CN115624612A - Weight-losing and lipid-lowering medicine and preparation method thereof - Google Patents
Weight-losing and lipid-lowering medicine and preparation method thereof Download PDFInfo
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- CN115624612A CN115624612A CN202211260153.0A CN202211260153A CN115624612A CN 115624612 A CN115624612 A CN 115624612A CN 202211260153 A CN202211260153 A CN 202211260153A CN 115624612 A CN115624612 A CN 115624612A
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- corn
- orlistat
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/01—Hydrolysed proteins; Derivatives thereof
- A61K38/011—Hydrolysed proteins; Derivatives thereof from plants
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/06—Preparation of peptides or proteins produced by the hydrolysis of a peptide bond, e.g. hydrolysate products
Abstract
The invention belongs to the technical field of medicines, and particularly relates to application of a corn oligopeptide-selenium chelate in preparation of weight-losing and lipid-lowering medicines and the weight-losing and lipid-lowering medicines containing the chelate. The weight-losing and lipid-lowering medicine also comprises orlistat, and experiments prove that the effect of inhibiting the weight gain of a nutritional rat by jointly administering the corn short peptide-selenium chelate and the orlistat is obviously better than that of singly administering the orlistat, and the number of animals with hair oil spilling is obviously reduced.
Description
Technical Field
The invention belongs to the technical field of medicines. More particularly, relates to a weight-losing and lipid-lowering medicine and a preparation method thereof.
Background
Zein (Zein) is a main storage protein of corn endosperm, accounts for 45-50% of corn protein, is rich in glutamic acid, leucine, proline and alanine, can be divided into four types of alpha-Zein, beta-Zein, gamma-Zein and delta-Zein according to the amino acid sequence, solubility and relative molecular mass of Zein, and has a molecular weight of 20-25 KDa.
Zein has different functional regions in its polypeptide chain, so that zein hydrolysate can exhibit many different physiological activities, such as Wang Shuyi [1] The corn peptide obtained by enzymolysis with neutral protease (the enzyme substrate ratio is 0.5%, the time is 2 hours, and the feed liquid ratio is 1; suiyu Jie [2] Etc. adopt neutralThe protease and the alkaline protease are used for preparing the corn crude peptide, and the low-hydrolysis-degree peptide (0.5 percent of enzyme substrate ratio, 2h, 1 to liquid ratio, 25) of the neutral protease can reduce the blood alcohol concentration of the mouse by 54.06 percent, and the medium-hydrolysis-degree crude peptide (0.5 percent of enzyme substrate ratio, 4h, 1 to liquid ratio, 20) of the alkaline protease can reduce the blood alcohol concentration of the mouse by 62.80 percent; wangshangyu (a king of two jade) [3] The corn peptide prepared by hydrolyzing zein by adopting alkaline protease has strong scavenging capacity on oxygen free radicals and hydroxyl free radicals; meanwhile, researches find that the hydrolysate has good viscosity, stability, foamability and emulsibility under the appropriate enzymolysis conditions.
However, the activity of zein hydrolysate in weight loss and lipid lowering has not been pointed out so far.
Cited document [1]: the study on the enzymatic hydrolysis of corn peptide and sobering-up activity of Wang Shuyi, wang Suying, neutral protease [ J ] the study and development of food, 2007,28 (4): 60-63.
Cited document [2]: the sobering activity of the corn crude peptide prepared by neutral protease and alkaline protease is compared [ J ], china food and oil science, 2006,21 (3): 102-106.
Cited document [3]: preparation of Wangshangyu, likun, corn antioxidant peptide and protection effect on acute alcoholic liver injury of mice [ J ] food research and development, 2007,28 (3): 29-33.
Disclosure of Invention
The inventors have surprisingly found that zein hydrolysate enzymatically hydrolyzed using pepsin has significantly improved solubility, has anti-obesity activity, and that this hydrolysate, when chelated with selenium, exhibits more significant anti-obesity activity.
Therefore, one of the purposes of the present invention is to provide a use of corn short peptide-selenium chelate in preparation of a weight-reducing and lipid-lowering drug, wherein the corn short peptide is prepared by the following steps:
preparing 10-30 mg/mL suspension of zein by adopting 60-75% ethanol solution, adjusting the pH of the solution to 7.0-9.0, adding pepsin accounting for 1-5% of the mass of the zein, carrying out enzymolysis for 1-3 h at 40-55 ℃, removing ethanol, inactivating enzyme, centrifuging, carrying out ultrafiltration, cooling and drying to obtain the zein.
