LU500771B1 - Composition for preventing and treating alcoholic liver injury and preparation method and application thereof - Google Patents

Composition for preventing and treating alcoholic liver injury and preparation method and application thereof Download PDF

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LU500771B1
LU500771B1 LU500771A LU500771A LU500771B1 LU 500771 B1 LU500771 B1 LU 500771B1 LU 500771 A LU500771 A LU 500771A LU 500771 A LU500771 A LU 500771A LU 500771 B1 LU500771 B1 LU 500771B1
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composition
parts
preventing
liver injury
alcoholic liver
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LU500771A
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German (de)
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Sitong Lu
Lingyu Zhang
Songzhi Kong
Zhaoyu Zhang
Pengzhi Hong
Yu Cheng
Mingneng Liao
Zhang Hu
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Univ Guangdong Ocean
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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Abstract

The invention discloses a composition for preventing and treating alcoholic liver injury and a preparation method and application thereof, belonging to the technical field of biomedicine. The composition comprises the following components in parts by weight: 10-30 parts of seaweed polyphenol, 2-6 parts of sodium alginate, 30-55 parts of abalone peptide and 0.5-3 parts of spermidine. The invention has good product stability, safe and non-toxic, with significant liver-protective effect on alcoholic liver injury, simple process, easy to industrialize production.

Description

DESCRIPTION Composition for preventing and treating alcoholic liver injury and preparation method and application thereof
TECHNICAL FIELD The invention relates to the technical field of biomedicine, in particular to a composition for preventing and treating alcoholic liver injury and a preparation method and application thereof.
BACKGROUND Wine is one of the main beverages in human life. Moderate drinking has the effects of promoting blood circulation, dredging channels and collaterals, invigorating qi and nourishing stomach, relieving pain and stopping dampness. However, with the development of economy and the increase of social activities, the proportion of people who like drinking 1s increasing, and the diseases and problems caused by alcohol are becoming more and more serious. Excessive drinking for a long time will cause chronic alcoholism, lead to alcoholic liver disease, cause pathological changes such as myocardial fatigue, mucosal injury, brittle blood vessels, renal failure, etc, and also cause physiological dysfunction and endanger human health.
After entering the human body, alcohol 1s firstly converted into acetaldehyde under the action of alcohol dehydrogenase, and then further oxidized into acetic acid and water by acetaldehyde dehydrogenase, and finally enters the tricarboxylic acid circulation system. When the body ingests a large amount of alcohol, alcohol itself will not cause harm to the body, but acetaldehyde and free radicals such as superoxide anion groups and highly active hydroxyl radicals formed in the metabolic process can cause adverse effects on the body. Acetaldehyde can combine with various proteins in cells to accumulate a large amount of protein and lipid in liver cells, which eventually leads to cytopathic necrosis, inflammatory reaction, and alcoholic hepatitis. Acetaldehyde can also inhibit DNA repair and methylation, induce activation of hepatic stellate cells by transforming growth factors, promote inflammation and destroy tissue regeneration and repair functions, and further promote pathological changes of liver fibrosis. The pathogenesis of alcoholic liver injury is complex. Modern pathological studies have found that the
"second strike" theory is oxidative stress and inflammatory reaction, among which oxidative stress is the key factor for the occurrence and development of alcoholic liver injury. Therefore, it has a certain market value to prepare a product that can quickly remove a large number of free radicals produced by the body after drinking, and further reduce the side effects of alcohol on the human body.
In the prior art, various substances for preventing and treating alcoholic liver injury are disclosed, for example, Chinese patent CN 202010728038.6 discloses a composition of Panax quiquefolium L. and Hovenia dulcis Thunb for preventing and treating alcoholic liver injury, which can protect alcoholic liver injury by improving lipid metabolism and enhancing oxidation resistance. Chinese patent CN 201210046322.0 discloses a lactobacillus rhamnosus capable of relieving chronic alcoholic liver injury, which has the functions of resisting oxidation and relieving chronic alcoholic liver injury. Chinese patent CN 201811162358.9 discloses a polypeptide for preventing and treating alcoholic liver injury, which is mainly composed of polypeptides with antioxidant and hepatoprotective activities. Chinese patent CN 201811339367.0 discloses demethyltetrahydroberberine hydrochloride for preventing and treating alcoholic liver injury, which mainly treats alcoholic liver disease through anti-inflammatory and antioxidant activities. Most of these products prevent and treat alcoholic liver injury through an antioxidant pathway, but antioxidants are unstable, which can not completely ensure the antioxidant activity of active ingredients in vivo, and can not quickly remove excessive free radicals in vivo, resulting in slow response.
SUMMARY The purpose of the invention is to provide a composition for preventing and treating alcoholic liver injury and a preparation method and application thereof, so as to solve the problems of unstable antioxidant active substances and single action path in the existing products for preventing and treating alcoholic liver injury in the prior art. The composition has simple formula, good stability, strong oxidation resistance and good liver protection effect.
To achieve the above purpose, the present invention provides the following scheme: The invention provides a composition for preventing and treating alcoholic liver injury, which comprises the following components in parts by weight: 10-30 parts of seaweed polyphenol, 2-6 parts of sodium alginate, 30-55 parts of abalone peptide and
0.5-3 parts of spermidine.
Furthermore, the composition comprises the following components in parts by weight: 20 parts of seaweed polyphenol, 4 parts of sodium alginate, 40 parts of abalone peptide and 1.5 parts of spermidine.
