CN108720007B - Lovastatin-containing functional red yeast rice liposome and preparation method thereof - Google Patents
Lovastatin-containing functional red yeast rice liposome and preparation method thereof Download PDFInfo
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- CN108720007B CN108720007B CN201810996492.2A CN201810996492A CN108720007B CN 108720007 B CN108720007 B CN 108720007B CN 201810996492 A CN201810996492 A CN 201810996492A CN 108720007 B CN108720007 B CN 108720007B
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Nutrition Science (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Medicinal Preparation (AREA)
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Abstract
The invention discloses a lovastatin-containing functional red yeast rice liposome and a preparation method thereof. The preparation method comprises the following steps: 1) dissolving functional red yeast rice containing lovastatin, phospholipid and cholesterol by using a nontoxic organic solvent to obtain a mixed solution; 2) removing the nontoxic organic solvent in the mixed solution until a layer of uniform film is formed; 3) obtaining liposome suspension after hydration; 4) obtaining the functional red yeast rice liposome containing lovastatin. Aiming at the problems of poor water solubility, low oral absorption rate, short in-vivo elimination half-life period and low bioavailability of the existing functional red yeast rice product rich in lovastatin, the prepared functional red yeast rice liposome containing the lovastatin can reduce the loss of the lovastatin in gastric juice and increase the digestion of the lovastatin in intestinal juice, thereby obviously increasing the bioavailability of the lovastatin in the functional red yeast rice.
Description
Technical Field
The invention belongs to the technical field of food processing, and particularly relates to a lovastatin-containing functional red yeast rice liposome and a preparation method thereof.
Background
Red yeast is prepared by inoculating Monascus into rice, fermenting, and refining, and can be used as natural dietary supplement because the statin substances can reduce cholesterol. Red Rice is rich in statin substances, and the highest content of lovastatin. Lovastatin is the first statin approved by FDA in the united states to be marketed, and can significantly reduce serum total cholesterol, triacylglycerol and low density lipoprotein cholesterol levels, while increasing serum high density lipoprotein cholesterol levels, significantly reducing the incidence of cardiovascular disease. Therefore, the functional red yeast rice rich in lovastatin (up to 5 percent) has the effects of strengthening body constitution, invigorating spleen to promote digestion, promoting blood circulation and removing blood stasis, and can be used for preventing and treating hyperlipidemia, coronary heart disease, diabetes, osteoporosis, cancer, non-alcoholic fatty liver, fatigue, central nervous degenerative diseases and the like. Therefore, the health food and the health medicine developed by the functional red yeast rice are very popular in domestic and international markets.
At present, the health care medicine developed by utilizing the functional red yeast rich in lovastatin is mainly an oral preparation, mainly tablets and capsules. However, the method for improving the bioavailability of the lovastatin and achieving the long-acting and slow-release effects has wide application prospect due to the poor water solubility, low oral absorption rate, short in-vivo elimination half-life period and low bioavailability and the obvious reduction of the effect of the lovastatin in the functional red yeast rice.
Disclosure of Invention
The invention aims to solve the problems of poor water solubility, low oral absorption rate, short in-vivo elimination half-life period and low bioavailability of the existing functional red yeast rice product rich in lovastatin.
In order to achieve the above object, the first aspect of the present invention provides a method for preparing lovastatin-containing functional red yeast rice liposomes, the method comprising:
1) dissolving functional red yeast rice containing lovastatin, phospholipid and cholesterol by using a nontoxic organic solvent to obtain a mixed solution;
2) carrying out reduced pressure rotary evaporation on the mixed solution to remove the non-toxic organic solvent in the mixed solution until a layer of uniform film is formed;
3) mixing the film with a solvent with the pH value of 5-7, and hydrating to obtain a liposome suspension;
4) and (3) carrying out ultrasonic treatment and filtration on the liposome suspension to obtain the lovastatin-containing functional red yeast rice liposome.
As a preferred embodiment of the present invention, the non-toxic organic solvent is ethanol and/or acetic acid.
As a preferred embodiment of the present invention, the phospholipid is selected from at least one of soybean lecithin, egg yolk lecithin, hydrogenated soybean phospholipid, hydrogenated lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, and phosphatidic acid.
