CN114344272B - Chitosan oligosaccharide enteric-coated dripping pill and application thereof in preparation of non-alcoholic fatty liver disease drugs - Google Patents
Chitosan oligosaccharide enteric-coated dripping pill and application thereof in preparation of non-alcoholic fatty liver disease drugs Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Abstract
The invention belongs to the field of medicines, and in particular relates to a chitosan oligosaccharide enteric-coated dripping pill and application thereof in preparing a non-alcoholic fatty liver disease drug. The chitosan oligosaccharide enteric-coated dripping pill provided by the invention consists of an enteric layer coating and a pill core according to the mass ratio of 6-10:13-17. The chitosan oligosaccharide enteric-coated dripping pill provided by the invention can improve lipid metabolism abnormality caused by high blood glucose level and high-fat high-sucrose diet of organisms, improve liver function index abnormality caused by high-fat high-sucrose diet to a certain extent, strengthen serum antioxidant function of non-alcoholic fatty liver mice, promote release of anti-inflammatory factors, achieve the aim of reducing inflammation, strengthen stability of chitosan oligosaccharide, and have better roundness.
Description
Technical Field
The invention belongs to the field of medicines, and in particular relates to a chitosan oligosaccharide enteric-coated dripping pill and application thereof in preparing a non-alcoholic fatty liver disease drug.
Background
Non-alcoholic fatty liver disease (NAFLD) is currently the most widespread chronic liver disease, further developing non-alcoholic steatohepatitis (NASH), and NAFLD-related complications mainly include hyperlipidemia, obesity, type II diabetes, etc., and the liver-specific mortality and total mortality of NAFLD and NASH are 0.77% and 11.77%. The harm to human caused by NAFLD is not negligible, and the current market for treating NAFLD has few medicines, and most of NAFLD is still in the test stage, and has a plurality of application defects and poor treatment effect. Therefore, there is an urgent need to develop safe, effective, less side-effect medicaments for treating NAFLD.
The chitosan oligosaccharide (ChitosanOligosaccharides, COS) is marine oligosaccharide formed by connecting glucosamine and a small amount of N-acetylglucosamine through beta-1, 4-glycosidic bond, has multiple biological activities, has a certain capability of regulating intestinal flora, and has physiological effects of bacteriostasis, obesity resistance, inflammation resistance, oxidation resistance, depressurization, alzheimer disease resistance, tumor resistance and the like, but has few reports when the chitosan oligosaccharide is applied to treating non-alcoholic fatty liver. The enteric-coated dripping pill has the characteristics of high bioavailability, strong drug stability, capability of controlling the release of the drug in intestinal tracts, and the like. However, in the existing preparation process of the dripping pill, more influencing factors are involved, and the dripping distance, the melting temperature of the liquid medicine and the like can influence the roundness of the dripping pill.
Patent publication No. CN112826876a discloses the application of ampelopsis grossedentata water extraction in preparation of a preparation for improving liver injury, which discloses liver injury including alcoholic liver injury, drug-induced liver injury, alcoholic fatty liver and non-alcoholic fatty liver, and further discloses a ampelopsis grossedentata composition for regulating intestinal microecology, the drug composition contains ampelopsis grossedentata water extract, prebiotics and pharmaceutical excipients; the prebiotic is at least one of xylo-oligosaccharide, fructo-oligosaccharide, chitosan oligosaccharide, mannooligosaccharide and gluco-oligosaccharide. Although the application of chitosan oligosaccharide in treating liver injury is disclosed, the composition is not an enteric coated dripping pill, and the chitosan oligosaccharide is easily oxidized and hydrolyzed by air, so that the treatment effect is reduced.
The patent publication No. CN105030816A discloses a compound liver-protecting traditional Chinese medicine for treating non-alcoholic fatty liver, which comprises chitosan oligosaccharide, salidroside, resveratrol, astaxanthin and stichopus japonicus selenka glycosaminoglycans, wherein the salidroside, the chitosan oligosaccharide, the resveratrol and the stichopus japonicus selenka glycosaminoglycans are scientifically proportioned, so that lipid metabolism related genes can be regulated, the content of triglyceride in NAFLD liver cells can be obviously reduced, apoptosis induced by fatty acid can be reduced, liver steatosis of a high-fat diet mouse can be reduced, the content of TG in the liver is reduced, and no obvious side effect is caused. However, the components playing the main roles are not chitosan oligosaccharide, and the research on the activity and mechanism of treating NAFLD by chitosan oligosaccharide is not given, meanwhile, the formula is not an enteric coated dripping pill, and the technical problem that chitosan oligosaccharide is easy to be oxidized and hydrolyzed by air and the treatment effect is reduced exists.
In summary, the technical problems of poor stability of chitosan oligosaccharide, poor roundness of enteric coated dripping pills and the like commonly exist in the prior art.
