CN101240014B - Lipopeptid composition with physiological activity and its preparation method and application - Google Patents
Lipopeptid composition with physiological activity and its preparation method and application Download PDFInfo
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- CN101240014B CN101240014B CN 200810014730 CN200810014730A CN101240014B CN 101240014 B CN101240014 B CN 101240014B CN 200810014730 CN200810014730 CN 200810014730 CN 200810014730 A CN200810014730 A CN 200810014730A CN 101240014 B CN101240014 B CN 101240014B
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Abstract
The invention relates to a natural lipopeptide composite with biological activity extracted from conch, preparation and application in pharmaceutical fields of the same, which pertains to biological and pharmaceutical technical fields. The invention protects a lipopeptide composite with biological activity, preparation and application thereof. The lipopeptide is produced from marine organisms, can be used in treatment and improving hypertension and congestive heart failure.
Description
Technical field
The present invention relates to a kind ofly from the marine products spiral shell, extract the natural lipopeptid composition of preparation with physiologically active, and the preparation method of this mixture and application aspect medical, the biological medicine technology field belonged to.
Background technology
Hypertension is one of modal cardiovascular disorder, and it can cause the infringement of brain, cardiovascular, kidney, is the important factor that causes diseases such as cerebral apoplexy, heart failure and coronary heart disease.
Though the hypotensive preparation of synthetic has tangible blood pressure lowering effect, because the side effect that long-term prescription brings but becomes a difficult problem of can't get rid of.And derive from small peptide in the natural food with hypotensive effect have antihypertensive effect significantly, do not have characteristics such as toxic side effect, security height, meet the demand of health of people more.
At present, many proteic hydrolyzate of marine organisms and peptide classes of deriving from are arranged, show to have hypotensive activity at experiment in vitro, and have antihypertensive function by after taking.Adopt enzyme engineering technology, the researchist has isolated the bioactive peptide with antihypertensive function from multiple marine organisms.In the zymolyte of sardines, tuna, stripped tuna, shrimp, crab, marine alga, all found to have new aminoacid sequence the step-down peptide (referring to what Helen, Chinese biological engineering magazine, 2004,24 (9): 7).
It is reported that up to now, people have utilized the various food proteins of multiple protein enzymic hydrolysis, and therefrom obtained to surpass 200 kinds little peptide with hypotensive effect.
It is significantly different that proteic main amino acid whose composition of marine organisms and sequence and land raw albumen have, and the marine organisms protein resource is in kind with quantitatively all much larger than the land protein resource simultaneously, exploitation value and having a high potential.
The preparation method of marine bioactivity peptide and approach have two: the one, from marine organism, extract the various natural radioactivity peptide matters of itself inherent; The 2nd, the approach by the hydrolysis of marine protein matter resource obtains to have the biologically active peptides section of various physiological functions.
Enzymatic hydrolysis is a method commonly used at present, can carry out under the condition of gentleness, can position hydrolytic scission under certain conditions and produce specific peptide.But because enzymolysis is a very complicated process, therefore, might generate some not clear products, or uncontrollable because of process, separate the difficulty of purifying thereby strengthen the later stage, and can reduce the security of final product.
Direct extraction method prepares the marine bioactivity peptide, uses various separating and purifying technologies exactly, and directly the biologically active peptides that from the nature biotechnology body organism itself is contained extracts.With the bioactive peptide of direct extraction method preparation owing to avoided organism inherent activeconstituents to wreck, so have security more reliably and clear and definite activity.
Yet with regard to existing state of the art, prepare biologically active peptides with the method for directly extracting purifying, face adverse conditions in actual at present application process: 1, this content in organism of bioactive peptide is very low, extracts purification difficult; 2, extract the process complexity of purifying, cause with high costs; 3, raw material availability is low, and it is limited to originate.
Basic reason is that the existence form of step-down peptide and product purity are not fully paid attention to for the relation of performance hypotensive effect.Thought in the past that the purity of step-down peptide was high more good more, the result causes purification step increase, operational path complexity, and cost improves, and can't realize real suitability for industrialized production.
Summary of the invention
At the deficiencies in the prior art, the invention provides a kind of natural lipopeptid composition of preparation that from the marine products spiral shell, extracts with physiologically active.
Preparation method that the present invention also provides this lipopeptid composition and application aspect medical.
Technical solution of the present invention is as follows:
A kind of lipopeptid composition with physiologically active, it is characterized in that, this lipopeptid composition extracts from ocean snail biological tissue, its composition comprises that every milliliter contains: inorganic nitrogen 804-900 μ g, inorganic phosphorus 340-280 μ g, unsaturated lipids 6.7-2.3 μ g, hydrolysis amino acid 4.0-8.0 μ g.
