CN115500516B - Probiotics slow-release carrier, slow-release dripping pill, and preparation method and application thereof - Google Patents
Probiotics slow-release carrier, slow-release dripping pill, and preparation method and application thereof Download PDFInfo
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- CN115500516B CN115500516B CN202211191630.2A CN202211191630A CN115500516B CN 115500516 B CN115500516 B CN 115500516B CN 202211191630 A CN202211191630 A CN 202211191630A CN 115500516 B CN115500516 B CN 115500516B
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- oil
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- sustained
- dripping pill
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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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- 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
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
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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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/015—Inorganic compounds
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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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/035—Organic compounds containing oxygen 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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
- A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
- A23L29/231—Pectin; Derivatives thereof
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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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
- A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
- A23L29/256—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin from seaweeds, e.g. alginates, agar or carrageenan
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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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
- A23L29/269—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of microbial origin, e.g. xanthan or dextran
- A23L29/272—Gellan
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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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
- A23L29/275—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of animal origin, e.g. chitin
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- A23L29/284—Gelatin; Collagen
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
- A23P10/30—Encapsulation of particles, e.g. foodstuff additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P20/00—Coating of foodstuffs; Coatings therefor; Making laminated, multi-layered, stuffed or hollow foodstuffs
- A23P20/20—Making of laminated, multi-layered, stuffed or hollow foodstuffs, e.g. by wrapping in preformed edible dough sheets or in edible food containers
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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
Landscapes
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- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
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- Dispersion Chemistry (AREA)
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention provides a probiotic slow release carrier, a slow release dripping pill, a preparation method and application thereof. The slow release carrier can effectively solve the problem that the ideal directional colon slow release effect is difficult to achieve by the multilayer dripping pill structure in the prior art, the slow release dripping pill has the advantages of good embedding rate of substances to be released, high survival rate, good gastric acid and bile salt resistance effect, excellent stability, safe and simple preparation process and suitability for industrial production, and stays and slowly releases in the colon in a directional way.
Description
Technical Field
The invention relates to the field of health products, in particular to a probiotic slow-release carrier, a slow-release dripping pill, a preparation method and application thereof.
Background
The sustained-release dripping pill is applied to a plurality of fields such as food, medicine and the like. The sustained-release dripping pill has various advantages, and the most prominent effect is that the embedding effect of the sustained-release dripping pill can prevent the chemical and physical degradation of sensitive substances, separate substances which are in contact with each other and are unfavorable, mask the original smell, color or taste of the substances, control the dispersibility of the substances and prevent the encapsulated substances from being damaged.
The probiotics are taken as a kind of probiotics functional components, the functional effects of the probiotics are gradually accepted by consumers, and scientific researches gradually reveal mechanisms of the probiotics on human health. The conventional probiotic products mainly comprise powder, tablets and capsules, on one hand, the good enteric effect cannot be achieved, so that the probiotics are destroyed in gastric acid, and on the other hand, the probiotics have no good intestinal tract residence capability, so that the probiotics are released in the intestinal tract too early or too late.
In order to solve the problem of slow release of the intestinal probiotics, the slow release dropping pill of the probiotics is taken as a development direction, but the existing slow release dropping pill of the probiotics has the following problems: the single-layer probiotics dripping pill can not resist gastric acid and can not ensure that probiotics in the dripping pill reach intestinal tracts, so that the double-layer or three-layer dripping pill is adopted at present. For example, patent cn201711334957.X discloses a double-layered probiotic drop pill provided with a gastric acid resistant layer and a core layer, however, the gastric acid resistant layer disintegrates once entering the small intestine, and probiotics are released at the small intestine, so that bile salt-sensitive probiotics are inactivated by bile salt, and the activity of the bile salt-sensitive probiotics cannot be guaranteed; for another example, patent CN201880063102.4 discloses a three-layer structure capsule composed of non-hydrogenated grease, which is provided with an outer layer (gastric acid resistant layer), a middle layer (protective layer) and a probiotic core layer, however, when the outer layer falls off, the middle layer structure is easily taken away, and the ideal directional colon slow release effect is difficult to achieve; patent CN202111098705.8 discloses a gastrointestinal tract controlled release type probiotic bead which is a three-layer dripping pill, and adopts a solid oil phase material as a middle layer. However, the solid oil phase is softened in the intestinal tract and decomposed by the bile in the small intestine, and the killing of the bile to the probiotics in the core layer cannot be completely avoided.
Therefore, there is still a need to further develop new probiotic slow release carriers and slow release dripping pills to solve the above-mentioned problems in the prior art.
Disclosure of Invention
The invention aims to overcome at least one defect of the prior art, and provides a slow release carrier and a slow release dripping pill using the slow release carrier, wherein the slow release carrier has a three-layer structure, and a specific micropore structure is formed between an outer layer and a middle layer, so that the outer layer can be completely peeled off from the middle layer when falling off, the integrity of the middle layer structure is not influenced, and the directional slow release of probiotics in the slow release dripping pill is facilitated, so that the problem that the ideal directional colon slow release effect is difficult to achieve by the multilayer dripping pill structure in the prior art is solved. The sustained-release dropping pill adopting the sustained-release carrier has the advantages of good embedding rate, high survival rate, good gastric acid and bile salt resistance effect, excellent stability, safe and simple preparation process and suitability for industrial production, and can be directionally remained in colon for sustained release.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
in a first aspect the invention provides a slow release carrier as shown in figure 1 comprising: the hydrophobic core 100, the middle layer 102 containing a colloid material and the outer layer 104 containing a macromolecule, wherein a micropore structure 103 is formed between the outer layer and the middle layer, wherein an enlarged schematic view of the micropore structure 103 is shown in fig. 2.
According to the invention, the outer layer is also referred to as a gastric acid resistant layer and the middle layer is also referred to as a protective layer. When the existing three-layer slow-release carrier structure enters a body to act, the outer layer is easy to take away the middle layer structure when falling off, and an ideal directional colon slow-release effect is difficult to achieve. The inventor of the invention discovers that by forming a micropore structure between the outer layer and the middle layer, the outer layer can be completely peeled off from the middle layer when falling off, the integrity of the middle layer structure is not affected, and the directional slow release of probiotics in the slow release dripping pill is facilitated.
According to some embodiments of the present invention, the sustained release carrier may further comprise at least one of the following additional technical features:
according to one embodiment of the invention, the outer layer of the slow release carrier further comprises an acid.
According to one embodiment of the invention, the middle layer also contains carbonate.
According to one embodiment of the invention, the microporous structure is a plurality of micropores formed by the reaction of an acid and a carbonate.
According to one embodiment of the invention, the micro-pores are nano-micro-pores. According to the invention, the nano micro-pores formed by the method can better realize the peeling of the outer layer and the middle layer, thereby ensuring that the outer layer completely falls off without affecting the middle layer.
According to one embodiment of the invention, the acid comprises one or more selected from sulfuric acid, hydrochloric acid, acetic acid, phosphoric acid and lactic acid.
According to one embodiment of the invention, the pH of the outer layer is 2.5 to 3.0, e.g. 2.5, 2.6, 2.8, 3.0, etc.