Disclosure of Invention
In order to overcome the technical problems, the invention aims to provide a chitosan oligosaccharide enteric-coated dripping pill and application thereof in preparing a non-alcoholic fatty liver medicament. The chitosan oligosaccharide enteric-coated dripping pill provided by the invention can improve lipid metabolism abnormality caused by high blood glucose level and high-fat high-sucrose diet of organisms, improve liver function index abnormality caused by high-fat high-sucrose diet to a certain extent, strengthen serum antioxidant function of non-alcoholic fatty liver mice, promote release of anti-inflammatory factors, achieve the aim of reducing inflammation, strengthen stability of chitosan oligosaccharide, and have better roundness.
In order to achieve the above object, the technical scheme of the present invention is as follows:
a chitosan oligosaccharide enteric-coated dripping pill comprises enteric coating layer and pill core at a mass ratio of 6-10:13-17.
Further, the enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following components in parts by weight: 100-55-40 parts of Eudragit L, 10-20 parts of talcum powder, 2-4 parts of polyethylene glycol 6000 and 218-436 parts of ethanol.
Further, the preparation method of the enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following steps: weighing Eudragit L100-55 in the formula amount, slowly adding into 95% ethanol which is uniformly mixed with talcum powder and polyethylene glycol 6000 in advance, preparing suspension with the mass fraction of L100-55 being 8%, and sieving with 80 mesh sieve to obtain the final product.
Further, the pill core in the chitosan oligosaccharide enteric-coated dripping pill consists of chitosan oligosaccharide and a matrix according to the mass ratio of 1:2-4.
Further, the core matrix in the chitosan oligosaccharide enteric-coated dripping pill consists of polyethylene glycol 6000 and stearic acid according to the mass ratio of 3-5:7-11.
Further, the preparation method of the pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following steps: taking a proper amount of matrix, placing into a beaker, heating in water bath, magnetically stirring until the matrix is sufficiently melted, slowly adding chitosan oligosaccharide while stirring, fully and uniformly mixing, placing into a self-made dripping pill device, dripping into liquid paraffin condensing medium precooled to 5-10 ℃ under the conditions that the dripping distance is 15-30cm and the dripping speed is 25-30 drops/min, condensing and solidifying, removing the condensing medium by centrifugation after forming dripping pills, drying and sealing for storage.
Further, the melting temperature of the pellet core in the chitosan oligosaccharide enteric-coated dripping pill is 80-90 ℃.
The invention also provides a preparation method of the chitosan oligosaccharide enteric-coated dripping pill, which comprises the following steps: placing the pill core into a high-efficiency coating machine, setting the rotating speed of the coating machine at 22-27rpm, the air inlet temperature at 40-50 ℃, the air outlet temperature at 25-30 ℃, the material temperature at 25-30 ℃, preheating for 15min, then coating, spraying the enteric coating layer coating liquid into a spray gun with the atomization pressure value of 0.11-0.13Mpa, taking out when the coating weight reaches 20% of the weight of the pill core, placing into a blast oven, and drying at 30 ℃ for 1h to obtain the product.
Further, the chitosan oligosaccharide enteric-coated dripping pill is applied to the preparation of the medicine for treating the non-alcoholic fatty liver.
The matrix in the chitosan oligosaccharide enteric-coated dripping pill core is a drug carrier of main drug chitosan oligosaccharide, so that the stability of the drug is not affected while the drug is stably and effectively released. Polyethylene glycol 6000 is a water-soluble matrix with more application, but the research process finds that polyethylene glycol 6000 often causes dependence on patients, and stearic acid and polyethylene glycol 6000 form a matrix of a pill core together in a ratio of 3-5:7-11, so that the dependence of patients on polyethylene glycol 6000 can be reduced, the dispersibility of the medicine in small intestine can be effectively improved, and the absorption rate of the medicine is enhanced.
According to the invention, in the preparation process of the pellet core, the melting temperature and the drop distance of the matrix can influence the roundness of the pellet core, and when the melting temperature is lower, the dripping pill drops into a condensing medium, the dripping pill is condensed too early because of the fact that the dripping pill is not too early to be spherical, so that tailing is easier, and the roundness is poorer; when the melting temperature is higher, the dripping pills are not immediately coagulated when being dripped into the condensing medium, but are sunk in the condensing medium for a period of time in a molten state, and the surface tension of the condensing medium can promote the dripping pills to be agglomerated into a round sphere. When the dripping distance is larger, the dripping pills reach the liquid level, the generated impact causes poor rounding of the dripping pills due to larger speed, most of dripping pills have small liquid medicine which is separated out, so that small holes are formed on the finally formed dripping pills, and meanwhile, the dripping pills are possibly not solidified, namely touch the bottom due to larger speed of dripping the liquid level, so that partial dripping pills are adhered; when the drop distance is smaller, the dropping pill does not form a sphere in the air, namely enters a condensing medium, so that a large amount of tailing is generated.
