CN110787287B - Application of fish scale collagen polypeptide in preparation of medicine for treating chronic heart failure - Google Patents
Application of fish scale collagen polypeptide in preparation of medicine for treating chronic heart failure Download PDFInfo
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Classifications
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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
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cardiology (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Public Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Wood Science & Technology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Epidemiology (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Toxicology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention discloses an application of fish scale collagen polypeptide in preparing a medicament for treating chronic heart failure; and discloses a preparation method thereof: the method is characterized in that a decalcified tilapia scale is used as a raw material and is subjected to the technical processes of treatment, soaking, enzymolysis, precipitation, filtration, concentration, spray drying, packaging and the like. Clinical tests prove that the fish scale collagen polypeptide has definite curative effect, good safety and no toxic or side effect in treating chronic heart failure, and remarkably improves the life quality of patients.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to application of fish scale collagen polypeptide in preparation of a medicine for treating chronic heart failure.
Background
Collagen is a biopolymer, the main component in the connective tissue of animals, and is also a functional protein with the largest content and the widest distribution in mammals. The collagen polypeptide is a small molecular polypeptide formed by processing collagen by artificial protease. The fish scale collagen polypeptide is prepared with fish scale as material and through acid process, alkali process, enzyme process, hot water process, composite process, enzymolysis, separation, refining, drying and other steps. The differences of the extraction method, the extraction process and the extraction raw materials of the fish scale collagen have certain influence on the extraction rate, the extraction speed, the extraction of specific protein and the like.
Collagen is macromolecular fibrous scleroprotein, has a relative molecular weight of up to 30 ten thousand daltons, cannot be directly absorbed by a human body after being eaten, and can be absorbed by the human body after being digested and decomposed into small molecular polypeptides or free amino acids, so that the collagen has the effect, and the absorption rate is very low and is only about 2.5 percent. The collagen polypeptide has the relative molecular mass of hundreds to thousands, can be effectively absorbed and utilized after being eaten by a human body, and the utilization rate can reach 90 percent or even more. Many researches have proved that the fish scale collagen as a natural biological resource has unique molecular structure and good intermolecular crosslinking capability, contains various essential amino acids for human body, has high nutritive value, and has obvious effects on improving skin health, improving bone strength, inhibiting blood pressure increase, protecting gastric mucosa, resisting oxidation and the like.
Chronic Heart Failure (CHF) is a clinical syndrome in which the heart structure and/or function is abnormal, resulting in ventricular filling and/or a decrease in ejection capacity, and is a critical and terminal stage in the development of various heart diseases. The novel epidemiological data show that the prevalence rate of adult heart failure in developed countries is about 1% -2%, the prevalence rate is positively correlated with age, and the prevalence rate of heart failure of old people over 70 years old exceeds 10%. According to data published in 'Chinese cardiovascular reports 2017', 450 thousands of existing heart failure patients in China are calculated, and the number of the patients is in an increasing situation.
Current dietary requirements for patients with chronic heart failure: (1) a small number of meals (2) a restricted sodium salt (3) a suitable restriction of protein and caloric intake (4) a ready-to-eat diet (5) to supply sufficient vitamins and a suitable amount of inorganic salts. The medicament treatment mainly comprises western medicines, mainly angiotensin converting enzyme inhibitor, diuretic, beta receptor blocker, angiotensin II receptor blocker, aldosterone inhibitor, etc. Although the medicines can improve clinical symptoms, the life quality and the quality of life of patients are not ideal, and the patients need to take the medicines for a long time, so that adverse reactions such as hypokalemia, hypomagnesemia, hyponatrium, hyperacidity hematuria, abnormal sugar tolerance, acid-base balance disorder, renal function deterioration, ventricular arrhythmia, sudden death and the like are easily caused.
No relevant experimental research and clinical research literature reports exist on the application of the fish scale collagen polypeptide in treating chronic heart failure.
Disclosure of Invention
In order to overcome the defects of the prior art in treatment of chronic heart failure, the invention aims to provide the application of the fish scale collagen polypeptide in preparing the medicament for treating chronic heart failure, and provide an effective treatment way for patients with chronic heart failure.