According to one embodiment of the invention, the carbonate comprises one or more selected from sodium carbonate, sodium bicarbonate, calcium carbonate.
According to one embodiment of the invention, the carbonate is preferably a nano-sized carbonate particle having a particle size of 200nm to 600nm, e.g. 200nm, 250nm, 300nm, 310nm, 400nm, 500nm, 600nm, preferably 300nm to 600nm.
According to one embodiment of the invention, the carbonate is calcium carbonate, preferably calcium carbonate particles, more preferably calcium carbonate particles having a particle size of 300nm to 600nm.
According to one embodiment of the invention, the first polymeric substance is selected from one or more of carrageenan, gellan gum, pectin, preferably gellan gum, e.g. low acyl gellan gum.
According to one embodiment of the present invention, the aforementioned second polymeric substance includes one or more selected from gelatin, agar, gellan gum and carrageenan pectin.
According to one embodiment of the invention, the second polymeric substance is preferably gelatin.
According to one embodiment of the invention, the gelatin is a small enteric gelatin protein, more preferably the small enteric gelatin protein has a molecular weight of 23-33kDa.
The inventor of the invention discovers that by controlling the molecular weight of the small enteric gelatin protein and using the small enteric gelatin protein with specific molecular weight, the gastric acid resistance effect of the dripping pill can be effectively improved, the structure of the dripping pill is prevented from being damaged by enzyme liquid in gastric acid, and the dripping pill is ensured to rapidly fall off the outer layer after entering the small intestine, so that the middle layer is exposed.
According to one embodiment of the invention, the middle layer further comprises probiotics.
According to one embodiment of the invention, the probiotic is a probiotic that adsorbs the colon.
According to one embodiment of the invention, the probiotic bacteria that adsorb the colon include probiotic bacteria that have an adsorption rate to colon cells of not less than 12 cfu/cell.
According to one embodiment of the invention, the activity of the probiotics is not less than 10-20 hundred million/g.
According to one embodiment of the invention, the probiotic comprises lactobacillus.
According to one embodiment of the present invention, the lactobacillus comprises one or more selected from lactobacillus reuteri, lactobacillus acidophilus and lactobacillus plantarum. The lactobacillus reuteri, lactobacillus acidophilus and lactobacillus plantarum all have the specificity of adsorbing colon mucous membranes.
According to one embodiment of the present invention, the mass ratio of the probiotics, the first polymer material and the carbonate in the middle layer is (4-11): (1-3): (0.1 to 0.5), for example, 4:1:0.1, 5:2:0.4, 10:1.5:0.3, etc.
According to an embodiment of the present invention, the mass ratio of the probiotics, the first polymer material and the carbonate in the middle layer is preferably (5 to 10): (1.5-2): (0.2-0.4).
According to the invention, the probiotic bacteria capable of specifically adsorbing the colon are added into the middle layer, so that the middle layer has the effect of specifically adsorbing the mucous membrane of the colon, the slow release time of the dripping pill in the colon is delayed, and the directional slow release of the probiotic bacteria in the oil phase core layer at the colon is further ensured. In addition, the first polymer substance is used for replacing a solid oil phase in the prior art to serve as a middle layer structural support material, so that the two functions are achieved: firstly, ensuring that the middle layer containing the probiotics thalli capable of specifically adsorbing the colon completely passes through the small intestine, so that the specific adsorption factors in the middle layer can exert an effect at the colon; secondly, the first polymer substance, especially gellan gum, has a certain effect of resisting intestinal juice, so that the middle layer is resistant to cholate corrosion, and has a certain strength without being destroyed in the small intestine, thereby effectively preventing bile acid, cholate, pancreatin and other components in the intestinal juice from destroying probiotics in the oil phase core layer.
According to one embodiment of the invention, the outer layer further comprises a food acceptable adjuvant comprising one or more selected from the group consisting of plasticizers, flavoring agents, opacifiers and preservatives.
According to one embodiment of the invention, the food acceptable auxiliary material comprises a plasticizer.
According to one embodiment of the present invention, the plasticizer includes one or more selected from the group consisting of glycerin, sorbitol, sodium carboxymethyl cellulose, propylene glycol, and hydroxypropyl cellulose.
According to one embodiment of the present invention, the mass ratio of the second polymer substance to the plasticizer in the outer layer is (8 to 10): (5-8).
According to one embodiment of the invention, the oil phase core layer contains vegetable oil.
According to one embodiment of the invention, the vegetable oil is selected from one or more of soybean oil, sunflower oil, olive oil, castor oil, peanut oil, rapeseed oil, sesame oil, cottonseed oil, linseed oil and safflower seed oil.
According to one embodiment of the invention, the vegetable oil is preferably one or more of soybean oil, sunflower oil and olive oil.
According to one embodiment of the invention, the oil phase core layer further contains a melting point modifier.
According to one embodiment of the invention, the melting point modifier comprises one or more selected from beeswax, hydrogenated palm oil, shortening and sitosterol.
According to one embodiment of the present invention, the melting point regulator has a melting point of 40 to 100 ℃.
According to one embodiment of the present invention, the melting point regulator preferably has a melting point of 60 to 80 ℃.
According to the invention, the oil phase core layer is ensured to be in a solid state under the normal temperature condition by adding the melting point regulator, the solid core layer can fix substances to be released, the substances to be released in the oil phase core layer are ensured to be uniformly distributed in the storage process, and aggregation is reduced; and the solid core layer has a slow release function when released in the colon, so that the release range of the substances to be released can be effectively enlarged.
In a second aspect of the present invention, the present invention provides a sustained release dripping pill. According to some embodiments of the invention, the sustained release dripping pill comprises the aforementioned sustained release carrier and the substance to be released.
According to an embodiment of the present invention, the sustained-release dripping pill may further include at least one of the following additional technical features:
according to one embodiment of the invention, the substance to be released is a probiotic bacterial flora.
According to one embodiment of the invention, the probiotic bacteria are dispersed in an oil phase core layer of a slow release carrier, namely the invention provides a slow release probiotic dripping pill, and further relates to a slow release colonic-soluble probiotic dripping pill.
According to one embodiment of the invention, the aforementioned probiotic flora comprises one or more probiotics.
According to one embodiment of the invention, the probiotic comprises one or more selected from the group consisting of lactobacillus, bifidobacterium, lactococcus and yeast.
According to one embodiment of the present invention, the lactobacillus comprises one or more selected from the group consisting of lactobacillus acidophilus, lactobacillus delbrueckii, lactobacillus casei, lactobacillus paracasei, lactobacillus rhamnosus, lactobacillus reuteri and lactobacillus plantarum.
According to one embodiment of the present invention, the bifidobacterium comprises one or more selected from bifidobacterium bifidum, bifidobacterium adolescentis, bifidobacterium infantis, bifidobacterium breve and bifidobacterium longum.
According to one embodiment of the invention, the lactococcus is selected from lactococcus lactis.
According to one embodiment of the invention, the probiotic flora comprises a plurality of probiotics, which are mixed, co-ordinated or inoculated in equal proportions. The equal ratio includes an equal weight ratio, a volume ratio, a molar ratio, a force ratio, or a weight-volume ratio.