In the coating process, the rotating speed of the coating machine plays a vital role, when the coating machine works, coating liquid is sprayed onto materials carried by the uniformly rotating coating barrel through the spray nozzle, the coating barrel rotates to enable the materials to be fully contacted with the coating liquid, and if the rotating speed of the material barrel is too high, coating is coated unevenly, the rotating speed is too low, and the coating liquid is not easy to volatilize.
Compared with the prior art, the chitosan oligosaccharide enteric-coated dripping pill and the application thereof in preparing the non-alcoholic fatty liver disease medicament have the following advantages:
(1) The chitosan oligosaccharide enteric-coated dripping pill provided by the invention has no influence on appetite and body weight of a non-alcoholic fatty liver mouse, and can improve abnormal lipid metabolism caused by high blood glucose level and high-fat high-sucrose diet of an organism;
(2) The chitosan oligosaccharide enteric-coated dripping pill provided by the invention can improve abnormal liver function indexes caused by high-fat and high-sucrose diet to a certain extent, and enhance the serum antioxidant function of a non-alcoholic fatty liver mouse;
(3) The chitosan oligosaccharide enteric-coated dripping pill provided by the invention can promote the release of anti-inflammatory factors, thereby achieving the purpose of reducing inflammation;
(4) The chitosan oligosaccharide enteric-coated dripping pill provided by the invention prepares the chitosan oligosaccharide into the enteric-coated dripping pill, so that on one hand, the oxidation and the hydrolysis of the chitosan oligosaccharide by air can be avoided, the stability of the preparation can be enhanced, and on the other hand, the targeting drug release to the intestinal tract can be realized, and the capability of the chitosan oligosaccharide for regulating intestinal flora can be enhanced.
Detailed Description
The present invention is further described below by way of specific embodiments, but the present invention is not limited to the following examples. Various modifications may be made by those skilled in the art in light of the basic idea of the invention, but are within the scope of the invention without departing from the basic idea of the invention.
In this embodiment, the coating temperature in the preparation method of the chitosan oligosaccharide enteric-coated dripping pill comprises a material temperature, an air inlet temperature and an air outlet temperature. In order to facilitate the animal experiment, the particle size of the chitosan oligosaccharide enteric-coated dripping pill is controlled to be 1.9mm in the specific embodiment.
Example 1, chitosan oligosaccharide enteric-coated drop pill and preparation method thereof
The chitosan oligosaccharide enteric-coated dripping pill consists of an enteric layer coating and a pill core according to the mass ratio of 6:13.
The enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following components in parts by weight: 100-55 parts of Eudragit L, 10 parts of talcum powder, 6000 parts of polyethylene glycol, and 218 parts of ethanol.
The preparation method of the enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following steps: weighing Eudragit L100-55 in the formula amount, slowly adding into 95% ethanol which is uniformly mixed with talcum powder and polyethylene glycol 6000 in advance, preparing suspension with the mass fraction of L100-55 being 8%, and sieving with 80 mesh sieve to obtain the final product.
The pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following components in parts by weight: chitosan oligosaccharide: matrix = 1:2; the matrix consists of polyethylene glycol 6000 and stearic acid according to a mass ratio of 3:7.
The preparation method of the pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following steps: taking a proper amount of matrix, placing into a beaker, heating in a water bath, magnetically stirring until the matrix is sufficiently melted, stirring at 80 ℃, slowly adding chitosan oligosaccharide while stirring, fully and uniformly mixing, placing into a self-made dripping pill device, dripping into a liquid paraffin condensing medium precooled to 5 ℃ under the conditions that the dripping distance is 15cm and the dripping speed is 25 drops/min, condensing, solidifying, removing the condensing medium by centrifugation, drying, sealing and preserving.
The preparation method of the chitosan oligosaccharide enteric-coated dripping pill comprises the following steps: putting the pill core into a high-efficiency coating machine, setting the rotating speed of the coating machine to be 22rpm, the air inlet temperature to be 40 ℃, the air outlet temperature to be 25 ℃, the material temperature to be 25 ℃, preheating for 15min, then coating, spraying the enteric coating layer coating liquid into a spray gun with the atomization pressure value of 0.11Mpa, taking out when the coating weight reaches 20% of the weight of the pill core, putting into a blast oven, and drying at 30 ℃ for 1h to obtain the product.
Example 2, chitosan oligosaccharide enteric-coated drop pill and preparation method thereof
The chitosan oligosaccharide enteric-coated dripping pill consists of an enteric layer coating and a pill core according to the mass ratio of 10:17.
The enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following components in parts by weight: 100-55 parts of Eudragit L, 20 parts of talcum powder, 6000 parts of polyethylene glycol, and 436 parts of ethanol.
The preparation method of the enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following steps: weighing Eudragit L100-55 in the formula amount, slowly adding into 95% ethanol which is uniformly mixed with talcum powder and polyethylene glycol 6000 in advance, preparing suspension with the mass fraction of L100-55 being 8%, and sieving with 80 mesh sieve to obtain the final product.
The pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following components in parts by weight: chitosan oligosaccharide: matrix = 1:4; the matrix consists of polyethylene glycol 6000 and stearic acid according to a mass ratio of 5:11.
The preparation method of the pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following steps: taking a proper amount of matrix, placing into a beaker, heating in a water bath, magnetically stirring until the matrix is sufficiently melted, stirring at 90 ℃, slowly adding chitosan oligosaccharide while stirring, fully and uniformly mixing, placing into a self-made dripping pill device, dripping into a liquid paraffin condensing medium precooled to 10 ℃ under the conditions that the dripping distance is 30cm and the dripping speed is 30 drops/min, condensing, solidifying, forming dripping pills, removing the condensing medium by centrifugation, drying, sealing and preserving.
The preparation method of the chitosan oligosaccharide enteric-coated dripping pill comprises the following steps: putting the pill core into a high-efficiency coating machine, setting the rotating speed of the coating machine to be 27rpm, the air inlet temperature to be 50 ℃, the air outlet temperature to be 30 ℃, the material temperature to be 30 ℃, preheating for 15min, then coating, spraying the enteric coating layer coating liquid into a spray gun with the atomization pressure value of 0.13Mpa, taking out when the coating weight reaches 20% of the weight of the pill core, putting into a blast oven, and drying at 30 ℃ for 1h to obtain the product.
Example 3, chitosan oligosaccharide enteric-coated drop pill and preparation method thereof
The chitosan oligosaccharide enteric-coated dripping pill consists of an enteric layer coating and a pill core according to the mass ratio of 8:15.
The enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following components in parts by weight: 100-55 parts of Eudragit L, 16 parts of talcum powder, 6000 parts of polyethylene glycol and 326 parts of ethanol.
The preparation method of the enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following steps: weighing Eudragit L100-55 in the formula amount, slowly adding into 95% ethanol which is uniformly mixed with talcum powder and polyethylene glycol 6000 in advance, preparing suspension with the mass fraction of L100-55 being 8%, and sieving with 80 mesh sieve to obtain the final product.
The pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following components in parts by weight: chitosan oligosaccharide: matrix = 1:3; the matrix consists of polyethylene glycol 6000 and stearic acid according to a mass ratio of 4:9.
The preparation method of the pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following steps: taking a proper amount of matrix, placing into a beaker, heating in a water bath, magnetically stirring until the matrix is sufficiently melted, stirring at 86 ℃, slowly adding chitosan oligosaccharide while stirring, fully and uniformly mixing, placing into a self-made dripping pill device, dripping into a liquid paraffin condensing medium precooled to 8 ℃ under the conditions that the dripping distance is 21cm and the dripping speed is 27 drops/min, condensing, solidifying, removing the condensing medium by centrifugation, drying, sealing and preserving.
The preparation method of the chitosan oligosaccharide enteric-coated dripping pill comprises the following steps: putting the pill core into a high-efficiency coating machine, setting the rotating speed of the coating machine to be 25rpm, the air inlet temperature to be 46 ℃, the air outlet temperature to be 27 ℃, the material temperature to be 28 ℃, preheating for 15min, then coating, spraying the enteric coating layer coating liquid into a spray gun with the atomization pressure value of 0.12Mpa, taking out when the coating weight reaches 20% of the weight of the pill core, putting into a blast oven, and drying at 30 ℃ for 1h to obtain the product.
Comparative example 1, a chitosan oligosaccharide enteric-coated dripping pill and preparation method thereof
The chitosan oligosaccharide enteric-coated dripping pill consists of an enteric layer coating and a pill core according to the mass ratio of 8:15.
The enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following components in parts by weight: 100-55 parts of Eudragit L, 16 parts of talcum powder, 6000 parts of polyethylene glycol and 326 parts of ethanol.
The pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following components in parts by weight: chitosan oligosaccharide: matrix = 1:3; the matrix is polyethylene glycol 6000.
The enteric coating, pellet core and chitosan oligosaccharide enteric drop pellets described in this comparative example were prepared in a similar manner to example 3.
The difference between this comparative example and example 3 is: the substrates in this comparative example were all polyethylene glycol 6000.