The invention also provides a preparation method of the composition for preventing and treating alcoholic liver injury, which comprises the following steps: S1, adding sodium alginate into water to prepare a sodium alginate solution, adjusting the pH value of the solution to 6.0-7.5, adding spermidine, stirring at room temperature for 5-8 hours, treating in an ice-water bath, cooling the solution system to 5- 10°C, adding seaweed polyphenol, continuing stirring for 1-3 hours, freeze-drying, and crushing with liquid nitrogen to obtain seaweed polyphenol composite powder; S2, dissolving abalone peptide with water to prepare abalone peptide solution, adding the seaweed polyphenol composite powder while stirring, uniformly suspending, and freeze-drying to obtain the composition for preventing and treating alcoholic liver injury.
Furthermore, the mass concentration of the sodium alginate solution is 1-3.5%; The mass concentration of the abalone peptide solution 1s 18-26%.
Further, the pH of the sodium alginate solution is adjusted to 6.5.
The invention also provides an application of the composition in preparing drugs for treating/preventing alcoholic liver injury.
The invention also provides a pharmaceutical preparation for preventing and treating alcoholic liver injury, which comprises the composition and pharmaceutically acceptable auxiliary materials.
Furthermore, the pharmaceutical preparation is a capsule, and the auxiliary materials include lactose, corn starch, and talcum powder; The mass fraction of each component in the capsule is as follows: 10-30wt% of the composition, 10-20wt% of lactose, 50-60wt% of corn starch and 5- 15wt% of talcum powder.
Furthermore, the pharmaceutical preparation is a tablet, and the auxiliary materials include corn starch, talcum powder and magnesium stearate;
The mass fraction of each component in the tablet 1s as follows: 10-20wt% of the composition, 65-75wt% of corn starch, 11-17wt% of talcum powder and 0.5-2wt% of magnesium stearate.
Furthermore, the pharmaceutical preparation is granule, and the auxiliary materials include corn starch, sodium hydroxymethyl cellulose and magnesium stearate.
The mass fraction of each component in the granules is as follows: 5-15wt% of the composition, 74-84wt% of corn starch, 5-15wt% of sodium hydroxymethyl cellulose and 0.5-2wt% of magnesium stearate.
The invention discloses the following technical effect: (1) The invention combines seaweed polyphenol with antioxidant and antibacterial functions with abalone peptide rich in various nutrients and multiple biological effects, and forms a composition by multiple actions such as hydrogen bonding, static electricity, T-7 stacking, and so on; Animal model tests prove that the composition plays a multi- approach, multi-target and synergistic role in the prevention and treatment of alcoholic liver injury.
(2) According to the invention, the hydrogel characteristics of alginate are utilized, alginate colloid is formed in the low pH environment in the stomach, and the composite of seaweed polyphenol and abalone peptide is wrapped, so that the loss of bioactivity of seaweed polyphenol and abalone peptide in the complex environment in vivo is avoided, Alginic acid is converted into an ionic salt state in the intestinal tract, and algae polyphenol and abalone peptide are released slowly and controlled, so as to exert a lasting active effect.
(3) The spermidine added in the invention is respectively connected with alginate and seaweed polyphenol by utilizing its "triamine" characteristics, so as to form an "umbrella" protection structure for seaweed polyphenol, which improves the stability, physical properties and taste of seaweed polyphenol, and is beneficial to play the role of protecting liver in alcoholic liver injury.
(4) The raw materials of the invention all come from natural food materials, which are green and safe; Simple preparation process and easy industrial production; And it is safe, non-toxic, convenient to take, free of bad smell and good in compliance.
BRIEF DESCRIPTION OF THE FIGURES To explain the embodiments of the present invention or the technical scheme in the prior art more clearly, the following will briefly introduce the drawings used in the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention, and for ordinary technicians in the field, other drawings can be obtained according to these drawings without paying creative labor.
Fig. 1 shows the DPPH radical scavenging ability of the composition for preventing and treating alcoholic liver injury prepared by the present invention.
Fig. 2 shows the scavenging ability of the composition for preventing and treating alcoholic liver injury prepared by the present invention on OH radical.
Fig. 3 shows the antioxidant stability of the composition for preventing and treating alcoholic liver injury prepared by the present invention.
Fig. 4 is the effect of the composition for preventing and treating alcoholic liver injury prepared by the present invention on the liver index of mice.
Fig. 5 is the effect of the composition for preventing and treating alcoholic liver injury prepared by the present invention on pathological sections of mouse liver.
DESCRIPTION OF THE INVENTION Now, various exemplary embodiments of the present invention will be described in detail. This detailed description should not be regarded as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention.
It should be understood that the terms described in the present invention are only for describing specific embodiments, and are not intended to limit the present invention. In addition, as for the numerical range in the present invention, it should be understood that every intermediate value between the upper limit and the lower limit of the range is also specifically disclosed. Intermediate values within any stated value or stated range and every smaller range between any other stated value or intermediate values within the stated range are also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded from the range.
Unless otherwise stated, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which this invention relates. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe methods and/or materials related to the documents. In case of conflict with any incorporated documents, the contents of this specification shall prevail.
Without departing from the scope or spirit of the invention, it is obvious to those skilled in the art that many modifications and changes can be made to the specific embodiments of the specification of the invention. Other embodiments derived from the description of the present invention will be apparent to the skilled person. The specification and examples of this application are only exemplary.
As used herein, "including", "comprising", "having", "containing", etc. are all open terms, which means including but not limited to.
As one aspect of the present invention, this embodiment aims to provide a composition for preventing and treating alcoholic liver injury, which comprises the following components in parts by weight: 10-30 parts of seaweed polyphenol, 2-6 parts of sodium alginate, 30-55 parts of abalone peptide and 0.5-3 parts of spermidine.
Among them, seaweed polyphenols are polyphenols extracted from seaweed, the main component is phloroglucinol and its derivatives, and its hydroxyl group is an important group with antioxidant activity. Seaweed polyphenols are considered as natural antioxidants to prevent or reduce chronic diseases because of their ability to directly or indirectly scavenge free radicals and reactive oxygen species. However, polyphenols have poor stability and low bioavailability in vivo.