As a preferred embodiment of the invention, the other components are used in the following amount by weight relative to the lovastatin-containing functional red yeast rice: 10-100 parts of phospholipid, 1-50 parts of cholesterol, 1000-11000 parts of nontoxic organic solvent and 1000-11000 parts of solvent with pH of 5-7.
According to the invention, the non-toxic organic solvent cannot fully dissolve phospholipid and cholesterol when the dosage is too small, and the subsequent rotary evaporation time is too long when the dosage is too large, so that the dosage is preferably 1000-11000 parts by weight.
In a preferred embodiment of the present invention, the weight ratio of phospholipid to cholesterol is 2 to 6: 1.
as a preferred embodiment of the present invention,
in the step 2), the temperature of reduced pressure rotary steaming is 10-50 ℃, the time is 10-60 min, and the rotating speed is 50-300 rpm;
and in the step 3), before the hydration step, the method further comprises the step of carrying out normal pressure rotary evaporation on the solution obtained by mixing the film with a solvent with the pH value of 5-7, wherein the temperature of the normal pressure rotary evaporation is 30-45 ℃, the time is 30-60 min, and the rotating speed is 100-300 rpm.
In a preferred embodiment of the present invention, the solvent having a pH of 5 to 7 is at least one selected from the group consisting of pure water, physiological saline, phosphate buffer, acetate buffer, citrate buffer, Tris-HCl buffer, and glycine-sodium hydroxide buffer. Under the pH condition, the reagent is selected, the lovastatin-containing functional red yeast rice is high in stability, and the prepared functional red yeast rice liposome is uniform in size, high in embedding rate and good in stability.
As a preferred embodiment of the present invention,
the hydration time is 30-90 min;
the power of the ultrasonic wave is 90-200 w, and the time of the ultrasonic wave is 5-40 min.
The second aspect of the invention provides the lovastatin-containing functional red yeast rice liposome prepared by the preparation method.
As a preferred embodiment of the invention, the particle size of the lovastatin-containing functional monascus liposome is 41 +/-5 nm, the polydispersity is 0.415 +/-0.106, and the Zeta potential is-11.83 +/-0.75 mV.
According to the present invention, the lovastatin-containing functional red yeast rice can be lovastatin-containing functional red yeast rice conventionally used by those skilled in the art, and the lovastatin-containing functional red yeast rice can be commercially available.
The invention has the advantages and positive effects that:
1) aiming at the problems of poor water solubility, low oral absorption rate, short in-vivo elimination half-life period and low bioavailability of the existing functional red yeast rice product rich in lovastatin, the prepared functional red yeast rice liposome containing the lovastatin can reduce the loss of the lovastatin in gastric juice and increase the digestion of the lovastatin in intestinal juice, thereby obviously increasing the bioavailability of the lovastatin in the functional red yeast rice.
2) The lovastatin-containing functional red yeast liposome prepared by the invention has the advantages of small particle size, uniform size and good dispersibility.
3) The liposome serving as a novel carrier drug delivery system has the characteristics of a biological membrane and drug delivery capacity, and the slightly soluble drug is wrapped in a lipid bilayer, so that the liposome has stronger amphipathy, can obviously improve the oral transmembrane absorption rate and the in-vivo bioavailability of the drug, and has the advantages of biocompatibility, low toxicity, easiness in preparation, capability of improving the therapeutic index of the drug and the like. The invention can effectively reduce the cytotoxicity of the functional red yeast rice, thereby further ensuring the safety of the functional red yeast rice.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
FIG. 1 shows a transmission electron microscope image of the lovastatin-containing functional red yeast rice liposome prepared by the invention;
FIG. 2 shows the effect of artificial gastric juice on the degradation rate of lovastatin in functional red yeast rice and lovastatin-containing functional red yeast rice liposomes;
FIG. 3 shows the effect of artificial intestinal juice on the degradation rate of lovastatin in functional red yeast rice and lovastatin-containing functional red yeast rice liposomes;
FIG. 4 shows the effect of functional red yeast rice containing lovastatin and functional red yeast rice liposome containing lovastatin on HepG-2, MKN-28 cell morphology observed by microscope.