According to one embodiment of the invention, the probiotic bacteria comprise lactobacillus plantarum, lactobacillus casei and lactobacillus acidophilus.
According to one embodiment of the invention, the weight ratio of lactobacillus plantarum, lactobacillus casei and lactobacillus acidophilus is 1:1:1.
according to one embodiment of the invention, the probiotic bacteria comprise lactobacillus paracasei, lactobacillus rhamnosus, lactobacillus reuteri and lactococcus lactis.
According to one embodiment of the invention, the weight ratio of lactobacillus paracasei, lactobacillus rhamnosus, lactobacillus reuteri and lactococcus lactis is 1:1:1:1.
according to one embodiment of the invention, the probiotic flora comprises bifidobacterium bifidum, bifidobacterium adolescentis, bifidobacterium infantis, bifidobacterium breve and bifidobacterium longum.
According to one embodiment of the invention, the weight ratio of bifidobacterium bifidum, bifidobacterium adolescentis, bifidobacterium infantis, bifidobacterium breve and bifidobacterium longum is 1:1:1:1:1.
according to one embodiment of the invention, the probiotic bacterial group activity is between 2000 and 4000 hundred million per gram.
According to one embodiment of the present invention, the content of the melting point modifier in the slow release carrier is 1% -10%, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% of the total weight of the oil phase core layer and the substance to be released in the slow release carrier.
According to one embodiment of the invention, the content of the melting point regulator in the slow release carrier is 3% -5% of the total weight of the oil phase core layer and the substances to be released in the slow release carrier. In some embodiments, the substance to be released is entrapped in the slow release carrier, and therefore, the total weight ratio of each component to the oil phase core and the substance to be released is used in calculating the ratio of each component.
According to one embodiment of the present invention, the substance to be released accounts for 2% -20%, for example, 2%, 3%, 5%, 8%, 9%, 10%, 13%, 15%, 17%, 20%, etc., of the total weight of the oil phase core layer and the substance to be released in the slow release carrier.
According to one embodiment of the present invention, the substance to be released accounts for 5% -10% of the total weight of the oil phase core layer and the substance to be released in the slow release carrier.
According to one embodiment of the present invention, the content of the vegetable oil in the slow release carrier is 70% -97%, for example, 70%, 72%, 75%, 80%, 92%, 93%, 96%, 97%, etc., of the total weight of the oil phase core layer in the slow release carrier and the substance to be released.
According to one embodiment of the present invention, the weight ratio of the outer layer, the middle layer and the oil phase core layer in the sustained release carrier to the total weight of the substances to be released is (2-4): (1-3): (4-6), e.g., 3:2:5, 2:2:5, 1:2:4, 3:1:6, 3:3:4, etc., preferably in a weight ratio of 3:2:5.
According to one embodiment of the invention, the diameter of the sustained release dripping pill is 25+/-3 mm.
According to one embodiment of the present invention, the weight of the sustained-release dripping pill is 20±3mg.
In a third aspect of the present invention, the present invention provides a method for preparing the sustained-release dripping pill, comprising: carrying out first mixing treatment on the second polymer substance and acid; carrying out second mixing treatment on the first high molecular substance and carbonate; carrying out third mixing treatment on the substances to be released and the vegetable oil; and shaping the first mixed treatment product, the second mixed treatment product and the third mixed treatment product to obtain the sustained-release dripping pill.
According to an embodiment of the present invention, the preparation method of the sustained-release dripping pill may further include at least one of the following additional technical features:
according to one embodiment of the invention, the first mixing treatment is used for preparing an outer layer, which further comprises adding a food acceptable adjuvant.
According to one embodiment of the invention, the first mixing treatment and/or the second mixing treatment further comprises a solvent, such as water. It will be appreciated by those skilled in the art that the solvent is not particularly limited and that any solvent acceptable for use in preparing foods or pharmaceuticals may be used.
According to one embodiment of the present invention, the first mixing treatment includes uniformly mixing the second polymer, the food auxiliary material and water, and adding an acid to adjust the pH to 2.0 to 3.5, so as to obtain the pH of the first mixing treatment product to 2.0 to 3.5.
According to one embodiment of the invention, the food acceptable auxiliary material comprises at least a plasticizer.
According to one embodiment of the present invention, the plasticizer includes one or more selected from the group consisting of glycerin, sorbitol, sodium carboxymethyl cellulose, propylene glycol, and hydroxypropyl cellulose.
According to one embodiment of the invention, the second polymeric substance comprises one or more selected from gelatin, agar, gellan gum, carrageenan and pectin.
According to one embodiment of the invention, the second polymeric substance comprises gelatin.
According to one embodiment of the present invention, the second polymeric substance is a small enteric gelatin protein, and in some specific embodiments, the preparation method of the small enteric gelatin protein comprises the following steps: performing gel filtration chromatography on the gelatin liquid by adopting a protein chromatography system, and collecting the protein with target molecular weight; concentrating under reduced pressure to obtain small enteric gelatin protein.
According to one embodiment of the invention, the small intestine-soluble gelatin protein has a molecular weight of 23-33kDa.
The inventor of the invention discovers that by controlling the molecular weight of the small enteric gelatin protein and using the small enteric gelatin protein with specific molecular weight, the gastric acid resistance effect of the dripping pill can be effectively improved, the structure of the dripping pill is prevented from being damaged by enzyme liquid in gastric acid, and the dripping pill is ensured to rapidly fall off the outer layer after entering the small intestine, so that the middle layer is exposed.
According to some specific embodiments of the invention, the first mixed treatment product is prepared from the second polymer substance with a mass-to-volume ratio of 8% -10% (g/mL), the plasticizer with a mass-to-volume ratio of 5% -8% (g/mL), water and an acid to adjust the pH value.
According to one embodiment of the present invention, the second mixing treatment is used for preparing the middle layer of the sustained-release dripping pill, and the second mixing treatment further comprises adding probiotics. The second mixing treatment comprises uniformly mixing the probiotics, the first high polymer substance, carbonate and water; in one embodiment, the carbonate and water are mixed to obtain an aqueous solution of nano-sized carbonate particles, and then the mixed probiotic and the first polymeric substance are added to be uniformly mixed.
According to one embodiment of the invention, the probiotic added in the second mixing treatment is a probiotic that adsorbs the colon.
According to the invention, the probiotic bacteria capable of specifically adsorbing the colon are added in the middle layer preparation process, so that the middle layer has the effect of specifically adsorbing the colon mucosa, the slow release time of the prepared slow-release dripping pill in the colon is prolonged, and the directional slow release of the substances to be released at the colon is further ensured. In addition, the first polymer substance is used for replacing a solid oil phase in the prior art to serve as a middle layer structural support material, so that the two functions are achieved: firstly, ensuring that the middle layer containing the probiotics thalli capable of specifically adsorbing the colon completely passes through the small intestine, so that the specific adsorption factors in the middle layer can exert an effect at the colon; secondly, the first polymer substance, especially gellan gum, has a certain effect of resisting intestinal juice, so that the middle layer is resistant to cholate corrosion, and has a certain strength without being destroyed in the small intestine, thereby effectively preventing bile acid, cholate, pancreatin and other components in the intestinal juice from destroying probiotics in the oil phase core layer.