Sodium alginate is a kind of biopolymer material extracted from the ocean, which has the advantages of biocompatibility, hydrophilicity and non-toxicity. It can form hydrogels by ionization under mild conditions. Alginate hydrogels are usually prepared by physical crosslinking, chemical crosslinking and enzyme crosslinking, which are widely used in the controlled release system of pharmaceutical active peptides and protein.
Abalone peptide is made from abalone meat by enzymolysis, and its amino acids are complete in variety and reasonable in proportion, so it is known as "soft gold" in the ocean. Abalone 1s rich in nutrients such as EPA, DHA, trace elements, taurine and superoxide dismutase, which has the functions of resisting oxidation, enhancing immunity and resisting fatigue.
Spermine 1s a natural polyamine, which 1s a safe and efficient inducer of autophagy. It exists in almost all cells and has anti-aging, anti-cancer, cardiovascular and nerve protection functions. Spermine is beneficial to assist drug delivery, improve the water solubility, stability and membrane permeability of drug molecules, and further improve drug absorption in organisms.
According to the invention, alginate and spermidine are blended with seaweed polyphenol with antioxidant and antibacterial functions to prepare seaweed polyphenol particles. The spermidine molecule contains three amino groups, and the amino groups at both ends and in the middle can be connected with sodium alginate and seaweed polyphenol respectively, which forms an umbrella-shaped protective structure for seaweed polyphenol and improves the stability of the product. Algae polyphenol particles and abalone peptides rich in various nutrients and multiple functions form a compound composition through multiple noncovalent interactions such as hydrogen bonding, static electricity, m-m stacking, etc, which has a synergistic effect on the prevention and treatment of alcoholic liver injury through multiple channels and multiple targets. When the composition enters the stomach, the sodium alginate forms an alginic acid colloid under the action of gastric acid, which wraps the seaweed polyphenol and abalone peptide to avoid the loss of activity in a complex environment in vivo. Alginic acid 1s converted into an ionic salt state in the intestinal tract, which can continuously release algae polyphenol and abalone peptide, exert lasting activity and improve its bioavailability.
As a preferred embodiment, the composition for preventing and treating alcoholic liver injury comprises the following components in parts by weight: 20 parts of seaweed polyphenol, 4 parts of sodium alginate, 40 parts of abalone peptide and 1.5 parts of spermidine.
Preferably, that seaweed polyphenol is derived from edible large seaweed including kelp, thallu laminariae, Sargassum, Gracilaria lemaneiformis, Sargassum fusiforme, Undaria pinnatifida or Gracilaria lemaneiformis. The extraction method of seaweed polyphenols can be carried out according to the conventional extraction method of seaweed polyphenols in the field. Further, preferably, the total phenol content in the seaweed polyphenols adopted in the embodiments of the present invention is not less than 30% by weight.
Preferably, that abalone peptide is a compound peptide prepare by adopting abalone meat through biological enzymolysis. The enzymolysis method of the abalone peptide can be carried out according to the conventional method in the field. Further, preferably, the molecular weight distribution range of abalone peptides used in the embodiments of the present invention is: 2.15% of polypeptide with molecular weight > 3.0 kDa, 16.59% of polypeptide with molecular weight of 1.0~3.0 kDa, and 81.26% of polypeptide with molecular weight < 1.0 kDa.
As another embodiment, the seaweed polyphenol can also be purchased from Shandong Jiejing Group Co., Ltd., and the abalone peptide can also be purchased from Shandong Donghai Longyuan Biotechnology Co., Ltd..
As another aspect of the present invention, this embodiment also provides a preparation method of the composition for preventing and treating alcoholic liver injury, which comprises the following steps: S1, adding sodium alginate into water to prepare a sodium alginate solution, adjusting the pH value of the solution to 6.0-7.5, adding spermidine, stirring at room temperature for 5-8 hours, treating in an ice-water bath, cooling the solution system to 5- 10°C, adding seaweed polyphenol, continuing stirring for 1-3 hours, freeze-drying, and crushing with liquid nitrogen to obtain seaweed polyphenol composite powder; S2, dissolving abalone peptide with water to prepare abalone peptide solution, adding the seaweed polyphenol composite powder while stirring, uniformly suspending, and freeze-drying to obtain the composition for preventing and treating alcoholic liver injury.
In the preparation process of the composition for preventing and treating alcoholic liver injury, the concentration of sodium alginate solution and abalone peptide solution has an important influence on the stability and synergistic effect of the composition.
As a preferred embodiment, the mass concentration of the sodium alginate solution is 1%-3.5%, more preferably 1.5%; If the mass concentration of sodium alginate solution is too high (> 3.5%), it is easy to agglomerate, and it is difficult to form uniform algal polyphenol particles, resulting in poor efficacy. If the mass concentration of sodium alginate solution is too small (< 1%), the interaction with spermidine is weak, and the protective effect on seaweed polyphenols cannot be achieved.
As a preferred embodiment, the mass concentration of the abalone peptide solution is 18%-26%, more preferably 22%; If the mass concentration of abalone peptide solution is too high (> 26%), it 1s susceptible to microbial infection and loses its activity. If the mass concentration of abalone peptide solution is too small (< 18%), the synergistic effect between abalone peptide solution and seaweed polyphenols will be weakened, and the effect of preventing and treating alcoholic liver injury will not be achieved.
As a preferred embodiment, in S1, it is necessary to strictly control the pH range of the solution. The method for adjusting the pH of the invention is a conventional method, and because the sodium alginate solution is weakly alkaline, 0.1mol/L HCI solution is adopted for adjusting the pH of the invention. If the pH of the solution is too small (<
6.0), the acidity is too strong, and sodium alginate forms alginate colloid and precipitates. If the pH of the solution is too high (> 7.5), it is difficult for spermidine to form a compound umbrella structure with sodium alginate and algal polyphenols by electrostatic action. Therefore, in this embodiment, the pH of the sodium alginate solution is preferably 6.0-7.5, and more preferably 6.5.