Regarding the selection of the enzyme, hydrolysates obtained by hydrolysis with different proteases exhibit different physiological activities, and even if the same protease is used for selection, the effects exhibited by the hydrolysates obtained differ to some extent depending on the degree of hydrolysis. The inventor compares the enzymolysis effect of various proteases, finds that the hydrolysate obtained by adopting pepsin enzymolysis has higher effect of inhibiting obesity after being chelated with selenium, and the results in table 1 show that the corn peptide-selenium chelate can obviously reduce the fat content of the whole body of obese mice by being singly fed, and has a certain anti-obesity effect.
Regarding the molecular weight of the corn short peptide, the corn short peptides with different molecular weights have different obesity inhibiting activities after chelating selenium, and the corn short peptide has the strongest anti-obesity effect when the molecular weight of the corn short peptide is 500-1000 Da through experiments.
The corn short peptide-selenium chelate is prepared by the following steps:
slowly adding a sodium selenite solution into the corn oligopeptide aqueous solution, carrying out shaking reaction on a water bath shaker at 25 ℃ for 1-2 h, collecting white precipitates, and drying to obtain the corn oligopeptide.
The invention also aims to provide a weight-losing and lipid-lowering medicine, which comprises the corn short peptide-selenium chelate.
In one embodiment of the present invention, the medicament may further comprise orlistat. Orlistat is a potent and specific intestinal lipase inhibitor, which exerts a weight loss effect mainly by inhibiting gastrointestinal pancreatic lipase, reducing fat absorption, and improving insulin resistance, but long-term administration of orlistat easily causes gastrointestinal adverse reactions, and the common main manifestations are: frequent gastrointestinal exhaust, urgent stool, increased stool frequency, fecal incontinence, fatty writing, oily stool, etc., and these adverse reactions are frequently occurred in the first 3 months of the initial period of taking medicine. According to another unexpected discovery of the invention, the inventor compares the combined effect of the corn oligopeptide-selenium chelate and the orlistat, and discovers that the weight reduction effect of the combination of high-content orlistat and the corn oligopeptide-selenium chelate is reduced on the contrary, however, as the content of orlistat is gradually reduced, the combination shows a weight reduction effect which is stronger than that of the combination of the orlistat and the corn oligopeptide-selenium chelate when the orlistat is singly administered or singly administered, and the number of observed adverse reaction patients is obviously reduced.
Since this particular effect occurs only in the combination of the orlistat and the corn short peptide-selenium chelate at a specific content, in one embodiment of the present invention, the weight ratio of the corn short peptide-selenium chelate to orlistat is 1:0.16,1:0.08,1:0.24, more preferably 1. In one embodiment of the present invention, the medicament is a tablet or capsule, wherein a capsule is a preferred dosage form of the present invention, and when made into a capsule, the capsule basically further comprises fillers, binders and the like which are commonly used in pharmacy.
Detailed Description
The present invention is further illustrated by the following specific examples, which are not intended to limit the invention in any way. The reagents, methods and apparatus employed in the present invention are conventional in the art, except as otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1 preparation of corn short peptide-selenium chelate (ZS) 1 )：
Preparing zein into suspension with the concentration of 15mg/mL by adopting 60% ethanol solution, adjusting the pH of the solution to 8.0, adding pepsin with the mass of 3.5% of the zein, carrying out enzymolysis for 2h at 45 ℃, removing ethanol, inactivating enzyme, centrifuging, filtering by adopting a 0.22 mu m microporous filter membrane, collecting corn short peptide with the molecular weight range of 500-1000 Da, cooling and drying to obtain the corn short peptide;
adding 1mL of 0.05mol/L sodium selenite solution slowly into 10mL of 3.0mg/L corn oligopeptide aqueous solution, oscillating and reacting for 1.5h in a water bath shaker at 25 ℃, collecting white precipitate, and drying to obtain the corn oligopeptide.
Example 2 preparation of corn short peptide-selenium chelate (ZS) 2 )：
Preparing zein into a suspension with the concentration of 20mg/mL by adopting a 60% ethanol solution, adjusting the pH of the solution to 8.0, adding pepsin with the mass of 5% of the zein, carrying out enzymolysis for 1.5h at 45 ℃, removing ethanol, inactivating enzyme, centrifuging, carrying out ultrafiltration by adopting a 0.22-micrometer microporous filter membrane, collecting corn short peptide with the molecular weight range of 500-1000 Da, cooling and drying to obtain the corn short peptide;
and (3) slowly adding 1mL of 0.05mol/L sodium selenite solution into 10mL of 3.0mg/L corn oligopeptide aqueous solution, carrying out shaking reaction on a water bath shaker at 25 ℃ for 2 hours, collecting white precipitate, and drying to obtain the corn oligopeptide.