Description of reference numerals: a: MKN-28 control group, b: MKN-28 functional red yeast rice liposome, c: MKN-28 functional red yeast rice, d: HepG-2 control group, e: HepG-2 functional red yeast liposomes, f: HepG-2 functional red yeast rice.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below. While the following describes preferred embodiments of the present invention, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
Example 1:
weighing the following substances in parts by weight: 1mg of lovastatin-containing functional red yeast rice, 50mg of soybean lecithin and 10mg of cholesterol;
fully dissolving the functional red yeast rice, the soybean lecithin and the cholesterol by using 5mL of analytically pure ethanol, and placing the obtained solution into a rotary steaming bottle;
placing the rotary evaporation bottle filled with the mixed solution on a rotary evaporator at 40 ℃ and 150rpm, and performing rotary evaporation at reduced pressure for 30min to sufficiently remove ethanol until a uniform film is formed;
adding 5mL of phosphate buffer solution with pH value of 6 into a rotary evaporation bottle;
placing the rotary evaporation bottle on a rotary evaporator at 40 ℃ and 200rpm, carrying out rotary evaporation for 30min under normal pressure, then placing for 30min for full hydration, and obtaining liposome suspension after hydration;
placing the suspension in an ultrasonic instrument with ultrasonic power of 150w, and performing water bath ultrasonic treatment for 20 min;
and sequentially filtering the solution after ultrasonic treatment with 0.45 μm and 0.22 μm water system microporous filter membrane to obtain lovastatin-containing functional red yeast rice liposome with particle size of 42 nm.
Example 2:
weighing the following substances in parts by weight: 2mg of lovastatin-containing functional red yeast rice, 100mg of phosphatidyl ethanolamine (cephalin) and phosphatidyl glycerol and 50mg of cholesterol;
fully dissolving the functional red yeast rice, the phosphatidylethanolamine, the phosphatidylglycerol and the cholesterol by using 10mL of analytically pure acetic acid, and placing the obtained solution into a rotary evaporation bottle;
placing the rotary evaporation bottle filled with the mixed solution on a rotary evaporator at 30 ℃ and 200rpm, and carrying out rotary evaporation under reduced pressure for 60min to fully remove acetic acid until a uniform film is formed;
add 10mL of citrate buffer pH 5 to the rotary retort;
placing the rotary evaporation bottle on a rotary evaporator at 35 ℃ and 100rpm, carrying out rotary evaporation for 60min under normal pressure, then placing for 90min for full hydration, and obtaining liposome suspension after hydration;
placing the suspension in an ultrasonic instrument with ultrasonic power of 200w, and performing water bath ultrasonic treatment for 30 min;
and sequentially filtering the solution after ultrasonic treatment with 0.45 μm and 0.22 μm water system microporous filter membrane to obtain lovastatin-containing functional red yeast rice liposome with particle size of 46 nm.
Tests prove that the average particle size of the functional red yeast rice liposome containing the lovastatin prepared by the invention is 41 +/-5 nm, the polydispersity is 0.415 +/-0.106, and the Zeta potential is-11.83 +/-0.75 mV. The observation result of a transmission electron microscope shows that the prepared lovastatin-containing functional red yeast rice liposome has uniform particle size and stable structure.
FIG. 1 shows a transmission electron microscope image of the lovastatin-containing functional red yeast rice liposome prepared by the invention.
FIG. 2 shows the effect of artificial gastric juice on the degradation rate of lovastatin in functional red yeast rice and lovastatin-containing functional red yeast rice liposomes, and FIG. 3 shows the effect of artificial intestinal juice on the degradation rate of lovastatin in functional red yeast rice and lovastatin-containing functional red yeast rice liposomes. As can be seen from the figures 2 and 3, the lovastatin-containing functional red yeast rice and the lovastatin-containing liposome are degraded to different degrees after being digested by the artificial simulated gastrointestinal fluid. The degradation rate of the lovastatin of the functional red yeast rice after being digested by gastric juice for 5h is about 50 percent, while the degradation rate of the lovastatin of the liposome-embedded functional red yeast rice after being digested by gastric juice for 5h is only 28 percent, which shows that the liposome has stronger protection effect on the lovastatin in the functional red yeast rice in the gastric juice environment. The degradation rate of lovastatin of the functional red yeast rice after 5h of intestinal fluid digestion is about 62%, and the degradation rate of lovastatin of the liposome-embedded functional red yeast rice after 5h of intestinal fluid digestion reaches 80%, which indicates that the digestion of lovastatin in the functional red yeast rice in the intestinal fluid can be enhanced by lipidization. Therefore, after the lovastatin in the functional red yeast rice is embedded by the liposome, the loss of the lovastatin in gastric juice is reduced on one hand, and the digestion of the lovastatin in intestinal juice is increased on the other hand, so that the bioavailability of the lovastatin in the functional red yeast rice is obviously increased.