As an illustration, the room temperature referred to in the present invention also becomes normal temperature or general temperature, which is generally defined as 25°C, which can be reasonably adjusted by a person skilled in the art, and which is also within the protection scope of the present invention.
In order to further illustrate the present invention, the compositions for preventing and treating alcoholic liver injury provided by the present invention are described in detail with examples below, but they cannot be understood as limiting the scope of protection of the present invention.
Example 1 A composition for preventing and treating alcoholic liver injury comprises the following components in parts by weight: 20 parts of seaweed polyphenol, 4 parts of sodium alginate, 40 parts of abalone peptide and 1.5 parts of spermidine.
The preparation method of the composition comprises the following steps: S1, adding sodium alginate into distilled water to prepare a 1.5wt% sodium alginate solution, adjusting the pH of the solution to 6.5, adding spermidine, stirring at room temperature for 6.5 hours, treating in an 1ce-water bath, cooling the solution system to 8°C, adding seaweed polyphenols, continuing stirring for 2 hours, freeze-drying, and crushing with liquid nitrogen to obtain seaweed polyphenol composite powder; S2, dissolving abalone peptide in distilled water according to the parts by weight to prepare 22wt% abalone peptide solution, adding the seaweed polyphenol composite powder in S1 while stirring, uniformly suspending, and freeze-drying to obtain the composition.
Example 2 A composition for preventing and treating alcoholic liver injury comprises the following components in parts by weight: 15 parts of seaweed polyphenol, 3 parts of sodium alginate, 35 parts of abalone peptide and 1 part of spermidine.
The preparation method of the composition comprises the following steps: S1, adding sodium alginate into distilled water to prepare 2.0wt% sodium alginate solution, adjusting the pH of the solution to 7.0, adding spermidine, stirring at room temperature for 7 hours, treating in an ice-water bath, cooling the solution system to 6°C, adding seaweed polyphenols, continuing stirring for 1.5 hours, freeze-drying, and crushing with liquid nitrogen to obtain seaweed polyphenol composite powder; S2, dissolving abalone peptide in distilled water according to the parts by weight to prepare 24wt% abalone peptide solution, adding the seaweed polyphenol composite powder in S1 while stirring, uniformly suspending, and freeze-drying to obtain the composition.
Example 3 A composition for preventing and treating alcoholic liver injury comprises the following components in parts by weight: 10 parts of seaweed polyphenol, 2 parts of sodium alginate, 30 parts of abalone peptide and 0.5 part of spermidine.
The preparation method of the composition comprises the following steps: S1, adding sodium alginate into distilled water according to the parts by weight to prepare a 1wt% sodium alginate solution, adjusting the pH value of the solution to 6.0,
adding spermidine, stirring for 5 hours at room temperature, treating in an ice-water bath, cooling the solution system to 5°C, adding seaweed polyphenol, continuing stirring for 1 hour, freeze-drying, and crushing with liquid nitrogen to obtain seaweed polyphenol composite powder; S2, dissolving abalone peptide in distilled water according to the parts by weight to prepare 18wt% abalone peptide solution, adding the seaweed polyphenol composite powder in S1 while stirring, uniformly suspending, and freeze-drying to obtain the composition.
Example 4 A composition for preventing and treating alcoholic liver injury comprises the following components in parts by weight: 30 parts of seaweed polyphenol, 6 parts of sodium alginate, 55 parts of abalone peptide and 3 parts of spermidine.
The preparation method of the composition comprises the following steps: S1, adding sodium alginate into distilled water to prepare a 3.5wt% sodium alginate solution, adjusting the pH value of the solution to 7.5, adding spermidine, stirring for 8 hours at room temperature, treating in an ice-water bath, cooling the solution system to 10°C, adding seaweed polyphenol, continuing stirring for 3 hours, freeze-drying, and crushing with liquid nitrogen to obtain seaweed polyphenol composite powder; S2, dissolving abalone peptide in distilled water according to the parts by weight to prepare 26wt% abalone peptide solution, adding the seaweed polyphenol composite powder in S1 while stirring, uniformly suspending, and freeze-drying to obtain the composition.
Comparative example 1 The only difference from Example 1 is that vitamin C is used instead of seaweed polyphenols.
Comparative example 2 The only difference from Example 1 is that spermine is used instead of spermidine.
Comparative example 3 Different from Example 1, only the direct raw material blending is as follows:
A composition for preventing and treating alcoholic liver injury comprises the following components in parts by weight: 20 parts of seaweed polyphenol, 4 parts of sodium alginate, 40 parts of abalone peptide and 1.5 parts of spermidine.
The preparation method of the composition comprises the following steps: According to the parts by weight, the raw materials of sodium alginate, spermidine, seaweed polyphenol and abalone peptide are added with distilled water, uniformly suspended, and freeze-dried to obtain the composition.
Comparative example 4 The only difference from Example 1 1s that oyster peptide 1s used instead of abalone peptide.
Application example 1 Anti-oxidation experiment of the composition for preventing and treating alcoholic liver injury
1. Experimental method.
(1) Determination of radical scavenging ability of 1,1-diphenyl -2- trinitrophenylhydrazine (DPPH).
2.0 mL of sample solutions with different mass concentrations (the compositions prepared in Examples 1-4 and Comparative Examples 1-4) were mixed with 2mL DPPH absolute ethyl alcohol solution, and the solution was kept away from light for 60 min at room temperature, and then the absorbance of the solution was measured at 517nm. Using distilled water instead of sample solution as blank control, calculate the scavenging rate of DPPH radical according to the following formula (1), and express the scavenging effect by 1. experimental method.