Comparative example 2, chitosan oligosaccharide enteric-coated dripping pill and preparation method thereof
The chitosan oligosaccharide enteric-coated dripping pill consists of an enteric layer coating and a pill core according to the mass ratio of 8:15.
The enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following components in parts by weight: 100-55 parts of Eudragit L, 16 parts of talcum powder, 6000 parts of polyethylene glycol and 326 parts of ethanol.
The pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following components in parts by weight: chitosan oligosaccharide: matrix = 1:3; the matrix consists of polyethylene glycol 6000 and stearic acid according to a mass ratio of 4:9.
The enteric coating, pellet core and chitosan oligosaccharide enteric drop pellets described in this comparative example were prepared in a similar manner to example 3.
The difference between this comparative example and example 3 is: the matrix in the comparative example consists of polyethylene glycol 6000 and stearic acid according to the mass ratio of 1:1.
Comparative example 3, enteric chitosan oligosaccharide dripping pill and its preparation method
The chitosan oligosaccharide enteric-coated dripping pill consists of an enteric layer coating and a pill core according to the mass ratio of 8:15.
The enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following components in parts by weight: 100-55 parts of Eudragit L, 16 parts of talcum powder, 6000 parts of polyethylene glycol and 326 parts of ethanol.
The pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following components in parts by weight: chitosan oligosaccharide: matrix = 1:3; the matrix consists of polyethylene glycol 6000 and stearic acid according to a mass ratio of 4:9.
The enteric coating, pellet core and chitosan oligosaccharide enteric drop pellets described in this comparative example were prepared in a similar manner to example 3.
The difference between this comparative example and example 3 is: the melting temperature of the matrix during the preparation of the pellet cores of this comparative example was 110 ℃.
Comparative example 4, a chitosan oligosaccharide enteric-coated dripping pill and preparation method thereof
The chitosan oligosaccharide enteric-coated dripping pill consists of an enteric layer coating and a pill core according to the mass ratio of 8:15.
The enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following components in parts by weight: 100-55 parts of Eudragit L, 16 parts of talcum powder, 6000 parts of polyethylene glycol and 326 parts of ethanol.
The pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following components in parts by weight: chitosan oligosaccharide: matrix = 1:3; the matrix consists of polyethylene glycol 6000 and stearic acid according to a mass ratio of 4:9.
The enteric coating, pellet core and chitosan oligosaccharide enteric drop pellets described in this comparative example were prepared in a similar manner to example 3.
The difference between this comparative example and example 3 is: the melting temperature of the matrix during the preparation of the pellet core of this comparative example was 60 ℃.
Comparative example 5, enteric chitosan oligosaccharide dripping pill and its preparation method
The chitosan oligosaccharide enteric-coated dripping pill consists of an enteric layer coating and a pill core according to the mass ratio of 8:15.
The enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following components in parts by weight: 100-55 parts of Eudragit L, 16 parts of talcum powder, 6000 parts of polyethylene glycol and 326 parts of ethanol.
The pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following components in parts by weight: chitosan oligosaccharide: matrix = 1:3; the matrix consists of polyethylene glycol 6000 and stearic acid according to a mass ratio of 4:9.
The enteric coating, pellet core and chitosan oligosaccharide enteric drop pellets described in this comparative example were prepared in a similar manner to example 3.
The difference between this comparative example and example 3 is: the drop distance in the preparation process of the pill core of the comparative example is 40cm.
Comparative example 6, enteric-coated chitosan oligosaccharide dropping pill and preparation method thereof
The chitosan oligosaccharide enteric-coated dripping pill consists of an enteric layer coating and a pill core according to the mass ratio of 8:15.
The enteric coating in the chitosan oligosaccharide enteric dripping pill comprises the following components in parts by weight: 100-55 parts of Eudragit L, 16 parts of talcum powder, 6000 parts of polyethylene glycol and 326 parts of ethanol.
The pill core in the chitosan oligosaccharide enteric-coated dripping pill comprises the following components in parts by weight: chitosan oligosaccharide: matrix = 1:3; the matrix consists of polyethylene glycol 6000 and stearic acid according to a mass ratio of 4:9.
The enteric coating, pellet core and chitosan oligosaccharide enteric drop pellets described in this comparative example were prepared in a similar manner to example 3.
The difference between this comparative example and example 3 is: the drop distance during the preparation of the pellet core in this comparative example was 10cm.
Test example I, activity test of Chitosan oligosaccharide for improving non-alcoholic fatty liver disease
The test method comprises the following steps: and (3) establishing a model: the experiments of feeding, modeling and administration of mice are carried out in SPF class laboratories with a temperature of 22-26 ℃ and a relative humidity of 55 + -5% and a 12h light and dark cycle time. Use license number: SYXK (Guangdong) 2017-0125. 70C 57BL/6 mice (20-24 g) 7 weeks old were given maintenance feed (NFD) adapted to 1 week of feeding, and all mice were randomly divided into 2 groups: blank 10, given maintenance feed; the module was built up to 60 animals, and high fat Gao Zhetang feed (HFHSD) was administered. After 8 weeks of feeding, the mice were randomly divided into 7 groups: blank (Control), NAFLD Model (Model), examples 1-3, comparative examples 1-2, 10 mice/group. The dosage is as follows: 425mg/kg/d.