According to one embodiment of the invention, the probiotic bacteria that adsorb the colon include probiotic bacteria that have an adsorption rate to colon cells of not less than 12 cfu/cell.
According to one embodiment of the invention, the activity of the probiotics is not less than 10-20 hundred million/g.
According to one embodiment of the invention, the probiotic comprises lactobacillus.
According to one embodiment of the present invention, the lactobacillus comprises one or more selected from lactobacillus reuteri, lactobacillus acidophilus and lactobacillus plantarum. The lactobacillus reuteri, lactobacillus acidophilus and lactobacillus plantarum all have the specificity of adsorbing colon mucous membranes.
According to an embodiment of the present invention, in the second mixing treatment, the mass ratio of the probiotics, the first polymer material and the carbonate is (4 to 11): (1-3): (0.1 to 0.5), for example, 4:1:0.1, 5:2:0.4, 10:1.5:0.3, etc.
According to an embodiment of the present invention, the mass ratio of the probiotic bacteria, the first polymer substance, and the carbonate salt in the second mixing treatment is preferably (5 to 10): (1.5-2): (0.2-0.4).
According to one embodiment of the present invention, the third mixing process is used for preparing the oil phase core layer of the sustained-release dripping pill, and the third mixing process further comprises adding a melting point regulator, and in some specific embodiments, the third mixing process comprises mixing and heating the vegetable oil and the melting point regulator to melt, and then adding the substance to be released and mixing uniformly.
According to one embodiment of the invention, the vegetable oil is selected from one or more of soybean oil, sunflower oil, olive oil, castor oil, peanut oil, rapeseed oil, sesame oil, cottonseed oil, linseed oil and safflower seed oil.
According to one embodiment of the invention, the vegetable oil is preferably one or more of soybean oil, sunflower oil and olive oil.
According to one embodiment of the invention, the substance to be released is a probiotic bacterial flora.
According to one embodiment of the invention, the probiotic bacteria are dispersed in an oil phase core layer of a slow release carrier, namely the invention provides a slow release probiotic dripping pill, and further relates to a slow release colonic-soluble probiotic dripping pill.
According to one embodiment of the invention, the aforementioned probiotic flora comprises one or more probiotics.
According to one embodiment of the invention, the probiotic comprises one or more selected from the group consisting of lactobacillus, bifidobacterium, lactococcus and yeast.
According to one embodiment of the present invention, the lactobacillus comprises one or more selected from the group consisting of lactobacillus acidophilus, lactobacillus delbrueckii, lactobacillus casei, lactobacillus paracasei, lactobacillus rhamnosus, lactobacillus reuteri and lactobacillus plantarum.
According to one embodiment of the present invention, the bifidobacterium comprises one or more selected from bifidobacterium bifidum, bifidobacterium adolescentis, bifidobacterium infantis, bifidobacterium breve and bifidobacterium longum.
According to one embodiment of the invention, the lactococcus is selected from lactococcus lactis.
According to one embodiment of the invention, the probiotic flora comprises a plurality of probiotics, which are mixed, co-ordinated or inoculated in equal proportions. The equal ratio includes an equal weight ratio, a volume ratio, a molar ratio, a force ratio, or a weight-volume ratio.
According to one embodiment of the invention, the probiotic bacteria comprise lactobacillus plantarum, lactobacillus casei and lactobacillus acidophilus.
According to one embodiment of the invention, the weight ratio of lactobacillus plantarum, lactobacillus casei and lactobacillus acidophilus is 1:1:1.
according to one embodiment of the invention, the probiotic bacteria comprise lactobacillus paracasei, lactobacillus rhamnosus, lactobacillus reuteri and lactococcus lactis.
According to one embodiment of the invention, the weight ratio of lactobacillus paracasei, lactobacillus rhamnosus, lactobacillus reuteri and lactococcus lactis is 1:1:1:1.
According to one embodiment of the invention, the probiotic flora comprises bifidobacterium bifidum, bifidobacterium adolescentis, bifidobacterium infantis, bifidobacterium breve and bifidobacterium longum.
According to one embodiment of the invention, the weight ratio of bifidobacterium bifidum, bifidobacterium adolescentis, bifidobacterium infantis, bifidobacterium breve and bifidobacterium longum is 1:1:1:1:1.
according to one embodiment of the invention, the probiotic bacterial group activity is between 2000 and 4000 hundred million per gram.
According to one embodiment of the present invention, the content of the melting point regulator in the third mixing process is 1% to 10%, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% of the total weight of the third mixing process product.
According to one embodiment of the present invention, the content of the melting point regulator is 3% to 5% of the total weight of the third mixed processed product.
According to one embodiment of the invention, the substance to be released comprises 2% -20% of the total weight of the third mixed treatment product, e.g. 2%, 3%, 5%, 8%, 9%, 10%, 13%, 15%, 17%, 20% etc.
According to one embodiment of the invention, the substance to be released accounts for 5% -10% of the total weight of the third mixed treatment product.
According to one embodiment of the invention, the vegetable oil comprises 70% -97%, e.g., 70%, 72%, 75%, 80%, 92%, 93%, 96%, 97%, etc., of the total weight of the third mixed treatment product.
According to one embodiment of the invention, the shaping treatment is a dropping method or a pressing method; preferably, the method of dripping is adopted, and in some specific embodiments, the products obtained by the first mixing treatment, the second mixing treatment and the third mixing treatment are formed by adopting three layers of dripping, and then dripping into condensate or a gas cooling column to be condensed into slow-release dripping pills.
According to one embodiment of the present invention, in the molding treatment, the weight ratio of the first mixed treatment product, the second mixed treatment product and the third mixed treatment product is (2 to 4): (1-3): (4-6), e.g., 3:2:5, 2:2:5, 1:2:4, 3:1:6, 3:3:4, etc., preferably in a weight ratio of 3:2:5.
The diameter and weight of the sustained-release dripping pills can be set by a person skilled in the art according to the requirements, and the diameter and weight of the sustained-release dripping pills prepared in some specific embodiments of the invention are 25+/-3 mm, and the weight is 20+/-3 mg.
Specifically, a preferred embodiment of the present invention includes:
Firstly, preparing the outer layer, uniformly mixing small enteric gelatin protein, glycerol and water, adding acid to adjust the pH value to 2.5-3.0, and standing for later use; then preparing a middle layer, uniformly mixing the middle layer probiotics and gellan gum, adding the mixture into an aqueous solution of nano-scale carbonate particles, and standing for later use; then preparing an oil phase core layer, mixing and melting a melting point regulator and vegetable oil uniformly, adding probiotics flora, mixing uniformly, and standing for later use; finally, three layers of the obtained three standby products are subjected to one-time dripping molding, and then dripped into condensate or a gas cooling column for condensation, so that the sustained-release dripping pill is obtained.