In order to achieve the purpose, the invention adopts the following technical scheme:
an application of fish scale collagen polypeptide in preparing medicine for treating chronic heart failure is disclosed.
The fish scale collagen polypeptide is characterized by being prepared from decalcified tilapia scales as a raw material;
the fish scale collagen polypeptide is characterized in that the weight percentage content of hydroxylysine is more than or equal to 1.3%, the weight percentage content of hydroxyproline is more than or equal to 9.0%, and the weight average molecular weight is 800-2400;
the preparation process of the fish scale collagen polypeptide comprises the following steps:
a. taking 100 parts by weight of decalcified tilapia scales as a raw material, adding 800-1200 parts by weight of deionized water, heating to 80-90 ℃, and keeping the temperature for 20-60 minutes;
b. then cooling to 30-65 ℃, adjusting the pH value to 8-9, adding 1-8 parts of alkaline protease, and degrading for 0.5-12 hours at constant temperature;
c. adding 1-8 parts of neutral protease at the constant temperature of 45-50 ℃, and stirring for reaction for 0.5-12 hours;
d. then heating to 75-90 ℃, and preserving the heat for 15-30 minutes to inactivate the enzyme;
e. adding flocculant, flocculating to precipitate impurities, filtering, concentrating the filtrate under reduced pressure, spray drying, and packaging.
The preparation process of the fish scale collagen polypeptide is characterized by comprising the following steps:
the alkaline protease in the step b is at least one of alcalase or pancreatin;
the neutral protease of step c is at least one of A1398, Neutrase enzyme or Flavourzyme;
the flocculant in the step e is one or two of diatomite and activated carbon.
The application of the fish scale collagen polypeptide in preparing the medicine for treating chronic heart failure is that the dosage of the fish scale collagen polypeptide is 10 g/person every day.
In the application of the fish scale collagen polypeptide, the fact that the chronic heart failure patients take the fish scale collagen polypeptide incidentally is discovered to have a good effect on improving symptoms. Therefore, the research on the treatment of chronic heart failure by the fish scale collagen polypeptide is carried out, and the result shows that the addition of the fish scale collagen polypeptide can effectively relieve the symptoms of patients with chronic heart failure, effectively improve the self-care ability of the patients, and obviously improve the survival and life quality of the patients; the medicine has no obvious toxic or side effect, has obvious advantages of drug tolerance and drug resistance compared with western medicines used alone, and particularly has obvious curative effects on the aspects of improving walking distance in six minutes, improving left ventricular ejection fraction, reducing serum NT-proBNP level and the like.
The specific study conditions are as follows
1 clinical data and methods
1.1 general data
Selecting 70 chronic heart failure patients, randomly dividing into a test group and a control group, wherein the test group comprises 35 patients, 18 patients and 17 patients, the age is 56-79 years, and the average age is 65.8 years; the control group had 35 cases, 17 men and 18 women, ages 55-78 years, and the mean age was 66.3 years. The treatment groups and the test groups have no statistical significance in the differences of disease conditions, age, sex and the like.
1.2 inclusion and exclusion criteria
1.2.1 inclusion criteria
Heart failure patients with grade II-IV cardiac function, aged 40-80 years, who met the criteria for western CHF diagnosis, were voluntarily admitted to the study without motor system dysfunction and deficits.
1.2.2 exclusion criteria
The patient is less than 30 years old or more than 80 years old, acute heart failure and chronic heart failure are in critical or serious symptoms in the acute attack stage, diseases which seriously affect the life quality exist, such as serious liver and kidney insufficiency, COPD, malignant tumors and the like, active tuberculosis or rheumatoid immune disease patients, patients with medicament contraindications for tests and patients with psychosis, and patients who have poor compliance and do not perform tests according to requirements and cannot take medicaments according to the dose on time and patients and family members object to perform the experimenter and quit the patient voluntarily.
1.3 methods of treatment
1.3.1 control group treatment methods
Patients in the control group were treated with conventional western medicines, and administered with valsartan capsules (manufacturer: Beijing Nowa pharmaceutical Co., Ltd., 80 mg/tablet, national standard of medicine: H20040217) and betalaks sustained-release tablets (manufacturer: Aslicon pharmaceutical Co., Ltd., 47.5 mg/tablet, national standard of medicine: J20150044) each orally for 1 time/day for eight weeks. During the treatment period, drugs for regulating lipid, stabilizing arterial plaque, resisting platelet, promoting urination, strengthening heart, dilating tube and the like are added according to the disease condition.