Each group of mice test samples were gavaged daily on a weight basis, with the Control group and Model group being gavaged with an equal amount of ultrapure water. After 6 weeks of drug administration intervention, blood is taken by adopting an eyeball blood taking method, and samples such as blood samples, liver, ileum, colon, cecum contents, faeces and the like are reserved and stored at the temperature of minus 80 ℃ for subsequent experiments.
The maintenance feed comprises the following components: 20% of crude protein, 9.7% of water, 4.8% of crude fiber, 4.3% of crude fat, 1.19% of calcium, 0.77% of phosphorus and 6.60% of crude ash, and is purchased from the medical laboratory animal center in Guangdong province; the main source of heat of the high-fat Gao Zhetang feed is as follows: 40% from fat and 17% from sucrose, available from Research diabetes, inc., USA, lot: D1237.
Body weight of mice: during the animal experiments, the mice body weight was weighed weekly and the average value of each group was recorded; the feed residual quantity and feed administration amount of each group of mice are weighed every week to calculate the daily feed intake of each group of mice; the mice were kept in mind and body, and recorded.
Oral glucose tolerance experiments: one week before the end of the experiment, 5 mice per group were randomly selected for the experiment, and the test mice were replaced with clean litter 12 hours in advance and fasted. When the test is carried out, firstly weighing the weight of the mice, then lightly wiping the tail of the mice with a disinfection cotton piece for disinfection, cutting off the tail end by about 0.1cm, dripping blood at the measuring position of the blood glucose test paper for measuring the blood glucose value, and obtaining the blood glucose value at the moment of 0 min; the mice were rapidly perfused with 20% glucose at 2.0g/kg of their body weight, blood glucose levels were measured at 15, 30, 60, 90 and 120min respectively and recorded, and the area under the curve (AUC) was calculated. The calculation formula is as follows: auc=15 min value x 0.25+30min value x 0.5+60min value x 0.75+120min value x 0.5.
Serum and liver index determination: serum index determination: the blood sample was allowed to stand at room temperature for 30min, centrifuged at 3000rpm for 15min at 4℃and the supernatant was taken, the serum TC, TG, HDL-C, LDL-C, FFA, AST, ALT, CAT, T-AOC levels were determined as required by the kit instructions and the serum IL-6, IL-10, TNF- α, insulin and LPS levels were determined using ELISA kits. Liver index measurement: precisely weighing equivalent liver tissue, adding appropriate amount of absolute ethanol and homogenizing steel balls, homogenizing in a homogenizer precooled at-20deg.C, centrifuging at 2500rpm at 4deg.C for 10min, collecting supernatant, and measuring TG and TC content with kit.
The test results are shown in the following table.
TABLE 1 influence of test samples on NAFLD mouse body weight
| Group of | For 1 week | For 2 weeks | 3 weeks | 4 weeks of | For 5 weeks | For 6 weeks |
| Example 1 | 32 | 37 | 42 | 47 | 53 | 59 |
| Example 2 | 34 | 39 | 42 | 48 | 54 | 60 |
| Example 3 | 33 | 37 | 41 | 45 | 51 | 58 |
| Comparative example 1 | 34 | 38 | 43 | 48 | 53 | 60 |
| Comparative example 2 | 33 | 39 | 44 | 49 | 55 | 61 |
| Model group | 28 | 33 | 36 | 40 | 44 | 49 |
| Control group | 34 | 39 | 44 | 50 | 56 | 63 |
TABLE 2 influence of test samples on NAFLD mice feed intake
| Group of | Food intake/g |
| Example 1 | 198.6 |
| Example 2 | 199.3 |
| Example 3 | 199.1 |
| Comparative example 1 | 200.4 |
| Comparative example 2 | 199.7 |
| Model group | 201.3 |
| Control group | 176.5 |
From tables 1 and 2, the body weight and feeding amount of the model group mice were higher than those of the blank group mice, which indicates that the model establishment was successful in this example. Examples 1-3 mice have a body weight and a food intake which are not different from those of the mice in the model group, which shows that the chitosan oligosaccharide enteric-coated dripping pill provided by the invention does not affect the body weight and the food intake of the mice.