Each constituents listed above is the essential substance of lipopeptid composition performance biological effect of the present invention, all the other are and the irrelevant or temporary transient unknown impurity component of therapeutic action that the existence of this part material is through experimental results show that and can't bringing detrimentally affect to therapeutic action of the present invention.
Preferably, also can be added with vitamin-E in the above-mentioned lipopeptid composition, making the weight percent of vitamin-E in finished product is 0.02-0.05%.
A kind of preparation method with lipopeptid composition of physiologically active, concrete steps are as follows:
The raw material of organizing of ocean snail biology is smashed to pieces or pulverized, use solvent extraction, united extraction liquid, temperature when cooling makes the extracting solution temperature be lower than extraction is separated out precipitation, gets supernatant liquid, concentrate and remove solvent, purifying treatment is used column chromatography to separate wash-out then and is obtained lipopeptid composition.
Described ocean snail biology is a Mollusca Caenogastropoda Muricidae biology; The preferred red spiral shell of arteries and veins, red spiral shell, murices, sour jujube spiral shell, wart dog whelk etc.; Being organized as except that the spiral shell shell of described ocean snail biology all organized, preferred trunk tissue, liver organization and/or reproductive organ tissue.
Described raw material can be fresh state, also can be freezing state.Guaranteeing under the bioactive condition of raw material that pulverize for making raw material be beneficial to biological tissue, preferred raw material treatment temp is below 0 ℃.
Described solvent extraction, extraction time are no less than 2 times, fully to carry most desired substance.
Described solvent extraction is carried out in 10-40 ℃ of scope, to guarantee not destroy the biological activity of ingredient in the raw material.For example can carry out, also can under subambient state, carry out at room temperature state.
Temperature when described cooling makes low extracting solution temperature be lower than extraction, the less impurity of one class polarity is separated out, reach the effect of removing impurity, adopt and reduce method of temperature, method is easy, and is with low cost, is the preferred method of the removal impurity groped on a series of experimental basis, preferably, separate out temperature of precipitation and be controlled at 0-10 ℃.
Described solvent extraction is extracted first and adopted the high density alcoholic solution, and is preferred, with the extraction using alcohol of 80-100%, adopts the alcoholic solution of low concentration when repeating to extract, preferred, with the extraction using alcohol of 30-60%.
The present invention discovers and adopts different gradient concentration solvents to extract, its extraction effect is better than the solvent that uses same concentrations, the dissolving territory broad of high concentration ethanol, for the first time can extract most of activated complex, extract with high concentration ethanol if continue, the activated complex ratio reduces in the extracting solution, and the overwhelming majority is an impurity.From reduce the angle consideration that impurity is sneaked into as far as possible, subsequent extracted selects for use low-concentration ethanol to continue to extract better.
Preferably, solvent adjustment is acid in the described solvent extraction step, and pH4.0-6.5 is good.Like this, can guarantee that on the one hand activated complex extracts fully, control impurity on the other hand as far as possible and sneak in the extracting solution.It is acid can regulating solvent with hydrochloric acid or organic acid, and the present invention preferably adopts organic acid to regulate and extracts solvent for acid, and concrete preferred organic acid is acetate or formic acid.
Extraction effect was fine when solvent adjustment was acid, can effectively remove impurity parts such as carbohydrate, pigment, cholesterol oxidation product and ester thereof.
The present invention has the purifying treatment described in the preparation method of lipopeptid composition of physiologically active in two steps, earlier with scavenging agent and extracting solution with volume ratio (1-5): 1 mixes, and except that a part of impurity of depolarization minimum, uses activated carbon treatment then, sloughs pigment.
Preferably, scavenging agent is selected from one of normal hexane, hexanaphthene, sherwood oil or combination, and activated carbon dosage is 1-5%wt in the purifying treatment, and further preferred, activated carbon dosage is 2%wt.
Preferably, after purifying treatment, add vitamin-E, making the weight percent of vitamin-E in the finished product composition is 0.02-0.05%.Can protect mixture not oxidated destruction in preparation process like this.
The present invention has the preparation method of the lipopeptid composition of physiologically active, and preferred, the column chromatography sorbing material is a dextrane gel, and further preferred, the column chromatography sorbing material is dextrane gel LH20 (sephadex LH20).It is few that this sorbing material has a sample loss, the advantage of good separating effect.