(1) Determination of radical scavenging ability of 1,1-diphenyl -2- trinitrophenylhydrazine (DPPH).
2.0 mL of sample solutions with different mass concentrations (the compositions prepared in Examples 1-4 and Comparative Examples 1-4) were mixed with 2 mL DPPH absolute ethyl alcohol solution, and the solution was kept away from light for 60 min at room temperature, and then the absorbance of the solution was measured at 517 nm. Using distilled water instead of sample solution as blank control, calculate the scavenging rate of DPPH radical according to the following formula (1), and express the scavenging effect by ICso.
Clearance rate (%) = Am x 100 Xo Wherein Ay is the absorbance of the sample and A,, is the absorbance of the blank control.
(2) Determination of hydroxyl radical scavenging ability Add 1 mL H,O; solution (8.8 mmol/L), 1 mL FeSO4 solution (9 mmol/L) and 12 mL sample solutions with different mass concentrations (the compositions prepared in Examples 1-4 and Comparative Examples 1-4) into the same colorimetric tube, and then add 1 mL salicylic acid ethanol solution (9 mmol/L), shake well, and place in a water bath at 37°C for 30 min. Use distilled water instead of sample solution as blank control. The hydroxyl radical scavenging rate was calculated according to formula (1), and the scavenging effect was expressed by ICso.
2. Experimental results.
(1)DPPH radical scavenging effect.
The smaller the ICs0 value, the stronger the ability to scavenge free radicals. Vitamin C(Vc) is a strong antioxidant and serves as a positive control. The DPPH radical scavenging effect of the composition for preventing and treating alcoholic liver injury is shown in Figure 1. The ICso of Examples 1-4 are close to that of vitamin C group, showing a strong DPPH radical-scavenging effect, especially the DPPH radical scavenging ability of Example 1 is the strongest. Although the group of Comparative Example 1 also showed a DPPH radical scavenging effect close to that of the groups of Examples 1-4, the DPPH radical scavenging ability of the groups of Comparative Example 2-4 was far less than that of the groups of Examples 1-4.
(2) Hydroxyl radical scavenging effect.
Vitamin C(Vc) is a strong antioxidant and serves as a positive control. The hydroxyl radical scavenging effect of the composition for preventing and treating alcoholic liver injury is shown in Fig. 2. the ICso of examples 1-4 is almost close to that of vitamin C group, showing a strong hydroxyl radical-scavenging effect, especially the hydroxyl radical scavenging ability of example 1 is the strongest. Although the group of Comparative Example 1 also showed a hydroxyl radical scavenging effect close to that of the groups of Examples 1-4, the hydroxyl radical scavenging ability of the groups of Comparative Example 2-4 was far less than that of the groups of Examples 1-4.
According to the above two experimental results, the groups of Examples 1-4 showed strong free radical scavenging effects, which indicated that the composition for preventing and treating alcoholic liver injury prepared by the present invention had strong antioxidant activity, especially the group of Example 1 had the strongest antioxidant activity. The formula or preparation method of the composition of the invention is changed, and the expected antioxidant effect cannot be achieved.
Application example 2 Experiment on antioxidant stability of composition for preventing and treating alcoholic liver injury The total antioxidant capacity of the composition during storage is detected by iron ion reduction / antioxidant capacity method (FRAP method).
Sample storage: store the samples in brown bottles at room temperature. Samples are taken at regular intervals to test the total antioxidant capacity.
Test method: take 0.02ml FeSO4 solution, add 0.18ml FRAP solution (prepared and used now), mix well, water bath at 37 °C for 10min, and measure the absorbance value at 593nm with an Ultraviolet-visible spectrophotometer. The FeSO4 equivalent standard curve was established with the FeSO4 solution concentration as the abscissa and the absorbance value as the ordinate. With Vc solution as the positive control, FeSO4 equivalent was calculated according to the standard curve. The relative percentage of Vc of each sample 1s calculated according to FeSO4 equivalent.
The antioxidant stability results of the composition for preventing and treating alcoholic liver injury are shown in Figure 3. Due to the instability of polyphenol properties, polyphenols are easy to be oxidized and easily deteriorate during long-term storage. The total antioxidant capacity of the composition of Comparative Example 3 almost linearly decreases during storage, while the total antioxidant capacity of the composition of Example 1 almost keeps stable with the extension of storage time within 5 days in the same environment. Therefore, the formula and preparation method of the composition can effectively improve the antioxidant stability of the composition.
Application example 3 Determination of liver protection efficacy of the composition for preventing and treating alcoholic liver injury
1. Experimental method Experimental animals: Kunming male mice, aged 6-8 weeks, weighing 18-22g, SPF grade, with the feeding conditions of (25£1)°C and relative humidity of (55£5)%.
Experiment: 132 mice were randomly divided into 11 groups, with 12 mice in each group, which are divided into blank control group, model group, silymarin positive control group, examples 1-4 groups and comparative examples 1-4 groups.
The mice in each group were given a dose of 10 g/kg: BW (body weight) every day, while the blank control group and the model group are given distilled water for 6 consecutive days. On the sixth day, they began to fast and keep water for 24 hours. After 24 h, the subjects were given continuously, and after 60 min, mice in each group are given 56% Red Star Erguotou liquor, while the blank control group 1s given distilled water, and samples are collected after 60 min.
(1) Taking blood from eyeball, standing till stratification, freezing and centrifuging at 1000 rpm and 4°C for 15 min to take the serum, and measuring the contents of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mouse serum by speed method with an automatic biochemical analyzer.
(2) After the mouse is dissected, take out the liver, wash away the blood on the surface with precooled normal saline, suck it dry with filter paper and quickly weigh fit, and calculate the liver index with the formula: Liver index (%) = liver weight (g)/ body weight (g) X 100%.