TABLE 3 influence of test samples on insulin resistance
As shown in table 3, the chitosan oligosaccharide enteric-coated dripping pill provided by the invention can significantly improve the hyperglycemia level of the mice with HFHSD, and simultaneously improve the high insulin level of the organism induced by HFHSD, which indicates that the chitosan oligosaccharide enteric-coated dripping pill provided by the invention can improve the hyperglycemia level by improving the insulin resistance of the organism. Among them, the mice in the group of example 3 had the lowest AUC and blood glucose and moderate insulin content, which is the best example of the present invention.
Compared with the example 3, the comparative examples 1 and 2 change the dosage ratio of the matrix in the pill core, but the AUC, blood sugar and insulin content of the mice in the corresponding group are all increased, which fully demonstrates that the chitosan oligosaccharide enteric-coated dripping pill core matrix provided by the invention can effectively improve the dispersibility of the drug in the small intestine and enhance the absorption rate of the base drug.
TABLE 4 Effect of test samples on NAFLD mice blood lipid
As shown in table 4, the chitosan oligosaccharide enteric-coated dripping pill provided by the invention can significantly improve serum triglyceride and serum total cholesterol level of the HFHSD mice, reduce serum low density lipoprotein cholesterol and free fatty acid of the HFHSD mice and improve serum high density lipoprotein cholesterol, which fully demonstrates that the chitosan oligosaccharide enteric-coated dripping pill provided by the invention can improve lipid metabolism abnormality caused by HFHSD diet.
TABLE 5 Effect of test samples on liver function in NAFLD mice
As can be seen from Table 5, the serum glutamic-oxaloacetic transaminase content and serum glutamic-pyruvic transaminase level of mice in the model group are significantly increased relative to those in the blank group, which indicates that long-term feeding with high-fat and high-sucrose feed has resulted in some degree of liver function impairment in mice. The serum glutamic-oxaloacetic transaminase content and serum glutamic-pyruvic transaminase content of the mice in the groups of examples 1-3 are obviously reduced, which fully shows that the chitosan oligosaccharide enteric-coated dripping pill can improve liver function index abnormality caused by high fat and high sucrose to a certain extent.
TABLE 6 influence of test samples on NAFLD mouse serum antioxidant function
| Group of | Serum catalase/U/L | Serum Total Oxidation Capacity/U/mg. Prot |
| Example 1 | 49.89 | 0.47 |
| Example 2 | 50.15 | 0.46 |
| Example 3 | 50.35 | 0.47 |
| Comparative example 1 | 40.16 | 0.40 |
| Comparative example 2 | 45.35 | 0.43 |
| Model group | 30.92 | 0.38 |
| Control group | 56.77 | 0.49 |
As can be seen from table 6, the feeding of the high-fat high-sucrose feed can significantly reduce the serum antioxidant function index catalase and the total antioxidant capacity, while the chitosan oligosaccharide enteric-coated dripping pill can improve the serum catalase and the serum total antioxidant capacity level of the non-alcoholic fatty liver mice to a certain extent, which indicates that the chitosan oligosaccharide enteric-coated dripping pill can enhance the antioxidant function of the non-alcoholic fatty liver mice.
TABLE 7 Effect of test samples on NAFLD mouse serum inflammatory factors
As can be seen from Table 7, the serum levels of TNF-alpha and IL-6 in mice in the model group were significantly increased relative to that in the blank group, indicating that prolonged feeding with the high-fat and high-sucrose feed caused systemic inflammatory responses in mice. The experiment shows that the enteric-coated chitosan oligosaccharide dropping pill provided by the invention can promote the release of anti-inflammatory factors and finally achieve the purpose of reducing inflammation, namely, the enteric-coated chitosan oligosaccharide dropping pill has a certain capability of improving the inflammation of the non-alcoholic fatty liver mice.
Test example II, quality test of chitosan oligosaccharide enteric-coated dripping pill
Test sample: the chitosan oligosaccharide enteric-coated dripping pills prepared in examples 1-3 and comparative examples 3-6;
the test method comprises the following steps: taking a test sample, and observing whether the dripping pill is glossy, uniform and round or not;
and (3) dissolving time limit: measuring under the rule 0108 pill item of four preparations of Chinese pharmacopoeia of 2020 edition, taking 6 pills of the test sample, selecting a screen with the aperture of 2.00mm, and placing in a disintegration time apparatus. Checking in artificial gastric juice for 2 hours, and preventing cracking, disintegration or softening. Taking out the hanging basket, adding a small amount of ultrapure water for rinsing, respectively placing 1 baffle plate, and checking in artificial intestinal juice according to the above method, wherein all the materials should be dissolved within 1 h.
The test results are shown in the following table.