The last aspect of the invention provides application of the sustained-release dripping pill in preparing an intestinal release health-care product. As described above, the slow release carrier of the invention can effectively solve the problem that the ideal directional colon slow release effect is difficult to achieve by the multilayer dripping pill structure in the prior art, the slow release dripping pill has good embedding rate, high survival rate, good gastric acid and bile salt resistance effect, and excellent stability, and can stay and slow release in the colon in a directional way, and the preparation process is safe and simple and is suitable for industrial production, therefore, the intestinal release health care product prepared by the slow release dripping pill also has the functional advantage and the preparation advantage of the slow release dripping pill.
According to one embodiment of the invention, the enteric release health product releases the active substance or substances to be released in the colon. Illustratively, in the present invention, the active substance or substances to be released are a probiotic population, i.e. one or more probiotics.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
Fig. 1 shows a schematic structural diagram of the sustained release carrier according to an embodiment of the present invention, which includes an oil phase core layer (i.e., hydrophobic core) 100, a middle layer 102, a microporous structure 103, and an outer layer 104;
FIG. 2 shows an enlarged schematic view of the microporous structure 103 of the slow release carrier according to one embodiment of the present invention;
FIG. 3 shows SDS-PAGE electrophoresis of isolated and purified samples of the enteric gelatin protein of test example 4 of the present invention, wherein: sample 1 is gelatin, sample 2 is pepsin hydrolyzed gelatin, sample 3 is pepsin and trypsin hydrolyzed gelatin, sample 4 is isolated and purified 23-33kDa gelatin protein, and sample 5 is trypsin hydrolyzed 23-33kDa gelatin protein.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings. The embodiments described below by referring to the drawings are illustrative and intended to explain the present invention and should not be construed as limiting the invention.
Furthermore, the terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In the description of the present invention, the meaning of "plurality" means at least two, for example, two, three, etc., unless specifically defined otherwise.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
Herein, "small enteric gelatin protein" refers to a type of gelatin protein that is resistant to pepsin digestion and is digested by trypsin.
The term "polymer" as used herein refers to a polymer having a linear long chain composed of repeating units as a basic structure, and is present in animals, plants and living bodies. Illustratively, the polymeric substance may include at least one of: polypeptides, proteins, enzymes, etc.; polyphosphates, ribonucleic acids, deoxyribonucleic acids, and the like; polysaccharides such as starch, liver sugar, inulin, chitin, etc.; rubber such as Brazil rubber, gutta percha, etc.; resins such as Arabic, agar, algin, etc. In the present application, the first polymer substance and the second polymer substance may be plant-derived or animal-derived polymer substances, wherein the first polymer substance is preferably plant-derived, the second polymer substance is preferably animal-derived polymer, and in some specific embodiments of the present application, gellan gum is used as the first polymer substance, and small enteric gelatin protein in gelatin is used as the second polymer substance.
As used herein, "gelatin" refers to a hydrocolloid which is a macromolecule, partially hydrolyzed from collagen, and any one or more edible gelatins or gelatin protein fragments may be used to prepare the slow release carriers and/or slow release drops of the present invention, e.g., small enteric gelatin proteins and/or small enteric gelatin proteins having a molecular weight of 23-33 kDa.
As used herein, "probiotic" refers to a class of active microorganisms that benefit a host by colonizing the human or animal body to alter the flora composition at a location in the host.
Herein, "vegetable oil" refers to a compound obtained by reacting higher fatty acid with glycerin, and is widely distributed in nature, and is an oil obtained from fruits, seeds, and germs of plants, such as soybean oil, sunflower seed oil, olive oil, castor oil, peanut oil, rapeseed oil, sesame oil, cottonseed oil, linseed oil, safflower seed oil, castor oil, and the like, for example.
Herein, "melting point modifier" refers to a substance having an effect of affecting the melting point of the vegetable oil or oil phase core layer for adjusting the melting point of one or more vegetable oils or a mixture of one or more vegetable oils and other substances, for example, beeswax, hydrogenated palm oil, shortening and sitosterol are used in the present invention to lower the melting point of the oil phase core layer.
Herein, a "food acceptable" ingredient is an edible substance suitable for use in humans and/or mammals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., commensurate with a reasonable benefit/risk ratio.
The beneficial effects of the invention at least comprise:
the invention provides a novel slow release carrier and a slow release dripping pill applied to the slow release carrier, the slow release carrier has a three-layer structure, namely an oil phase core layer, a middle layer and an outer layer, a micropore structure is formed between the outer layer and the middle layer by adding specific substances into the middle layer and the outer layer by utilizing a nano micropore technology, so that the structure can effectively ensure that the outer layer completely falls off without affecting the middle layer when the slow release carrier plays a role in vivo, and further the slow release carrier is beneficial to the directional slow release of probiotics in the slow release dripping pill, so as to solve the problem that the multilayer dripping pill structure in the prior art is difficult to achieve an ideal directional colon slow release effect.
Furthermore, the invention can optimize each layer structure by strictly screening the composition of each layer and the corresponding proportioning relation so as to achieve more excellent directional slow release effect. Specifically, for the outer layer, the outer layer is prepared by using the preferable small enteric gelatin protein, so that the outer layer of the sustained-release dripping pill has gastric acid resistance effect, can fall off rapidly after entering the small intestine, and exposes the protective layer of the dripping pill for specifically adsorbing colon; for the middle layer, the first polymer substance gellan gum is used as the main component of the middle layer, so that the middle layer can resist cholate corrosion, and the middle layer has certain strength and is not damaged in the small intestine; in addition, the slow release time of the dripping pill in the colon can be effectively prolonged by adding the middle layer probiotics which specifically adsorb the colon; for the oil phase core layer, the core layer structure has complete embedding of the probiotics colony and high survival rate, and the solid core layer at normal temperature is obtained by adding the melting point regulator, so that the probiotics colony can be fixed, the probiotics colony in the interior is ensured to be uniformly distributed in the storage process, and the thallus aggregation is reduced; and the solid core layer has a slow release function when released in the colon, so that the release range of probiotics can be effectively enlarged. The research shows that the slow release dripping pill has long-term stability, and the viable count is reduced by about 10% after being preserved for 12 months at the temperature of 4 ℃.
In a word, the slow release carrier is applied to slow release dropping pills, can realize complete embedding of substances to be released, such as probiotics, high survival rate, good gastric acid and bile salt resistance effect, can directionally transfer the probiotics to be released to the colon for stay and slow release, has excellent stability, safe and simple process, is suitable for industrial production, and can be effectively applied to preparing intestinal release health care products.
The invention will now be described with reference to specific examples, which are intended to be illustrative only and not limiting in any way. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
All reagents and probiotics of the invention are commercially available.
Example 1 preparation of sustained-release dripping pill
An outer layer: 10g of small enteric gelatin protein (23-33 kDa), 5g of glycerol are mixed, the pH value is regulated to 2.5 by 1M dilute hydrochloric acid, and purified water is added for dissolution and volume fixation to 100mL;
middle layer: mixing 10g lactobacillus reuteri thallus (thallus is not less than 100 hundred million), 1.5g low acyl gellan gum and 0.2g nano-sized calcium carbonate particles, adding purified water, dissolving and fixing volume to 100mL;
Oil phase core layer containing probiotics: melting 5g beeswax and 90g soybean oil, adding 10g probiotic bacteria (Lactobacillus plantarum, lactobacillus casei and Lactobacillus acidophilus at a weight ratio of 1:1:1, and mixing with activity of not less than 20000 hundred million).