(3) Rapidly dissect the liver, fix the left lobe of the liver in 4% paraformaldehyde, gradually dehydrate it with gradient ethanol, make it transparent in xylene, embed it in paraffin, slice it, stain it with hematoxylin and eosin (HE), and observe it with an ordinary optical microscope.
(4) Rapidly dissect the liver, store it at -80°C, prepare 10% liver homogenate, and strictly operate according to the requirements of the corresponding kit, and measure the contents of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the liver homogenate.
(5) The liver was dissected quickly and stored at -80°C to prepare 10% liver homogenate, and the contents of catalase (CAT), superoxide dismutase (SOD),
glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in antioxidant system were determined according to the requirements of corresponding kits.
2. Experimental results (1) Liver index The liver index is of certain significance to the assessment of the health status of the liver. The changes of the liver index of mice taking the composition for preventing and treating alcoholic liver injury are shown in Figure 4. When the liver index increases, it is likely that the liver is enlarged, with hyperplasia, congestion, edema and other diseases. After modeling, the liver index of the model group increased significantly, which was significantly different from that of the blank control group (P < 0.01), indicating the success of modeling. Compared with the model group, the liver index of mice in groups Examples 1-4 decreased significantly, with statistical differences (P < 0.01), and the effect of Example 1 was better, which was almost close to the level of the blank control group, indicating that the composition for preventing and treating alcoholic liver injury prepared by the invention can effectively improve the liver index, reduce liver hyperplasia, edema and other diseases, and has a significant prevention and treatment effect on alcoholic liver injury. Compared with the model group, although the liver index of mice in comparative examples 1-4 decreased, there was no statistical difference, and they were all higher than those in the positive control group. Therefore, changes in the formula or preparation method of the composition of the invention can not effectively improve the liver index.
(2) HE staining results.
Through HE staining of liver tissue sections, we can visually observe the pathological changes of mouse liver tissue. As shown in Figure 5 (HE staining, magnification X 200), in the blank control group, the structure of liver lobules is clear, liver cells are arranged radially and orderly, liver sinuses are normal, and the nuclear structure 1s clear. In contrast, alcohol gavage caused severe liver injury in mice. In alcohol model group, liver cells are disordered, liver sinuses are narrowed and dispersed, and pathological changes such as vascular congestion were observed. Hepatocytes in groups 1 to 4 are obviously normalized to varying degrees, especially in group 1, where the arrangement of hepatocytes gradually tended to be neat and the structure of hepatic lobules recovered. Therefore, the composition for preventing and treating alcoholic liver injury prepared by the invention can effectively relieve liver cell injury caused by alcohol.
(3) ALT and AST analysis results.
In the early stage of alcoholic liver injury, the permeability of liver cell membrane increased, while the activity of ALT and AST released into blood increased significantly. The effect of the composition for preventing and treating alcoholic liver injury on the activity content of ALT and AST in mice is shown in Table 1. In the model group, the content of ALT and AST in mice serum 1s significantly higher than that in the blank control group, with a significant difference (P < 0.01). Compared with the model group, the contents of ALT and AST in the serum of mice in Examples 1-4 are significantly reduced, with statistical differences (P < 0.01), and the effect of Example 1 is better, indicating that the composition for preventing and treating alcoholic liver injury prepared by the invention can effectively reduce the contents of ALT and AST in the serum and alleviate liver injury. Compared with the model group, there is no statistical difference in the changes of ALT and AST contents in the serum of mice in groups 1-4 of Comparative Examples, which indicates that the changes in the formula or preparation method of the composition of the present invention have no obvious influence on the ALT and AST contents in the serum of mice, and have no prevention and treatment effect on alcoholic liver injury.
Table 1 Serum ALT and AST concentrations of mice in each group (U/L) © Gow ALT (UL AST WD Model 47.04+0.78# 195.00+5.03# Positive control 33.534131" 147.33+6.68"" Example 1 28.03+1.26™ 101.9445.37" Example 2 29.41+0.86™ 108.43+7.59" Example 3 33.68+1.17" 136.6746.43"* Example 4 32.074056" 125.67+5.62"* Comparative example 1 45.75+1.62 181.4147.11 Comparative example 2 44 ,58+1.61 178.63+6.60
Comparative example 3 45.49+1 54 185.59+6.22 Comparative example 4 47.48+1.27 184.21+5.92 “Note: Compared with the blank control group, ”p <0.01; Compared with the model group, **p <0.01.
(4) Analysis of ALDH and ADH results ADH and ALDH are the main metabolic enzymes after ethanol enters the body. Firstly, ADH catalyzes ethanol to acetaldehyde, then ALDH catalyzes acetaldehyde to acetic acid, and finally enters the tricarboxylic acid cycle to generate carbon dioxide and water. As the acetaldehyde produced has a direct toxic effect on liver cells, excessive intake of ethanol will inhibit the activities of ADH and ALDH in liver to a certain extent. When the cellular defense system in vivo fails to remove acetaldehyde in time, the residual acetaldehyde will lead to liver cell injury or inflammation, extracellular matrix and fibrosis. The effects of the composition for preventing and treating alcoholic liver injury on ADH and ALDH activities in mice liver are shown in Table 2. Compared with the blank control group, the activities of ADH and ALDH in the liver of mice in the model group decreased significantly, with statistical differences (p < 0.01), which indicated that acute heavy alcohol intake inhibited the activities of ADH and ALDH in the liver and easily caused alcoholic liver injury. Compared with the model group, the activities of ADH and ALDH in the liver of mice in Examples 1-4 were significantly improved (p<0.01) , indicating that the intervention of the composition for preventing and treating alcoholic liver injury prepared by the invention can improve the activities of ADH and ALDH in the liver of mice, accelerate the metabolic decomposition of ethanol, catalyze the further oxidation of acetaldehyde into acetic acid, and slow down the direct poisoning of the liver of mice by ethanol and its metabolites, thus protecting the acute liver injury of mice induced by alcohol. Compared with the model group, in Comparative Examples 1-4, except Comparative Example 3, there was no statistical difference in the changes of ADH and ALDH activity of mouse liver, which indicated that the formula change of the composition of the present invention had no obvious effect on ADH and ALDH activity of mouse liver, and had no prevention and treatment effect on alcoholic liver injury.