Table 8 appearance of enteric-coated chitosan oligosaccharide dropping pill
| Group of | Appearance of |
| Example 1 | Gloss, uniformity and rounding |
| Example 2 | Gloss, uniformity and rounding |
| Example 3 | Gloss, uniformity and rounding |
| Comparative example 3 | Gloss, unevenness, tailing |
| Comparative example 4 | Gloss, unevenness, tailing |
| Comparative example 5 | Uneven, tailing and holes on the surface of dripping pill |
| Comparative example 6 | Uneven and severe tailing |
As can be seen from Table 8, the enteric-coated chitosan oligosaccharide dropping pill provided by the invention is a round-like pill with uniform gloss, the melting temperature of the pill core matrix is changed in comparative examples 3-4, the dropping distance of the pill core is changed in comparative examples 5-6, but the prepared enteric-coated chitosan oligosaccharide dropping pill has poor roundness, which indicates that the melting temperature and dropping distance of the pill core provided by the invention are optimized.
Table 9 bulk time limit test
| Group of | Time limit/min of bulk |
| Example 1 | 9.52 |
| Example 2 | 9.64 |
| Example 3 | 9.49 |
| Comparative example 3 | 9.79 |
| Comparative example 4 | 10.01 |
| Comparative example 5 | 9.81 |
| Comparative example 6 | 9.92 |
As shown in Table 9, the dispersion time limit of the chitosan oligosaccharide enteric-coated dripping pill provided by the invention is within 10min, and meets the specification of Chinese pharmacopoeia 2020.
The above examples are only illustrative of the preparation method of the present invention and are not intended to limit the present invention. The above-described embodiments may be modified by those skilled in the art without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications and changes which are accomplished by those skilled in the art without departing from the technical spirit provided by the present invention are intended to be covered by the claims of the present invention.
Claims (6)
1. The chitosan oligosaccharide enteric-coated dripping pill is characterized by comprising an enteric coating layer and a pill core according to the mass ratio of 6-10:13-17;
the enteric coating comprises the following components in parts by weight: 100-55-40 parts of Eudragit L, 10-20 parts of talcum powder, 2-4 parts of polyethylene glycol 6000 and 218-436 parts of ethanol; the pill core consists of chitosan oligosaccharide and a matrix according to the mass ratio of 1:2-4; the matrix consists of polyethylene glycol 6000 and stearic acid according to the mass ratio of 3-5:7-11.
2. The chitosan oligosaccharide enteric-coated dripping pill according to claim 1, wherein the enteric-coated preparation method comprises the following steps: weighing Eudragit L100-55 in the formula amount, slowly adding into 95% ethanol which is uniformly mixed with talcum powder and polyethylene glycol 6000 in advance, preparing suspension with the mass fraction of L100-55 being 8%, and sieving with 80 mesh sieve to obtain the final product.
3. The chitosan oligosaccharide enteric-coated dripping pill according to claim 1, wherein the preparation method of the pill core is as follows: taking a proper amount of matrix, placing into a beaker, heating in water bath, magnetically stirring until the matrix is sufficiently melted, slowly adding chitosan oligosaccharide while stirring, fully and uniformly mixing, placing into a self-made dripping pill device, dripping into liquid paraffin condensing medium precooled to 5-10 ℃ under the conditions that the dripping distance is 15-30cm and the dripping speed is 25-30 drops/min, condensing and solidifying, removing the condensing medium by centrifugation after forming dripping pills, drying and sealing for storage.
4. The chitosan oligosaccharide enteric-coated dripping pill according to claim 3, wherein the melting temperature of the pill core is 80-90 ℃ in the preparation process.
5. The preparation method of the chitosan oligosaccharide enteric-coated dripping pill according to any one of claims 1-4, which is characterized by comprising the following steps: placing the pill core into a high-efficiency coating machine, setting the rotating speed of the coating machine at 22-27rpm, the air inlet temperature at 40-50 ℃, the air outlet temperature at 25-30 ℃, the material temperature at 25-30 ℃, preheating for 15min, then coating, spraying the enteric coating layer coating liquid into a spray gun with the atomization pressure value of 0.11-0.13Mpa, taking out when the coating weight reaches 20% of the weight of the pill core, placing into a blast oven, and drying at 30 ℃ for 1h to obtain the product.
6. The use of the chitosan oligosaccharide enteric-coated dripping pill according to claim 1 in preparing a medicament for treating non-alcoholic fatty liver disease.
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| PCT/CN2022/130815 WO2023138173A1 (en) | 2022-01-18 | 2022-11-09 | Chitosan oligosaccharide enteric dripping pill and application thereof in preparing non-alcoholic fatty liver disease drug |
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| 壳寡糖、氨基葡萄糖减肥活性及载辣椒碱壳聚糖微球肠溶片的研究;陈健;《中国优秀硕士学位论文全文数据库（电子期刊） 医药卫生科技辑》(第3期);摘要，第46页第1-2段 * |
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