The present invention has the preparation method of the lipopeptid composition of physiologically active, the column chromatography eluting solvent is an alcohol-water compounded solvents, preferably methanol-water double solvents, propyl alcohol-water compounded solvents or butanols-water compounded solvents are further preferred, use butanols-water compounded solvents; Wherein, the two volume ratio of fourth alcohol and water (10-20): 1.
The application of the lipopeptid composition that the present invention has a physiologically active aspect medical, it is characterized in that it being to prepare in order to the application in the medicinal substance of treatment, prevention, improvement, inhibition or minimizing hypertension, particularly Q volume of blood increase type hypertension and congestive heart failure disease symptom.
The present inventor's unexpected discovery in the process of research hypertension is derived from a halobiontic class lipopeptid composition and has powerful hypotensive physiologically active.By the secular experimental study of contriver, the activity that proves this mixture is not that simple increase with lipopeptid component content in the mixture raises, in other words, by the design production technique, the content control of lipopeptid in the mixture can be brought into play significant antihypertensive effect within the specific limits, further refining purifying, activity does not significantly improve.This conclusion makes from organism the step-down lipopeptid composition of extraction separation be applied to medicine and controls the method for patient's blood pressure and become feasible, has reduced purification step, has reduced production cost significantly.
Lipopeptid composition effect with physiologically active of the present invention is better than general hypotensive small peptide, because of lipopeptid composition through oral back by gi tract protease hydrolysis destructive degree well below general hypotensive small peptide, bioavailability improves greatly.
Lipopeptid composition provided by the invention can be used separately, also can be with lipopeptid composition and other drug applied in any combination.Also can make the pharmaceutically various preparations of acceptable, as tablet, capsule, patch, film, gelifying agent, nasal spray, injection etc. by adopting the acceptable accessories combination.
The application of the lipopeptid composition that the present invention has a physiologically active aspect medical can be adopted medically acceptable any way, as oral, Transdermal absorption, injection (intravenous injection, intramuscular injection, subcutaneous injection), mucous membrane absorption, cavity absorption etc.
In the present invention, described lipopeptid composition with independent use, unite uses with other drug, add auxiliary material make preparation use the time, can be in continuous administration every day of treatment phase, also can the administration at intermittence.The lipopeptid composition effective dose is calculated to take what milligram lipopeptid compositions every day, it is 10mg/ days～2000mg/ days that the male patient of a normal type can adopt every day dosage, the difference of route of administration can cause the difference of dosage, and for example the dosage of injection use is little more than the dosage that orally uses this mixture medicament.
For the singularity of better explanation lipopeptid composition of the present invention, the composition of mixture is carried out chemical analysis, analytical data sees the following form 1.
Table 1: the composition analysis of lipopeptid composition provided by the invention (n=6)
| Project | Inorganic phosphorus (μ g/ml) | Inorganic nitrogen (μ g/ml) | Unsaturated lipids (mg/ml) | Hydrolysis amino acid (μ g/ml) |
| Lipopeptid composition | 340～280 | 804～900 | 6.7～2.3 | 4.0-8.0 |
From last table, show,, can find that the formation of lipopeptid composition of the present invention is different from existing all medicines by the physical and chemical experiment analysis of routine.Nitrogen, hydrolysis amino acid have reflected the peptide chain that wherein contains, and unsaturated lipids has reflected fat chain wherein.
The superiority for preparing the method for physiologically active lipopeptid composition provided by the invention is:
1. adopted temperature controlled extraction equipment,, guaranteed that on the one hand the activity of biological raw material is not damaged, reached the purpose of removing impurity on the other hand by adjusting in raw materials pretreatment, extraction, scavenging process temperature;
2. adopt the method coupling of solvent extraction and chromatography, guaranteed that the utilization of bioactive ingredients is complete in the raw material, and obtain the higher lipopeptid composition of purity, shown extremely significant physiological characteristic.
3. with respect to the present Technology of extracting the step-down peptide from marine organisms, productive rate obviously improves, and the lipopeptid composition yield is higher than 20%.
Embodiment
Below by specific examples the present invention is set forth, but do not limit the scope of the invention in any form.
Embodiment 1:
Get the red spiral shell tissue of 100g (trunk, liver, reproductive organ) under freezing state, smashs to pieces, add 10 times of amount 95% extraction using alcohol 1h, filter, stir with 50% acidic ethanol again and extract 3h, filter, merge extracted twice liquid, put cold, separate out precipitation, inclining supernatant liquid, concentrates, handle with 3 times of amount hexanes, discard hexane layer, lower floor's lipoprotein layer 2% activated carbon purification, ultrafiltration, concentrate, service temperature remains and is lower than 40 ℃, adds vitamin-E and makes final concentration to 0.03%, and concentrating under reduced pressure is removed solvent, obtain crude product, use sephadex LH20 column chromatography for separation again, butanols-acetate-water elution obtains lipopeptid composition, and yield is 25%.