Table 2 ADH and ALDH contents in liver of mice in each group (U/mg-protein)
© Group ADH (U/mg-protein) ALDH (U/mg-protein) — © No-treatment Control 7.15027 953x037
Model 5.21+0.35 6.39+0.31 Positive control 9.29+0.19"" 11.51+0.42 Example 1 12.04+0.22"" 13.58+0.49"" Example 2 11.37+0.31" 12.85+0.53" Example 3 10.59+0.26™ 11.71+0.40™ Example 4 10.74+0.24™ 11.46+0.38" Comparative example 1 5.66+0.46 7.02+0.34 Comparative example > 5.61+0.32 6.86+0.46 Comparative example . . 3 5.93+0.29 7.34+0.33 Comparative example 4 5.75+0.36 6.54+0.41 Note: Compared with the blank control group, *p <0.01; Compared with the model group, **p <0.01. (4) Analysis of CAT, SOD, GSH-Px and MDA Alcohol can produce a large amount of reactive oxygen species (ROS) in human metabolism, which affects the body's antioxidant system and leads to alcoholic liver injury.
Various antioxidant enzymes were used as parameters to evaluate the oxidative stress level of mouse liver, and the results are shown in Table 3. Compared with the blank control group, the contents of SOD, GSH-Px and CAT in the liver tissue of the model group were significantly reduced, with statistical differences (p<<0.01), which indicated that the oxidative stress ability of the liver of the model mice was reduced, and it was easy to cause alcoholic liver injury.
Compared with the model group, the contents of SOD, GSH-Px and CAT in the liver tissues of mice in Examples 1-4 were significantly increased (p<0.01), especially in Example 1, indicating that the composition for preventing and treating alcoholic liver injury prepared by the invention can significantly reduce the peroxide level in the liver of mice caused by alcohol and enhance the antioxidant capacity of the body.
It is the product of free radicals acting on lipid peroxidation, and the degree of lipid peroxidation in vivo can be reflected by measuring the amount of MDA. The content of MDA in the liver tissue of mice in Examples 1-4 groups was significantly lower than that of the model control group (pP<0.01), and the content of MDA in Example 1 group was the lowest, indicating that the composition for preventing and treating alcoholic liver injury prepared by the present invention can reduce the degree of lipid peroxidation in vivo and alleviate alcoholic liver injury.
Table 3 Contents of SOD, GSH-Px, CAT and MDA in liver of mice in each group SOD GSH-Px CAT MDA Group (U/mg-protein) (U/mg-protein) (U/mg-protein) (nmol/mg-protein) No-treatment
284.56+12.27 938.27+£23 47 71.29+2.15 2.16+0.13 Control Model 224.77+8.75"# 721.44+21.32## 30.23+2.12#* 5.36+0,89# Positive control ~~ 311.97+11.57” 959.48+19.22™ 49 44+£331™ 3.53+0.17"" Example 1 353.40+11.10"" 1078.63+23.04" 69.60+3.51"" 2.31#0.11"* Example 2 332.44+10.67"* 1037.78+24.77" 63.26+4.08"" 2.484011 Example 3 309.22+16.41™ 983.56+23.44™ 57.85+3.07"” 3.01+0.17* Example 4 321.96+10.63™ 952.89+24 35" 55.48+3.48" 3.17+0.17* Comparative . .
238.45+7.85 768.74+25.72 34 082.77 3.82+0.11 example 1 Comparative .
246.82+6.70 747.52+22 90 33.60+3.51 4.87+0.12 example 2 Comparative
231.49+15.40 739.31+26.07 35.10+4.04 4.58+0.15 example 3 Comparative
236.57+15.31 756.24+27.52 31.26+3.55 5.02+0.27 example 4 Note: Compared with the blank control group, *p <0.01; Compared with the model group, *p <0.05, **p <0.01. Application example 4 Acute toxicity test Animals: 20 healthy mice, weighing 18-22g, half male and half female, were randomly divided into experimental group and blank control group. Subject: The composition of Example 1 was used as the subject. Experimental method: In the pre-experiment, the median lethal dose could not be measured, so the above experimental dosage was selected for the experiment. According to the weight of the mice, the mice in the experimental group were gavaged once every 24h at a dose of 10g/kg for 2 weeks, while the mice in the blank control group were gavaged with distilled water. During the feeding period, they all drank water and foraged freely. During the experiment, the activities, diet, feces, respiration, weight and death of the mice were observed.
Results: The mice in the experimental group did not die within 2 weeks. Compared with the control group, there was no significant difference in weight change, and there was no abnormality in eating and drinking water. Moreover, the mice were in a good mental state and active. After the animals were put to death, no abnormalities were found in the main organs by naked eyes. The results show that the oral application of the composition for preventing and treating alcoholic liver injury of the invention has no obvious damage to animals and no toxic reaction to organisms, and is safe and nontoxic.
Example 5 A tablet for preventing and treating alcoholic liver injury The tablet for preventing and treating alcoholic liver injury comprises the following components by mass fraction: composition prepared in Example 1 15 wt%; corn starch 70 wt%; talcum powder 14 wt%; Magnesium stearate 1 wt%.