1.3.2 test group treatment methods
The patients in the experimental group are treated by taking the fish scale collagen polypeptide in addition to the conventional western medicines in the control group, and the fish scale collagen polypeptide is taken 10g each time for 1 time/day with warm water for eight weeks.
1.4 Observation index
The study mainly observes the 6-minute walking test of two groups of patients with chronic heart failure before and after administration for eight weeks to evaluate the change of the motor ability of the patients (significant: 426-550m, effective 150-426 m, ineffective < 150m, and the sum of the significant efficiency and the effective rate is the total effective rate), and observes NT-proBNP and left ventricular ejection fraction. Safety observation indexes are as follows: blood routine, urine routine, liver function, kidney function, etc. were examined once on the day of initiation of treatment and once on the day of termination of treatment, and the occurrence of adverse events was observed at any time.
1.5 statistical methods
The data analysis adopts SPSS 13.0 statistical software, the measurement data is expressed by mean plus or minus standard deviation (x plus or minus s), and the comparison between the two groups adopts t test; the counting data were examined by X2. The difference of P is more than 0.05 and has no statistical significance, and the difference of P is less than 0.05 and has statistical significance.
2.0 test results
2.1 comparison of Total effective Rate in six minute walk test
In two groups of six-minute walk tests, the effective rate of the test group is 20 (57.14%), the effective rate is 13 (37.14%), the ineffective rate is 2 (8.57%), and the total effective rate is 94.28%. The control group showed 12 cases (34.29%), 17 cases (48.57%) and 6 cases (17.14%) of no effect, and the total effective rate was 82.86%. The clinical effect of the test group is obviously better than that of the control group, and the difference has statistical significance (P is less than 0.05). See table 1.
TABLE 1 comparison of the total effective rates of six-minute walk tests for two groups of patients
The total effective rate of the two groups is compared with P < 0.05.
2.2 serum NT-proBNP level comparison
The level of serum NT-proBNP of two groups of patients is reduced after treatment, the level of serum NT-proBNP of the test group is lower than that of the test group before treatment and that of the control group after treatment, and the difference has statistical significance (P is less than 0.05). See table 2.
TABLE 2 comparison of NT-proBNP before and after two groups of treatment
P < 0.05 compared to control group after treatment.
2.3 Left Ventricular Ejection Fraction (LVEF) comparison
After treatment, the cardiac function of the two groups of patients is improved, the cardiac function is improved more obviously after the treatment of the test group, and the difference is statistically significant (P is less than 0.05) when the statistical analysis is carried out after the treatment of the control group. See table 3.
TABLE 3 comparison of Left Ventricular Ejection Fraction (LVEF) before and after two groups of treatments
P < 0.05 compared to control group after treatment.
The test result shows that: compared with a control group, the test group has statistical significance difference, and shows that the fish scale collagen polypeptide has obvious effects on improving symptoms, improving cardiac function and improving motor ability of chronic heart failure patients.
The mechanism is still under study, and the current curative effect is presumed as follows:
1) repair damaged myocardium. Proteins are important raw materials for building and repairing the body, and the development of the human body and the repair and renewal of damaged cells cannot be separated from proteins. On one hand, heart failure patients need to supplement nutrients to repair damaged cardiac muscle, on the other hand, the patients are generally required to properly limit the intake of protein and heat energy, so that the problems that the digestion and absorption processes of macromolecular protein increase the burden of organs such as heart, liver, kidney and the like, and the contradiction between physical demand and supply can cause the vicious circle of the patients with heart failure are avoided. The fish scale collagen polypeptide has small molecular weight, and can well solve the contradiction. Domestic and foreign researches have proved that the collagen polypeptide has small molecular weight and high absorption and utilization rate, and supplements the protein demand urgently needed by patients. Meanwhile, the polypeptide body has a protective film, cannot be subjected to secondary hydrolysis of pepsin, digestive enzyme and the like of a human body, can quickly enter small intestines through the oral cavity and the stomach of the human body, passes through intestinal mucosa cells and is directly absorbed by tissues, and reaches target connective tissue organ composition cells without passing through an amino acid path. Therefore, the weight average molecular weight of the fish scale collagen polypeptide is 800-2400, the fish scale collagen polypeptide is rich in various essential amino acids of a human body, and the self-repair of damaged cardiac muscle cells can be promoted on the premise of not additionally increasing the cardiac burden.