Detect through chemical analysis, resultant lipopeptid composition composition comprises that every milliliter contains: inorganic nitrogen 900 μ g, inorganic phosphorus 280 μ g, unsaturated lipids 6.7 μ g, hydrolysis amino acid 8.0 μ g.
Embodiment 2:
Get the whole flesh tissues of the red spiral shell of 100g arteries and veins, tissue is smashed to pieces, adds 9 times of amount 60% ethanol, be not less than 4.5 with the acetate adjust pH, have in the container that mixes agitating function at one and to extract 2h, filter, concentrate, put cold analysis and go out precipitation, inclining supernatant liquor, handles with 3 times of amount hexanes, discards hexane layer, lower floor's lipoprotein layer 2% activated carbon purification, ultrafiltration concentrates, and service temperature remains and is lower than 40 ℃, add 0.02% vitamin-E, concentrating under reduced pressure is removed solvent, obtains crude product, uses sephadex LH20 column chromatography for separation again, butanols-water obtains lipopeptid composition, and yield is 24.5%.
Detect through chemical analysis, resultant lipopeptid composition composition comprises that every milliliter contains: inorganic nitrogen 850 μ g, inorganic phosphorus 310 μ g, unsaturated lipids 5.3 μ g, hydrolysis amino acid 6.0 μ g.
Embodiment 3:
Get 100g murices tissue (trunk, liver, reproductive organ) under freezing state, smashs to pieces, add 8 times of amount 80% ethanol, be not less than 4.5, stir and extract 3h with the acetate adjust pH, filter, be concentrated into 1/10 of original volume, put cold analysis and go out precipitation, inclining supernatant liquor, handle with 3 times of amount hexanes, discard hexane layer, lower floor's lipoprotein layer 2% activated carbon purification, ultrafiltration, concentrate, service temperature remains and is lower than 40 ℃, adds 0.03% vitamin-E, and concentrating under reduced pressure is removed solvent, obtain crude product, use sephadex LH20 column chromatography for separation again, propyl alcohol-acetate-water obtains lipopeptid composition, and yield is 30%.
Detect through chemical analysis, resultant lipopeptid composition composition comprises that every milliliter contains: inorganic nitrogen 804 μ g, inorganic phosphorus 340 μ g, unsaturated lipids 2.3 μ g, hydrolysis amino acid 4.0 μ g.
Embodiment 4: the lipopeptid composition medicinal preparations of embodiment 1
Lipopeptid composition 10mg; Starch 17mg; Icing Sugar 18mg; Dextrin 15mg; 47% ethanol an amount of (the system softwood is used); Magnesium Stearate 0.6g makes tablet.
Embodiment 5: the lipopeptid composition medicinal preparations of embodiment 2
Prescription 2: lipopeptid composition 2mg, add 0.02% vitamin-E, add 10% dissolve with ethanol solution, ultrafiltration, sterilization is filled into 2ml peace bottle, and-30～-40 ℃ of freeze-drying are sealed, and make frozen powder for injection.
Embodiment 6: the experimentation on animals example
The product that used lipopeptid composition obtains for embodiment 1-3
The invention provides a kind of medicine for the treatment of hypertension and congestive heart failure disease, in order to prove the hypertensive effect of treatment, the inventor has carried out pharmacodynamic experiment according to the preparation of the method preparation that provides in the foregoing description, and result of study is as follows:
1, lipopeptid composition of the present invention (heavy dose of 2mg/kg, middle dosage 1mg/kg, low dose of 0.5mg/kg) drug administration by injection can obviously reduce the dog systolic pressure, diastolic pressure and mean arterial pressure, reduce the rhythm of the heart, cardiac output, cardiac index, prolong left ventricular pressure, chamber, left side diastasis pressure, the maximum climbing speed of left indoor pressure, stroke work index, total oxygen consumption index and total peripheral resistance, chamber, a left side begins to be contracted to left indoor pressure climbing speed peak time, increase stroke output, SI, coronary flow, point out lipopeptid composition of the present invention to have remarkable coronary artery dilating blood flow, reduce the effect of myocardial consumption of oxygen.
2, the blood pressure and the heart rate of lipopeptid composition energy obvious less spontaneous hypertensive rat (SHR) of the present invention and two kidneys, one folder type Hypertensive Rats (2K1C-RHR), generally 1 all blood pressures begin to descend after administration, the maximum reducing amplitude of two kinds of rats is respectively 26.3% and 26.4% approximately, and heavy dose can also delay the rise after the drug withdrawal.