Dripping pill: and (3) the three layers of materials are subjected to one-time dripping forming through three layers of concentric circle drippers, and are dripped into a gas cooling column to be condensed into dripping pills.
Example 2 preparation of sustained-release dripping pill
An outer layer: 8g of small enteric gelatin protein (23-33 kDa), 6.5g of glycerol are mixed, the pH value is adjusted to 2.7 by 1M dilute hydrochloric acid, and purified water is added for dissolution and volume fixation to 100mL;
middle layer: mixing 8g lactobacillus acidophilus thalli (thalli are not less than 100 hundred million) with low acyl gellan gum (1.7 g) and 0.3g nano-sized calcium carbonate particles, adding purified water to dissolve and fix volume to 100mL;
oil phase core layer containing probiotics: 3g of hydrogenated vegetable oil and 90g of sunflower seed oil are melted uniformly, 5g of probiotics flora (lactobacillus paracasei, lactobacillus rhamnosus, lactobacillus reuteri and lactococcus lactis are mixed according to the weight ratio of 1:1:1, and the vitality of the mixture is 15000 hundred million) is added, and the mixture is uniformly mixed.
Dripping pill: and (3) the three layers of materials are subjected to one-time dripping forming through three layers of concentric circle drippers, and are dripped into a gas cooling column to be condensed into dripping pills.
Example 3 preparation of sustained-release dripping pill
An outer layer: 9g of small enteric gelatin protein (23-33 kDa), 8g of glycerol are mixed, the pH value is regulated to 3.0 by 1M dilute hydrochloric acid, and purified water is added for dissolution and volume fixation to 100mL;
middle layer: mixing lactobacillus plantarum thalli (thalli are not less than 100 hundred million) with 5g of specificity adsorption colon, 2g of low acyl gellan gum and 0.4g of nano-grade calcium carbonate particles, adding purified water to dissolve and fix the volume to 100mL;
oil phase core layer containing probiotics: 3g of sitosterol, 3g of shortening and 85g of olive oil are melted uniformly, 8g of probiotics flora (bifidobacterium bifidum, bifidobacterium adolescentis, bifidobacterium infantis, bifidobacterium breve and bifidobacterium longum are mixed according to the weight ratio of 1:1:1, and the vitality is not lower than 16000 hundred million) is added, and the mixture is uniformly mixed.
Dripping pill: and (3) the three layers of materials are subjected to one-time dripping forming through three layers of concentric circle drippers, and are dripped into a gas cooling column to be condensed into dripping pills.
Example 4 preparation of sustained-release dripping pill
An outer layer: 10g of small enteric gelatin protein (23-33 kDa), 5g of glycerol are mixed, the pH value is regulated to 2.5 by 1M dilute hydrochloric acid, and purified water is added for dissolution and volume fixation to 100mL;
middle layer: mixing 10g lactobacillus reuteri thallus (thallus is not less than 100 hundred million), 1.5g low acyl gellan gum and 0.2g nano-sized calcium carbonate particles, adding purified water, dissolving and fixing volume to 100mL;
Oil phase core layer containing probiotics: melting 5g beeswax and 90g soybean oil, adding 10g probiotic bacteria (Lactobacillus plantarum, lactobacillus casei and Lactobacillus acidophilus at a weight ratio of 1:1:1), and mixing.
Dripping pill: and (3) the three layers of materials are subjected to one-time dripping forming through three layers of concentric circle drippers, and are dripped into liquid paraffin condensate to be condensed into dripping pills.
Example 5 preparation of sustained-release dripping pill
In the step of preparing the outer layer, instead of using small enteric gelatin protein, 10g of ordinary gelatin solution was used, and the rest of experimental procedures and conditions were the same as in example 1, to obtain a dripping pill.
Comparative example 1
In the step of preparing the outer layer, the pH value is not adjusted (no acid); in the step of preparing the middle layer, no nano-sized calcium carbonate particles were added, and the rest of experimental steps and conditions were the same as in example 1, to obtain a dripping pill.
Comparative example 2
In the step of preparing the middle layer, 1.5% of low acyl gellan gum was replaced with an equal volume of oil phase containing 90% soybean oil and 5% beeswax, and the rest of experimental procedures and conditions were the same as in example 1 to obtain a dripping pill.
Test example 1
This test example was used to evaluate the effect of different formulations on colon disintegration and on the removal of the outer and middle layers.
According to the third division (general rule 0921) of the pharmacopoeia of the people's republic of China, whether each sample accords with colon disintegration and the outer layer and the middle layer fall off is detected. The method comprises the following specific steps:
taking 6 grains of test sample, firstly, checking in artificial gastric juice (16.4 mL of hydrochloric acid, about 800mL of water and 10g of pepsin) for 2 hours without a baffle, and recording the crack or disintegration phenomenon of each grain; taking out the hanging basket, washing with a small amount of water, checking for 3 hours in artificial small intestine liquid (100 mL phosphate buffer with pH of 6.8 and 10g pancreatin) without baffle according to the method, and recording each crack or disintegration phenomenon; taking out the basket, washing with small amount of water, adding baffle plate into each tube, and checking in artificial intestinal juice (pH 7.8 phosphate buffer solution) according to the above method, and recording disintegration within 1 hr. The experimental results are shown in table 1:
TABLE 1
Test results: examples 1-3 the outer small enteric gelatin layer was not deformed or broken after simulated digestion in artificial gastric acid for 2 hours; after simulated digestion for 3 hours in artificial intestinal juice, the outer layer is completely separated, the middle layer is exposed, the middle layer is not damaged, then the middle layer is disintegrated in artificial intestinal juice simulated digestion, and an oil phase core layer containing probiotics is exposed for slow release of the probiotics. It can be seen that the probiotic sustained-release dropping pill of the embodiment 1-3 is colon-soluble.
Example 5 during simulated artificial digestion, the outer layer of common gelatin is not broken in the simulated digestion of artificial gastric juice and intestinal juice, and falls off successively in the simulated digestion of artificial colon juice, and the core layer is completely delayed for more than 1 hour; therefore, the common gelatin cannot achieve the small enteric effect of the small enteric gelatin protein, cannot achieve the colon dissolution, and is not suitable for being used as an outer layer material of the colon-soluble dripping pill.
Comparative example 1 when simulated artificial digestion, the outer layer small enteric gelatin protein was not broken in simulated artificial gastric juice digestion, split but not shed in simulated artificial intestinal juice digestion, the outer layer and the middle layer shed together in simulated artificial intestinal juice digestion, and the core layer was dissolved over 1 hour; therefore, when the nano microporous structure is not arranged between the outer layer and the middle layer, the outer layer cannot completely fall off from the middle layer, and normal exposure of the middle layer is affected.
Comparative example 2 when simulated artificial digestion, the outer small enteric gelatin protein was not broken in simulated artificial gastric juice digestion, and after complete shedding in simulated artificial intestinal juice digestion, the middle and core layers were broken in artificial intestinal juice; therefore, the middle layer cannot protect the oil when the oil is used as a protective layer.