2) Improving myocardial function. The angiotensin converting enzyme inhibitor is a common medicine for treating heart failure, and collagen polypeptide prepared by taking fish scales as a raw material and adopting an enzyme method has a certain activity of inhibiting angiotensin converting enzyme. The clinical findings show that the dosage of the fish scale collagen polypeptide is increased from 5 g/day to 10 g/day conventionally, the fish scale collagen polypeptide can play a therapeutic role similar to an angiotensin converting enzyme inhibitor for chronic heart failure patients, and the fish scale collagen polypeptide is supposed to improve the myocardial function in the aspects of reducing blood pressure, delaying and reversing ventricular remodeling, preventing further development of myocardial hypertrophy, improving the vascular endothelial function and the cardiac function, reducing arrhythmia and the like.
Clinical test results show that the fish scale collagen polypeptide has a remarkable effect in treating chronic heart failure.
Meanwhile, the fish scale collagen polypeptide has no obvious toxic or side effect, has obvious advantages of drug tolerance and drug resistance compared with western medicines used alone, and obviously improves the survival and life quality of patients.
Compared with the prior art, the invention has the following advantages:
1. has definite curative effect. Can effectively treat chronic heart failure and improve the life quality and the life quality of patients with chronic heart failure.
2. Is safe to take. Has no obvious toxic or side effect, has obvious comparative advantages in the aspects of drug tolerance and drug resistance, and can obviously improve the life quality of patients with chronic heart failure.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the embodiments of the present invention are not intended to limit the present invention. The simple modification of the present invention according to the technical solution of the present invention is within the scope of the claimed invention.
Example 1: preparation of fish scale collagen polypeptide
Washing 100 g of decalcified new gift tilapia scales, adding 1000 ml of deionized water, heating to 85 ℃ for 30 minutes, cooling to 45 ℃, adjusting the pH value to 8.0, adding 8 g of alkaline protease alcalase, degrading for 4 hours, adding 8 g of neutral protease A1398 after keeping the temperature to 45 ℃, reacting for 2 hours, completely dissolving the scales, heating to 90 ℃, preserving the temperature for 15-30 minutes to inactivate the enzyme, adding a proper amount of flocculating agent diatomite and active carbon (mixed according to the ratio of 1: 1), settling for 8 hours, and directly taking the supernatant; and distilling the supernatant under reduced pressure at the vacuum degree of 0.06-0.10 Mpa and the temperature of 40-65 ℃, and finally performing spray drying to obtain the solid scale collagen polypeptide powder. Through determination, wherein: hydroxyproline content 9.4%; 1.4 percent of hydroxylysine.
Example 2: preparation of fish scale collagen polypeptide
Washing 100 g of decalcified tilapia scales, adding 800 ml of deionized water, heating to 90 ℃, preserving heat for 25 minutes, cooling to 40 ℃, adjusting the pH value to 8.0, adding 7 g of pancreatin, degrading for 6 hours, keeping the temperature to 48 ℃, adding 6 g of neutral protease Neutrase, reacting for 5 hours, completely dissolving the scales, heating to 85 ℃, preserving heat for 15-30 minutes to inactivate the enzymes, adding a proper amount of flocculating agent diatomite and active carbon (mixed according to the ratio of 1: 1), settling for 10 hours, and directly taking supernatant; and distilling the supernatant under the vacuum degree of 0.06-0.10 Mpa and the temperature of 40-65 ℃, and finally performing spray drying to obtain the solid scale collagen polypeptide powder. Through determination, wherein: hydroxyproline content: 9.3 percent; hydroxylysine, 1.3%.
