ACNs, a layer of floc can be observed on the surface of the microparticles during gastrointestinal digestion, which is caused by DS coating. Furthermore, as the DS fraction increases, the curd structure formed by the respective microparticles in the stomach gradually decreases. When MC: DS ═ 1:1, only some tiny aggregates were observed during gastric digestion. Upon entering the small intestine, the ACNs-loaded MC microparticles quickly disintegrate into many small fragments. While some well-structured MC-DS microparticles remain retained, showing sustainable protection of ACNs in the small intestine.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A composition, comprising:
an active ingredient, wherein the active ingredient is a natural or synthetic ingredient,
a casein micelle-dextran sulfate complex, the casein micelle-dextran sulfate complex supporting the active ingredient.
2. The composition according to claim 1, wherein the casein micelle-dextran sulfate complex has a particle size of 145 to 180nm, the composition has a particle size of 5 to 9 μm, and a moisture content of less than 6.5 mass%.
3. The composition according to claim 1, wherein the casein micelles comprise casein and colloidal calcium phosphate,
wherein the content of the colloidal calcium phosphate is 18-65% by mass of the casein micelle.
4. The composition according to claim 1, wherein the mass ratio of casein micelles to dextran sulfate in the casein micelle-dextran sulfate complex is (0.5-5): 1.
5. a process for preparing the composition of any one of claims 1 to 4, comprising:
(1) preparing a first solution containing a casein micelle-dextran sulfate complex and a second solution containing an active ingredient, respectively;
(2) mixing the first solution and the second solution to load the casein micelle-dextran sulfate complex with the active ingredient to obtain the composition.
6. The method of claim 5, wherein the method of preparing the first solution comprising the casein micelle-dextran sulfate complex comprises:
dispersing casein micelles in water, adding dextran sulfate into the obtained solution, and mixing to obtain a suspension;
adjusting the pH value of the suspension, and stirring the obtained solution to obtain the first solution;
wherein the pH value is 7-8, the stirring temperature is 30-50 ℃, the rotating speed is 700-900 rpm, and the time is 10-14 hours.
7. The method of claim 5, wherein the method of preparing the second solution comprises:
dissolving the active ingredient in water to obtain the second solution.
8. The method of claim 5, wherein the loading of the casein micelle-dextran sulfate complex with the active ingredient comprises:
(2-1) adjusting the pH value of the first solution to a first pH value, and stirring and mixing;
(2-2) mixing the mixed solution obtained in the step (2-1) with the second solution, adjusting the pH value of the mixed solution to a second pH value, and stirring and mixing;
(2-3) subjecting the mixed solution obtained in the step (2-2) to ultrahigh pressure microjet treatment so as to load the casein micelle-dextran sulfate complex with the active ingredient, thereby obtaining a solution containing the composition;
optionally, in the step (2-1), the first pH value is 10-12, the stirring and mixing temperature is 22-28 ℃, and the stirring and mixing time is 0.5-1.5 hours;
optionally, in the step (2-2), the second pH value is 5-7, the mixing time is 20-30 seconds, the stirring and mixing temperature is 22-28 ℃, and the mixing time is 0.5-1.5 hours;
optionally, in the step (2-3), the pressure of the ultrahigh-pressure micro-jet treatment is 150-250 MPa, the cycle time is 2-5 times, and the temperature of a cooling system is 20-30 ℃;
optionally, the method of loading the casein micelle-dextran sulfate complex with the active ingredient further comprises:
and carrying out spray drying treatment on the solution containing the composition.
9. A pharmaceutical, food or health product comprising: a composition as claimed in any one of claims 1 to 4.
10. A non-diagnostic and non-therapeutic method for precise controlled release of an active ingredient comprising:
providing an active ingredient in the form of a composition according to any one of claims 1 to 4;
applying the composition to an object to be treated;
preferably, the object to be processed includes: simulated gastric and intestinal digestive fluids in vitro;
optionally, the release amount of the active ingredient in simulated gastric digestive fluid in vitro is 60-69% by mass within 2 hours, and the release amount of the active ingredient in simulated intestinal digestive fluid in vitro is 19-35% by mass within 2 hours.
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| JPH053756A (en) * | 1991-02-01 | 1993-01-14 | Snow Brand Milk Prod Co Ltd | Agglomerate of casein submicelle and its production |
| CN1139380A (en) * | 1993-11-18 | 1997-01-01 | 癌症研究所 | Controlled release preparation |
| JP2009040722A (en) * | 2007-08-09 | 2009-02-26 | Fujifilm Corp | Casein nano particles consisting of multiple number of protein |
| CN111012760A (en) * | 2019-12-28 | 2020-04-17 | 复旦大学 | Casein/anionic polysaccharide nano particle loaded with hydrophobic drug and nutrient and preparation method thereof |
| CN113080468A (en) * | 2021-04-13 | 2021-07-09 | 苏州朗邦营养科技有限公司 | Slow-digestion casein nano micelle powder and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH053756A (en) * | 1991-02-01 | 1993-01-14 | Snow Brand Milk Prod Co Ltd | Agglomerate of casein submicelle and its production |
| CN1139380A (en) * | 1993-11-18 | 1997-01-01 | 癌症研究所 | Controlled release preparation |
| JP2009040722A (en) * | 2007-08-09 | 2009-02-26 | Fujifilm Corp | Casein nano particles consisting of multiple number of protein |
| CN111012760A (en) * | 2019-12-28 | 2020-04-17 | 复旦大学 | Casein/anionic polysaccharide nano particle loaded with hydrophobic drug and nutrient and preparation method thereof |
| CN113080468A (en) * | 2021-04-13 | 2021-07-09 | 苏州朗邦营养科技有限公司 | Slow-digestion casein nano micelle powder and preparation method thereof |
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