Test example 2
The test example is used for evaluating the activity influence of different formulas on probiotics to be released
The live bacteria detection of the samples is carried out according to the standard of GB4789.35 food safety national Standard food microbiology test lactic acid bacteria test, and the change of the live bacteria in the disintegration time limit detection of each group of samples is tested. The method comprises the following specific steps:
each group of samples is sampled for 1g, according to the treatment standard of the disintegration time limit checking method in the third part (general rule 0921) of the pharmacopoeia of the people's republic of China, the artificial gastric juice and the artificial intestinal juice are respectively sampled after the simulated digestion, the artificial intestinal juice is sampled when the simulated digestion is carried out for 1h or the core layer is disappeared, and the viable bacteria count is carried out according to the national standard GB 4789.35; homogenizing the samples before simulated digestion, pulverizing dripping pills, adding the samples into physiological saline according to a proportion of 1%, homogenizing in ice bath for 5min at 20000r/min, and taking homogenized liquid to count viable bacteria according to national standard GB 4789.35. The experimental results are shown in table 2.
TABLE 2
As can be seen from Table 2 above, the total number of viable bacteria of the sample obtained in example 1 was 2.1X10 10 cfu, wherein the core layer is not damaged due to simulated digestion in the artificial gastric juice and the artificial intestinal juice, and the living bacteria in the core layer are not slowly released, so that the living bacteria cannot be detected in the artificial gastric juice and the artificial intestinal juice; after simulated digestion of the artificial intestinal juice, the slow release of the core layer is complete within 1h, and the total number of viable bacteria is 2.3 multiplied by 10 10 cfu, the total number of viable bacteria before relative simulated digestion was not reduced.
EXAMPLE 5 the total number of viable bacteria in the obtained sample was 2.1X10 10 cfu, wherein the core layer is not damaged due to simulated digestion in the artificial gastric juice and the artificial intestinal juice, and the living bacteria in the core layer are not slowly released, so that the living bacteria cannot be detected in the artificial gastric juice and the artificial intestinal juice;after simulated digestion of the artificial intestinal juice, the core layer is not completely released after more than 1 hour, and the total number of the viable bacteria is detected to be 7.7x10 8 cfu showed a significant decrease in the number of viable bacteria relative to that before simulated digestion, so the effect of example 1 was not achieved by slow release.
Comparative example 1 the total viable count of the obtained samples was 2.0X10 10 cfu, wherein the core layer is not damaged due to simulated digestion in the artificial gastric juice and the artificial intestinal juice, and the living bacteria in the core layer are not slowly released, so that the living bacteria cannot be detected in the artificial gastric juice and the artificial intestinal juice; after simulated digestion of the artificial intestinal juice, the core layer is not completely released after more than 1 hour, and the total number of the viable bacteria is detected to be 1.9x10 8 cfu showed a significant decrease in the number of viable bacteria relative to that before simulated digestion, so the effect of example 1 was not achieved by slow release.
Comparative example 2 the total viable count of the obtained samples was 2.1X10 10 cfu, wherein the core layer is not damaged due to simulated digestion in the artificial gastric juice, and the living bacteria in the core layer are not released slowly, so that the living bacteria cannot be detected in the artificial gastric juice; the middle layer and the core layer are completely damaged by simulated digestion in artificial intestinal juice, and the artificial intestinal juice is used for detecting viable bacteria 4.8X10% 6 cfu, compared with the number of viable bacteria before simulated digestion, is obviously reduced, and the viable bacteria are corroded by intestinal juice, so that the slow release effect of the embodiment 1 is not achieved.
Test example 3
This test example was used to evaluate the effect of different formulations on storage stability.
Placing the obtained dripping pill sample in sealed bag, standing at 4deg.C and 25deg.C for 6 months, adding the sample into physiological saline at a ratio of 1% after expiration, homogenizing in ice bath at 20000r/min for 5min, and collecting homogenized liquid for viable count according to national standard GB 4789.35. The experimental results are shown in table 3.
TABLE 3 Table 3
| Sample of | 0 month/(cfu/g) | 4 ℃ for 6 months/(cfu/g) | 25 ℃ and 6 months/(cfu/g) |
| Example 1 | 2.1×10 10 | 1.9×10 10 | 1.7×10 9 |
| Example 2 | 2.1×10 10 | 2.0×10 10 | 2.2×10 9 |
| Example 3 | 2.2×10 10 | 1.9×10 10 | 1.1×10 9 |
| Example 5 | 2.1×10 10 | 1.2×10 10 | 1.3×10 9 |
| Comparative example 1 | 2.0×10 10 | 5.6×10 9 | 2.9×10 8 |
| Comparative example 2 | 2.1×10 10 | 6.9×10 9 | 3.4×10 8 |
As can be seen from table 3 above, the storage stability of the colonic-dissolving probiotic sustained-release pellets prepared in examples 1, 2 and 3 was significantly better than that of the other examples and comparative examples.
Test example 4
This test example was used to screen the effect of enteric gelatin proteins.
Sample 1:15% gelatin solution
Sample 2: preparing 15% gelatin solution, regulating pH value to 2.0, adding 2000 units of bovine pepsin per gram of gelatin, and hydrolyzing at 37deg.C and 50r/min for 2 hr to obtain pepsin hydrolyzed gelatin;
sample 3: adding one tenth volume of 1M phosphate buffer solution into the sample 2, adjusting the pH value to 6.8, adding 2000 units of bovine trypsin, and hydrolyzing at 25 ℃ for 2 hours at 50r/min to obtain gelatin hydrolyzed by pepsin and trypsin in sequence;
Mark: trichromatic pre-dye protein molecular weight standard (GoldBand Plus 3-color Regular Range Protein Marker (8-70 kDa))
The method comprises the following steps: sample 1 unhydrolyzed sample, sample 2 bovine pepsin hydrolyzed sample, sample 3 bovine pepsin and bovine trypsin hydrolyzed sample were taken, respectively, and subjected to SDS-PAGE gel electrophoresis.
Results: as shown in samples 1, 2 and 3 of FIG. 3, the molecular weight distribution of the protein resistant to bovine pepsin hydrolysis and hydrolyzable by bovine trypsin was measured at 23-33kDa. From the above experimental results, the molecular weight distribution of the enteric gelatin protein was 23-33kDa.
Test example 5
The test example is used for separating, purifying and verifying the enteric gelatin protein
And (3) separating and purifying: performing gel filtration chromatography on 5% gelatin solution by using a protein chromatography system, and collecting target molecular weight protein; the collected protein solution was concentrated to a concentration of 10% by mass using a reduced pressure concentration system.
Results: as in sample 4 of FIG. 3, the isolated and purified enteric gelatin protein was subjected to a measurement (molecular weight 23-33 kDa) to give a molecular weight of 23-33kDa.
And (3) verification: the separated and purified gelatin protein (molecular weight 23-33 kDa) was subjected to SDS-PAGE gel electrophoresis after trypsin hydrolysis, and the electrophoresis result is shown in sample 5 of FIG. 3.