Example 3: preparation of fish scale collagen polypeptide
Washing 100 g of decalcified tilapia scales, adding 1200 ml of deionized water, heating to 80 ℃, preserving heat for 60 minutes, cooling to 55 ℃, adjusting the pH value to 9.0, adding 7 g of pancreatin, degrading for 5 hours, keeping the temperature to 50 ℃, adding 8 g of neutral protease Flavourzyme, reacting for 3 hours, completely dissolving the scales, heating to 90 ℃, preserving heat for 15-30 minutes to inactivate the enzymes, adding a proper amount of flocculant (diatomite and activated carbon are mixed in a ratio of 1: 1) and settling for 8 hours, and directly taking supernatant; and concentrating the supernatant under reduced pressure at the vacuum degree of 0.06-0.10 Mpa and the temperature of 40-65 ℃, and finally performing spray drying to obtain the solid scale collagen polypeptide powder. Through determination, wherein: hydroxyproline content: 9.4 percent; hydroxylysine, 1.4%.
Example 4: therapeutic effects
The following 4 patients were part of the patients included in our study, and the basic cases were as follows:
liu XX Male 75 years old group diagnosis: coronary heart disease heart function IV grade hypertension 3 grade high risk group
Diagnosis of once XX female 76 years of age group: coronary heart disease heart function III grade hypertension 3 grade extremely high risk group
Plum XX female 67 years old group diagnosis: coronary heart disease cardiac function grade IV atrial fibrillation
Wang XX male 72 years old group diagnosis: coronary heart disease heart function III grade hypertension 3 grade extremely high risk group
The treatment method comprises the following steps: the valsartan capsules and the betamethasone sustained release tablets are respectively orally taken for 1 time per day for eight weeks, and simultaneously the fish scale collagen polypeptides are taken 10g each time and 1 time per day with warm water for eight weeks.
NT-proBNP before and after treatment
Distance of 6 minutes walk test
Left ventricular ejection fraction before and after treatment (LVEF)
Four patients in the test groups take the conventional western medicine and the fish scale collagen polypeptide 10g each time for 1 time/day with warm water, after taking the medicine for eight weeks, the four patients have remarkable improvements in a six-minute walk test (6MWT), a Left Ventricular Ejection Fraction (LVEF) and an amino terminal brain natriuretic peptide (NT-proBNP), so that the heart failure degree is controlled satisfactorily, and the improvement of the life quality of the patients can be predicted from the increase of the distance of the 6-minute walk test.
When the basic medical institution evaluates, the movement risk and the rehabilitation effect of the patient can be evaluated by utilizing a six-minute walking test, and the method is safe and easy to implement.
Claims (4)
1. An application of fish scale collagen polypeptide combined with valsartan capsules and betalaks sustained release tablets in preparing a medicament for treating chronic heart failure;
the preparation process of the fish scale collagen polypeptide comprises the following steps:
a. adding 800-1200 parts by weight of deionized water into 100 parts by weight of decalcified tilapia scales, heating to 80-90 ℃, and keeping the temperature for 20-60 minutes;
b. then cooling to 30-65 ℃, adjusting the pH value to 8-9, adding 1-8 parts of alkaline protease, and degrading for 0.5-12 hours at constant temperature;
c. then under the constant temperature condition of 45-50 ℃, 1-8 parts of neutral protease are added, and the mixture is stirred and reacts for 0.5-12 hours;
d. then heating to 75-90 ℃, and preserving the temperature for 15-30 minutes to inactivate the enzyme;
e. adding flocculant, flocculating to precipitate impurities, filtering, concentrating the filtrate under reduced pressure, spray drying, and packaging.
2. The use of claim 1, wherein the weight percentage of hydroxylysine in the fish scale collagen polypeptide is greater than or equal to 1.3%, the weight percentage of hydroxyproline in the fish scale collagen polypeptide is greater than or equal to 9.0%, and the weight average molecular weight of the fish scale collagen polypeptide is 800-2400.
3. Use according to claim 1, characterized in that:
the alkaline protease in the step b is at least one of alcalase or pancreatin;
the neutral protease of step c is at least one of A1398, Neutrase enzyme or Flavourzyme;
and e, the flocculating agent in the step e is one or two of diatomite or activated carbon.
4. The use according to claim 1, wherein the amount of the fish scale collagen polypeptide is 10 g/human/day.
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