Example 6 A tablet for preventing and treating alcoholic liver injury The tablet for preventing and treating alcoholic liver injury comprises the following components by mass fraction: composition prepared in Example 2 10 wt%; corn starch 75 wt%: talcum powder 13 wt%; magnesium stearate 2 wt% Example 7 A tablet for preventing and treating alcoholic liver injury The tablet for preventing and treating alcoholic liver injury comprises the following components by mass fraction: composition prepared in Example 3 20 wt%; corn starch 65 wt%;
talcum powder 14.5 wt%; magnesium stearate 0.5 wt%.
Example 8 A capsule for preventing and treating alcoholic liver injury The capsule for preventing and treating alcoholic liver injury comprises the following components by mass fraction: Composition prepared in Example 1 20 wt%; lactose 15 wt%; corn starch 55wit%o; talcum powder 10 wt%.
Example 9 A capsule for preventing and treating alcoholic liver injury The capsule for preventing and treating alcoholic liver injury comprises the following components by mass fraction: composition prepared in Example 3 12 wt%; lactose 20 wt%; corn starch 53wit%o; talcum powder 15 wt% Example 10 A capsule for preventing and treating alcoholic liver injury The capsule for preventing and treating alcoholic liver injury comprises the following components by mass fraction: composition prepared in Example 4 27 wt%; lactose 10 wt%; corn starch 58wt%o; talcum powder 5 wt% Example 11 A granule for preventing and treating alcoholic liver injury The capsule for preventing and treating alcoholic liver injury comprises the following components by mass fraction: composition prepared in Example 1 10 wt%; lactose 79 wt%:; sodium carboxymethylcellulose 10 wt%; magnesium stearate 1 wt% Example 12 A granule for preventing and treating alcoholic liver injury
The capsule for preventing and treating alcoholic liver injury comprises the following components by mass fraction:
composition prepared in Example 3 Twt%;
corn starch 84 wt%;
sodium carboxymethylcellulose Twt%;
magnesium stearate 2 wt%
Example 13 A granule for preventing and treating alcoholic liver injury
The capsule for preventing and treating alcoholic liver injury comprises the following components by mass fraction:
composition prepared in Example 2 13.5 wt%;
corn starch 74 wt%;
sodium carboxymethylcellulose 12 wt%;
magnesium stearate 0.5 wt%
The above embodiments only describe the preferred mode of the invention, but do not limit the scope of the invention.
On the premise of not departing from the design spirit of the invention, various modifications and improvements made by ordinary technicians in the field to the technical scheme of the invention shall fall within the protection scope determined by the claims of the invention.

Claims (10)

1. A composition for preventing and treating alcoholic liver injury, which is characterized by comprising the following components in parts by weight: 10-30 parts of seaweed polyphenol, 2-6 parts of sodium alginate, 30-55 parts of abalone peptide and
0.5-3 parts of spermidine.
2. The composition according to claim 1, which is characterized by comprising the following components in parts by weight: 20 parts of seaweed polyphenol, 4 parts of sodium alginate, 40 parts of abalone peptide and 1.5 parts of spermidine.
3. The preparation method of the composition for preventing and treating alcoholic liver injury according to any one of claims 1 or 2, which is characterized by comprising the following steps: sl, adding sodium alginate into water to prepare a sodium alginate solution, adjusting the pH value of the solution to 6.0-7.5, adding spermidine, stirring at room temperature for 5-8 hours, treating in an ice-water bath, cooling the solution system to 5- °C, adding seaweed polyphenol, continuing stirring for 1-3 hours, freeze-drying, and crushing with liquid nitrogen to obtain seaweed polyphenol composite powder; s2, dissolving abalone peptide with water to prepare abalone peptide solution, adding the seaweed polyphenol composite powder while stirring, uniformly suspending, and freeze-drying to obtain the composition for preventing and treating alcoholic liver injury.
4. The preparation method according to claim 3, wherein the mass concentration of the sodium alginate solution is 1%-3.5%; the mass concentration of the abalone peptide solution is 18-26%.
5. The preparation method according to claim 3, wherein the pH of the sodium alginate solution is adjusted to 6.5.
6. Application of the composition according to any one of claims 1-2 in preparing a medicament for treating/preventing alcoholic liver injury.
7. A pharmaceutical preparation for preventing and treating alcoholic liver injury, which is characterized by comprising the composition of claim 1 or claim 2 and pharmaceutically acceptable adjuvants.
8. The pharmaceutical preparation according to claim 7, characterized in that the pharmaceutical preparation is a capsule, and the auxiliary materials include lactose, corn starch and talcum powder; the mass fraction of each component in the capsule is as follows: 10-30wt% of the composition, 10-20wt% of lactose, 50-60wt% of corn starch and 5- 15wt% of talcum powder.
9. The pharmaceutical preparation according to claim 7, wherein the pharmaceutical preparation is a tablet, and the auxiliary materials include corn starch, talcum powder and magnesium stearate; the mass fraction of each component in the tablet is as follows: 10-20wt% of the composition, 65-75wt% of corn starch, 11-17wt% of talcum powder and 0.5-2wt% of magnesium stearate.
10. The pharmaceutical preparation according to claim 7, characterized in that the pharmaceutical preparation is a granule, and the auxiliary materials include corn starch, sodium hydroxymethyl cellulose and magnesium stearate; the mass fraction of each component in the granules is as follows: 5-15wt% of the composition, 74-84wt% of corn starch, 5-15wt% of sodium hydroxymethyl cellulose and 0.5-2wt% of magnesium stearate.
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CN110742878A (en) * 2019-11-15 2020-02-04 浙江工业大学 Application of nitrilamine in preparation of medicine for treating fatty liver
CN110710678A (en) * 2019-11-20 2020-01-21 颐海产业控股有限公司 Marine polypeptide donkey-hide gelatin paste capable of nourishing liver and kidney, nourishing blood and soothing nerves and preparation method thereof
CN112870331B (en) * 2021-02-23 2021-10-15 广东海洋大学 Composition for preventing and treating alcoholic liver injury and preparation method and application thereof

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