Test example 6
The test example is used for measuring the adsorption quantity of the specific adsorption colon strain.
The HT-29 cells are passaged 3 times by DEME culture medium, pancreatin digestion is carried out, the cell concentration is adjusted to 100000cells/mL, 1mL of HT-29 cell fluid is added into each hole of a 24-hole plate containing a cell climbing sheet, and the cell climbing sheet is cultured to a fully differentiated single cell layer at 37 ℃ by 5 percent carbon dioxide; activating the strain to be selected by using a BS or MRS culture medium, culturing for 24 hours at 37 ℃, centrifugally collecting thalli at 5000r/min, washing for three times by using PBS (0. M, pH =6.8) buffer solution, and then regulating the bacterial concentration to 1 hundred million cfu/ml by using the same PBS; adding 1mL of strain solution to be selected into HT-29 cells of each hole, incubating for 60min at 37 ℃ under 5% carbon dioxide, washing for 5 times with PBS, and then solidifying with anhydrous methanol for 20min; cell climbing sheets in the well plate were taken out, gram staining was performed, 20 fields were randomly observed and counted using an oil mirror, and the average bacterial count was calculated.
The detection results show that the probiotic strains with the adsorption capacity of more than 12cells/cfu are obtained, as shown in Table 4.
TABLE 4 Table 4
| Strain | Adsorption capacity (cells/cfu) |
| Lactobacillus reuteri | 22 |
| Lactobacillus acidophilus | 16 |
| Plant milk rod | 13 |
| Lactobacillus delbrueckii | 6 |
| Lactococcus lactis | 3 |
| Streptococcus hygropyrecus | 1 |
As can be seen from Table 4 above, lactobacillus reuteri, lactobacillus acidophilus and Lactobacillus plantarum are capable of specifically adsorbing colon cells.
Test example 7
The test example is used for optimizing the nano microporous structure.
For the sustained-release dripping pill, the acidity of the outer layer reacts with calcium carbonate in the middle layer to produce carbon dioxide pores, so that the integrity of the middle layer can not be influenced when the outer layer falls off. Taking the falling-off condition of the outer layer from the middle layer as a standard, and optimizing the calcium carbonate particles and the pH value; calcium carbonate particles with different particle sizes are manufactured by using a miniature planetary ball mill, the pH value of the outer layer is regulated by using 0.1M dilute hydrochloric acid, and the manufacturing method of the dripping pill is carried out according to the example 1; each group of samples was examined and recorded for the falling-off of the outer layer according to the disintegration time limit examination method of the third part (general rule 0921) of the pharmacopoeia of the people's republic of China, and the influence of the falling-off of the outer layer on the integrity of the middle layer was determined. The experimental results are shown in table 5.
Table j
As can be seen from table 5 above, the preferred preparation parameters are: the granularity of the calcium carbonate particles is 300nm-600nm, the addition amount is 0.2% -0.4%, and the pH value of the outer layer is 2.5-3.0.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means 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 present invention. In this specification, schematic representations of the above terms are not necessarily directed 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, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (18)
1. A sustained release carrier comprising:
an oil phase core layer;
a middle layer containing a first polymer substance selected from gellan gum; and
An outer layer containing a second polymer substance, wherein the second polymer substance comprises gelatin, the gelatin is small enteric gelatin protein, the molecular weight of the small enteric gelatin protein is 23-33kDa, and the pH value of the outer layer is 2.5-3.0;
wherein a microporous structure is formed between the outer layer and the middle layer;
the outer layer also contains acid, the middle layer also contains carbonate, the microporous structure is a plurality of micropores formed by the reaction of the acid and the carbonate, the carbonate is nano carbonate particles, the particle size of the nano carbonate particles is 300-600 nm, and the addition amount of the nano carbonate particles is 0.2-0.4%;
the mass ratio of the first polymer substance and the carbonate in the middle layer is (1-3): (0.1 to 0.5);
The dosage of the second polymer substance in the outer layer is 0.08g/ml-0.1g/ml;
the small enteric gelatin protein adopts a protein chromatography system to carry out gel filtration chromatography on gelatin liquid and collect target molecular weight protein; concentrating under reduced pressure.
2. The slow release carrier according to claim 1, wherein the acid is selected from one or more of sulfuric acid, hydrochloric acid, acetic acid, phosphoric acid and lactic acid;
the carbonate is selected from one or more of sodium carbonate, sodium bicarbonate and calcium carbonate.
3. The slow release carrier of claim 1, wherein the middle layer further comprises a probiotic.
4. A slow release carrier according to claim 3 wherein the probiotic is a colon adsorbing probiotic.
5. The slow release carrier according to claim 4, wherein the probiotics adsorbing the colon comprises probiotics adsorbing the colon cells at a rate of not less than 12 cfu/cell.
6. The sustained-release carrier according to claim 5, wherein the mass ratio of the probiotics, the first polymer substance and the carbonate in the middle layer is (4 to 11): (1-3): (0.1-0.5).
7. The slow release carrier of claim 1, wherein the oil phase core comprises a vegetable oil.
8. The slow release carrier of claim 7, wherein the vegetable oil is selected from one or more of soybean oil, sunflower seed oil, olive oil, castor oil, peanut oil, rapeseed oil, sesame oil, cottonseed oil, linseed oil, and safflower seed oil.
9. The slow release carrier of claim 8, wherein the oil phase core further comprises a melting point modifier.
10. The slow release carrier according to claim 9, wherein the melting point regulator has a melting point of 40 ℃ to 100 ℃.
11. A sustained-release dripping pill comprising the sustained-release carrier according to any one of claims 1 to 10 and a substance to be released.
12. The sustained-release dripping pill according to claim 11, wherein the substance to be released is a probiotic bacterial group dispersed in the oil phase core layer of the sustained-release carrier.
13. The sustained-release drop pill of claim 12, wherein the probiotic flora comprises one or more probiotics.
14. The sustained-release dripping pill according to claim 13, wherein the probiotics are selected from one or more of lactobacillus, bifidobacterium, lactococcus and yeast.
15. The sustained-release dripping pill according to claim 13, wherein the probiotic bacteria group comprises a plurality of probiotics, and the probiotics are mixed according to equal proportion.
16. A method of preparing the sustained-release dripping pill as claimed in any one of claims 11 to 15, comprising:
carrying out first mixing treatment on a second high molecular substance and acid, wherein the second high molecular substance is small enteric gelatin protein, and the pH value of a first mixing treatment product is 2.0-3.5;
carrying out second mixing treatment on the first high molecular substance and carbonate;
carrying out third mixing treatment on the substances to be released and the vegetable oil; and
and carrying out molding treatment on the first mixed treatment product, the second mixed treatment product and the third mixed treatment product to obtain the sustained-release dripping pill.
17. The method of claim 16, wherein the first mixing process further comprises adding food acceptable excipients and/or water;
the second mixing treatment further comprises adding probiotics;
the third mixing treatment further comprises adding a melting point regulator;
the shaping treatment is carried out by a dropping method or a pressing method.
18. The method of claim 17, wherein the probiotic is a colon-adsorbing probiotic; the melting point of the melting point regulator is 40-100 ℃.
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