3, lipopeptid composition of the present invention obviously reduces the ratio of SHR rat left chamber weight/right ventricle weight, heart weight/body weight, makes left ventricle and the attenuation of aortic arch tube wall, shows the cardiac shape that can improve SHR.
4, lipopeptid composition of the present invention can show plasma renin activity and the Angiotensin II level that reduces Hypertensive Rats, increases the renal artery blood flow amount, has the arteriorenal effect of expansion.
5, lipopeptid composition heavy dose of the present invention, middle dosage, the low dose of blood pressure and the heart rate that all can significantly reduce anesthetized rat, heavy dose is organized 30min onset after administration, and 2h also has good hypotensive effect after administration.
6, lipopeptid composition of the present invention when high dosage hypotensive effect, to hemodynamic improvement effect, and reduce effects such as plasma renin activity and Angiotensin II level, effect is moved the capital to another place all similar to captopril, and can delay the rise of the blood pressure after the drug withdrawal.
Claims (8)
1. preparation method with lipopeptid composition of physiologically active is characterized in that concrete steps are as follows:
The raw material of organizing of Mollusca Caenogastropoda Muricidae biology is smashed to pieces or pulverized, use solvent extraction, solvent is regulated pH4.0～6.5 with hydrochloric acid or organic acid, united extraction liquid, the temperature when cooling makes the extracting solution temperature be lower than extraction, separate out precipitation, get supernatant liquid, concentrate and remove solvent, purifying treatment, use column chromatography to separate wash-out then and obtain lipopeptid composition, the column chromatography sorbing material is a dextrane gel;
Described solvent extraction is carried out in 10-40 ℃ of scope, and extraction time is no less than 2 times, extracts the high density alcoholic solution that adopts 80-100% first and extracts, and adopts the alcoholic solution of the 30-60% of low concentration when repeating to extract;
Described purifying treatment in two steps, earlier with scavenging agent and extracting solution with volume ratio (1-5): 1 mixes, and uses activated carbon treatment then, sloughs pigment, and activated carbon dosage is 1-5%wt in the purifying treatment;
Described column chromatography eluting solvent is methanol-water double solvents, propyl alcohol-water compounded solvents or butanols-water compounded solvents.
2. the preparation method with lipopeptid composition of physiologically active as claimed in claim 1, it is characterized in that, described Mollusca Caenogastropoda Muricidae biology is the red spiral shell of arteries and veins, red spiral shell, murices, sour jujube spiral shell, wart dog whelk, described Mollusca Caenogastropoda Muricidae biology be organized as trunk tissue, liver organization and/or reproductive organ tissue.
3. the preparation method with lipopeptid composition of physiologically active as claimed in claim 1 is characterized in that, described organic acid is acetate or formic acid.
4. the preparation method with lipopeptid composition of physiologically active as claimed in claim 1 is characterized in that, described scavenging agent is selected from one of normal hexane, hexanaphthene, sherwood oil or combination, and activated carbon dosage is 2%wt.
5. the preparation method with lipopeptid composition of physiologically active as claimed in claim 1 is characterized in that, after purifying treatment, adds vitamin-E, and making the weight percent of vitamin-E in the finished product composition is 0.02-0.05%.
6. the preparation method of the lipopeptid composition of physiologically active as claimed in claim 1 is characterized in that, described column chromatography sorbing material is dextrane gel LH20.
7. the preparation method with lipopeptid composition of physiologically active as claimed in claim 1 is characterized in that, in described butanols-water compounded solvents, and the two volume ratio of fourth alcohol and water (10-20): 1.
8. the application of the lipopeptid composition that makes of the described preparation method of claim 1, it is characterized in that be preparation in order to treatment, prevention, improve, suppress or reduce application in the medicinal substance of hypertension and Q volume of blood increase type hypertension and congestive heart failure disease symptom.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109402206A (en) * | 2018-11-22 | 2019-03-01 | 浙江海洋大学 | A kind of preparation method of Thais clavgeria Antihypertensive Peptides |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ES2728243T3 (en) * | 2012-11-12 | 2019-10-23 | Univ Heidelberg Ruprecht Karls | Lipopeptides for use in the treatment of liver diseases and cardiovascular diseases |
| CN103571728B (en) * | 2013-08-16 | 2016-08-10 | 江南大学 | Lipopeptide compound is for improving purposes and the assay method thereof of distilled spirit fragrance |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109402206A (en) * | 2018-11-22 | 2019-03-01 | 浙江海洋大学 | A kind of preparation method of Thais clavgeria Antihypertensive Peptides |
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