Example 3 preparation of corn short peptide-selenium chelate (ZS) 3 )：
Preparing zein into a suspension with the concentration of 10mg/mL by adopting a 60% ethanol solution, adjusting the pH of the solution to 8.0, adding pepsin with the mass of 2% of the zein, performing enzymolysis for 3 hours at 45 ℃, removing ethanol, inactivating enzyme, centrifuging, performing ultrafiltration by adopting a 0.22-micrometer microporous filter membrane, collecting corn short peptide with the molecular weight range of 500-1000 Da, cooling and drying to obtain the corn short peptide;
and (3) slowly adding 1mL of 0.05mol/L sodium selenite solution into 10mL of 3.0mg/L corn oligopeptide aqueous solution, carrying out shaking reaction on a water bath shaker at 25 ℃ for 1 hour, collecting white precipitate, and drying to obtain the corn oligopeptide.
Comparative example 1 preparation of corn oligopeptide-selenium chelate (ZS) 4 )
The difference from example 1 is that equal amount of alkaline protease is used to replace pepsin, and the enzymolysis conditions are as follows: pH8.0, 50 ℃,2h.
Comparative example 2 preparation of corn oligopeptide-selenium chelate (ZS) 5 )
The difference from example 1 is that the corn short peptides with a molecular weight range < 500Da are collected, and the rest parameters are the same as example 1.
Comparative example 3 preparation of corn oligopeptide-selenium chelate (ZS) 6 )
The difference from the example 1 is that the corn short peptide with the molecular weight range of 1000-1500 Da is collected, and the rest parameters are the same as the example 1.
Test example I, evaluation of weight loss effect of corn peptide-selenium chelate on nutritionally obese rats
1. The test method comprises the following steps: 80 male SD rats were selected, and were randomly divided into 8 groups (n = 10) after being fed with standard feed, namely, a standard control group, a high-fat group, and a test group A 1 ～A 6 Wherein the standard control group is fed with standard diet, the high fat group is fed with high fat diet, and the test group A 1 ～A 6 Administration of the formulations containing examples 1 to 3 (ZS) 1 ～ZS 3 ) And comparative examples 1 to 3 groups of corn peptide-selenium chelate (ZS) 4 ～ZS 6 ) Feeding the animals with the high-fat feed, wherein the corresponding feed is provided for each group of animals at 9 am every day, the animals are taken away at 7 pm, the animals are quantitatively fed every day, the intervention is continuously carried out for 7 weeks, all the animals are fed in a single cage, and the change of the body mass of each group of rats is measured and recorded at the same time every week during the intervention period.
2. Test results
Table 1: weight change after 7 weeks for each group of rats
Note: compared with the standard control group, the compound preparation, ** p is less than 0.01; compared with the high fat group # P < 0.05, and test group A 1 In contrast to the above-mentioned results, ∧ P＜0.05。
the results show that test group A 1 ～A 3 、A 5 ～A 6 The weight gain of the group body is obviously lower than that of the high-fat group, which shows that the products of pepsin enzymolysis have the function of inhibiting the weight growth of fat mice induced by high-fat diet after chelating selenium, and the smaller the molecular weight of the enzymolysis products, the stronger the activity of inhibiting the obesity is; this activity was not observed with the product enzymatically digested with alkaline protease.
Experimental example II evaluation of weight loss Effect of corn peptide-selenium chelate in combination with orlistat on nutritionally obese rats
The weight loss effect of the corn peptide-selenium chelate and orlistat with different contents on nutritionally obese rats was examined according to the method of test example and method after the standard feed adaptive feeding of 110 male SD rats, the administration and test results are shown in the following table 2, the change of body weight and the amount of oil distribution of rat hair in each group were observed and counted after the administration for 7 weeks.