FIG. 4 shows the effect of functional red yeast rice containing lovastatin and functional red yeast rice liposome containing lovastatin on HepG-2, MKN-28 cell morphology observed by microscope. In order to test the toxic effect of the functional red yeast rice liposome containing the lovastatin on cells, the functional red yeast rice solution containing the lovastatin and the functional red yeast rice liposome containing the lovastatin with the same concentration are simultaneously acted on HepG-2 cells and MKN-28 cells in a logarithmic phase, a bottle of cells without a sample is simultaneously cultured to be used as a control group, after 12 hours of action, all liquid in a culture dish is sucked out, 2mL of PBS buffer solution is added, the buffer solution is sucked out after 30 seconds of washing, and the process is repeated once. After washing, 1mL of HBSS solution was added, and the cell morphology was observed by microscope. As can be seen from FIG. 4, the cells without the effect of the functional red yeast solution and the liposome thereof have compact structure, vigorous growth, unique morphology of the cells and no obvious apoptosis. After the functional red yeast solution with the same concentration and the liposome thereof are treated for 12 hours, compared with an untreated control group, the number of cells is reduced, the cell morphology is changed, part of the cells are shrunk or broken, and the functional red yeast solution treated cells have the characteristic of apoptosis, and show more reduction of the number of the cells and more change of the cell morphology. Therefore, the functional red yeast solution and the liposome thereof have certain influence and toxicity on the cell morphology of HepG-2 and MKN-28, and the functional red yeast solution has larger toxicity, which shows that the liposome embedding can reduce the cytotoxicity of the functional red yeast.
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.
Claims (5)
1. A preparation method of a lovastatin-containing functional red yeast liposome is characterized by comprising the following steps:
1) dissolving functional red yeast rice containing lovastatin, phospholipid and cholesterol by using a nontoxic organic solvent to obtain a mixed solution;
2) carrying out reduced pressure rotary evaporation on the mixed solution to remove the non-toxic organic solvent in the mixed solution until a layer of uniform film is formed;
3) mixing the film with a solvent with the pH = 5-7, carrying out normal pressure rotary evaporation on the obtained solution, and then placing and hydrating to obtain a liposome suspension;
4) carrying out ultrasonic treatment and filtration on the liposome suspension to obtain the lovastatin-containing functional red yeast rice liposome;
the dosage of other components is as follows according to the weight part of the functional red yeast containing lovastatin:
10-100 parts of phospholipid, 1-50 parts of cholesterol, 1000-11000 parts of nontoxic organic solvent and 1000-11000 parts of solvent with pH = 5-7;
in the step 2), the temperature of reduced pressure rotary steaming is 10-50 ℃, the time is 10-60 min, and the rotating speed is 50-300 rpm;
in the step 3), the temperature of the normal-pressure rotary evaporation is 30-45 ℃, the time is 30-60 min, and the rotating speed is 100-300 rpm;
the solvent with the pH = 5-7 is phosphate buffer with the pH =6 or citrate buffer with the pH = 5;
the weight ratio of the phospholipid to the cholesterol is 2-6: 1;
the hydration time is 30-90 min;
the power of the ultrasonic wave is 90-200 w, and the time of the ultrasonic wave is 5-40 min.
2. The method of claim 1, wherein the non-toxic organic solvent is ethanol and/or acetic acid.
3. The production method according to claim 1, wherein the phospholipid is at least one selected from the group consisting of soybean lecithin, egg yolk lecithin, hydrogenated soybean phospholipid, hydrogenated lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, and phosphatidic acid.
4. A functional red yeast rice liposome containing lovastatin prepared by the preparation method of any one of claims 1 to 3.
5. The lovastatin-containing functional red yeast rice liposome of claim 4, wherein the particle size of the lovastatin-containing functional red yeast rice liposome is 41 ± 5nm, the polydispersity is 0.415 ± 0.106, and the Zeta potential is-11.83 ± 0.75 mV.
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