Table 2: weight loss effect of combined medication of corn oligopeptide-selenium chelate and orlistat
| Group of | Dosage of drug (mg/kg/d) | Weight gain, mean (g) |
| Standard control group | 0 | 146.21±25.36 |
| High fat group | 0 | 205.68±37.41 ** |
| Orlistat low dose group | Orlistat 20mg/kg/d | 186.17±18.64 # |
| Orlistat medium dose group | Orlistat 30mg/kg/d | 172.55±20.16 # |
| Orlistat high dose group | Orlistat 60mg/kg/d | 151.34±22.63 ## |
| Group A | ZS 1 125mg/kg/d + orlistat 20mg/kg/d | 106.37±25.63 ∧∧ |
| Group B | ZS 1 125mg/kg/d + orlistat 30mg/kg/d | 136.28±16.14 ∧∧ |
| Group C | ZS 1 125mg/kg/d + orlistat 60mg/kg/d | 142.25±19.78 |
| Group D | ZS 4 125mg/kg/d + orlistat 20mg/kg/d | 182.10±20.52 |
| Group E | ZS 5 125mg/kg/d + orlistat 20mg/kg/d | 108.61m17.06 ∧ ＾ |
| Group F | ZS 6 125mg/kg/d + orlistat 20mg/kg/d | 172.94±25.48 |
Note: compared with the standard control group, the composition has the advantages that, ** p is less than 0.01; compared with high fat group # P＜0.05， ## P is less than 0.01; compared with the corresponding dose group of orlistat, ∧ P＜0.05， ∧∧ P＜0.01。
the results show that the effect of inhibiting the weight gain of the nutritional rats by combined administration of the corn oligopeptide with specific molecular weight obtained by adopting pepsin enzymolysis after chelating selenium (less than 500Da and 500-1000 Da) and orlistat is obviously better than that of a corresponding dose group (P less than 0.01) by singly administering orlistat; the product of the alkaline protease enzymolysis and the product with the molecular weight range of 1000-1500 Da chelate selenium and do not have the strong synergistic effect with orlistat.
Table 3: number of rats with greasy hair
The results show that after orlistat is given alone for 7 weeks, the hair of all animals shows oil spill, and after the corn short peptide is given at the same time, the hair of the animals shows oil spill to be reduced to different degrees, wherein after the corn short peptide-selenium chelate (500-1000 Da) with specific molecular weight obtained by pepsin enzymolysis and the orlistat with different doses are given in combination, rats do not show oil spill, and the combination of the corn short peptide-selenium chelate and the orlistat can obviously reduce the adverse reaction of the orlistat in medication.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. The application of the corn short peptide-selenium chelate in preparing weight-losing and lipid-lowering medicines is characterized in that the corn short peptide is prepared by the following steps:
preparing 10-30 mg/mL suspension of zein by adopting 60-75% ethanol solution, adjusting the pH of the solution to 7.0-9.0, adding pepsin accounting for 1-5% of the mass of the zein, carrying out enzymolysis for 1-3 h at 40-55 ℃, removing ethanol, inactivating enzyme, centrifuging, carrying out ultrafiltration, cooling and drying to obtain the zein.
2. The use according to claim 1, wherein the molecular weight of the corn short peptide is 500-1000 Da.
3. The use of claim 1, wherein the corn short peptide-selenium chelate is prepared by the following steps:
slowly adding a sodium selenite solution into the corn oligopeptide aqueous solution, carrying out shaking reaction on a water bath shaker at 25 ℃ for 1-2 h, collecting white precipitates, and drying to obtain the corn oligopeptide.
4. A weight-losing and lipid-lowering drug, which comprises the corn oligopeptide-selenium chelate complex according to any one of claims 1 to 4.
5. The medicament of claim 4, wherein the medicament further comprises orlistat.
6. The drug according to claim 5, wherein the weight ratio of the corn oligopeptide-selenium chelate to orlistat is 1.
7. The drug of claim 6, wherein the weight ratio of the corn short peptide-selenium chelate to orlistat is 1.
8. The drug of claim 6, wherein the weight ratio of the corn short peptide-selenium chelate to orlistat is 1.
9. The drug according to any one of claims 4 to 8, which is a tablet or capsule.
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| CN202211260153.0A CN115624612A (en) | 2022-10-14 | 2022-10-14 | Weight-losing and lipid-lowering medicine and preparation method thereof |
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| CN202211260153.0A CN115624612A (en) | 2022-10-14 | 2022-10-14 | Weight-losing and lipid-lowering medicine and preparation method thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100113580A1 (en) * | 2008-10-16 | 2010-05-06 | Aronne Louis J | Combination therapies for the treatment of obesity |
| WO2022136393A1 (en) * | 2020-12-23 | 2022-06-30 | Universidad De Navarra | Zein nanoparticles for use in hyperglycemic conditions |
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2022
- 2022-10-14 CN CN202211260153.0A patent/CN115624612A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100113580A1 (en) * | 2008-10-16 | 2010-05-06 | Aronne Louis J | Combination therapies for the treatment of obesity |
| WO2022136393A1 (en) * | 2020-12-23 | 2022-06-30 | Universidad De Navarra | Zein nanoparticles for use in hyperglycemic conditions |
Non-Patent Citations (1)
| Title |
|---|
| 李红等: "药物生产与合成技术研究", 天津：天津科学技术出版社 * |
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