CN107072966B - Capsaicin-vitamin E prodrug self-assembly nanoparticles and preparation method and application thereof - Google Patents
Capsaicin-vitamin E prodrug self-assembly nanoparticles and preparation method and application thereof Download PDFInfo
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
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Abstract
The invention relates to a preparation method of a capsaicin-vitamin E prodrug self-assembly nano drug delivery system. Capsaicin-vitamin E prodrugs (Cap-SVE) are prepared by linking capsaicin to vitamin E using dithiodiglycolic acid. On the basis, capsaicin-vitamin E prodrug self-assembly nanoparticles (Cap-SVE NPs) are further prepared. The prodrug self-assembled nanoparticles have some characteristics: the average particle diameter is less than 200nm, the particles are uniformly distributed in a similar spherical shape, and the drug loading can reach 8 mg/mL calculated by capsaicin‑1. Is stable under acidic condition and is hydrolyzed gradually under the condition of pH 7.4. The prodrug self-assembly nanoparticles can reduce gastrointestinal irritation of capsaicin, remarkably improve bioavailability of the capsaicin, increase targeting effect of the capsaicin in liver, and remarkably improve the anti-oxidation and blood fat reduction drug effects of the capsaicin. Good stability, high safety and wide market prospect.
Description
Technical Field
The invention belongs to the field of new auxiliary materials and new dosage forms of medicinal preparations, and comprises synthesis of a capsaicin-vitamin E prodrug, construction of a capsaicin-vitamin E prodrug self-assembled nanoparticle and application of the capsaicin-vitamin E prodrug in medicament delivery.
Background
Capsaicin (Cap), the main pungent component in capsicum. Capsicum is herbaceous plant of Capsicum of Solanaceae (Solanaceae), and is native to south America. The pepper is pungent in flavor and hot in nature, and has the effects of warming spleen and stomach, dispelling cold, stimulating appetite and promoting digestion. Is widely applied to the treatment of diseases such as vomit, diarrhea and dysentery, chilblain, cold stagnation and abdominal pain, and the like. In addition, the pepper has the effects of promoting digestion, killing insects, detoxifying and the like. Modern pharmacological research shows that capsaicin is the main active component of capsicum, has various pharmacological activities such as oxidation resistance, inflammation resistance, pain relief, blood fat reduction and tumor resistance, and has great development value. However, capsaicin has poor bioavailability due to its low water solubility, and has great irritation, which seriously hinders its development and utilization as a food-borne drug.
The self-assembly drug delivery system refers to a drug or prodrug with certain surface activity which is self-assembled in an aqueous solution to form highly dispersed aggregates such as micelles and vesicles. Compared with the conventional nanometer preparation method, the method overcomes the problems of leakage, burst release, auxiliary material toxicity and the like, and has the advantages of stability, safety, high efficiency and the like. Hydrophobic natural molecules, such as vitamin E and the like, are modified with hydrophobic drug molecules to form small molecular structures with hydrophobic ends, and then the small molecular structures are self-assembled into nanoparticles in water, so that the effects of increasing the permeability of biological membranes, improving the bioavailability of drugs, reducing the irritation of the drugs and the like are achieved, and the method is one of the strategies for preparing prodrug self-assembled nanoparticles. Disulfide bonds due to their flexible structure, the attached drug and lipophilic group readily self-assemble in water to form relatively stable nanoparticles.
Therefore, by combining the structural characteristics of capsaicin, the capsaicin is connected with the vitamin E by utilizing the dithiodiglycolic acid to synthesize the capsaicin-vitamin E prodrug, and the capsaicin-vitamin E prodrug self-assembly nanoparticles are further prepared. Thereby reducing the irritation of the gastrointestinal tract of the capsaicin, improving the bioavailability of the capsaicin, increasing the targeting effect of the capsaicin in the liver and improving the drug effect of the capsaicin for resisting oxidation and reducing blood fat.
Disclosure of Invention
It is an object of the present invention to provide capsaicin-vitamin E prodrugs and methods of preparation.
The second purpose of the invention is to provide capsaicin-vitamin E prodrug self-assembly nanoparticles and a preparation method thereof.
The invention also aims to provide application of the capsaicin-vitamin E prodrug self-assembled nanoparticles in preparing liver-protecting and blood fat-reducing medicines and reducing capsaicin gastrointestinal irritation.
The fourth purpose of the invention is to provide the application of the capsaicin-vitamin E prodrug self-assembly nanoparticles in a capsaicin injection administration, oral administration or local administration drug system.
The technical scheme of the invention is as follows:
a capsaicin-vitamin E prodrug is formed by taking capsaicin as a parent drug and connecting capsaicin with a molecule of vitamin E by dithiodiglycolic acid, and the structural formula of the capsaicin-vitamin E prodrug is as follows:
a method of preparing the capsaicin-vitamin E prodrug described above, comprising the steps of:
And 2, dissolving 500mg of S-VE in dichloromethane, adding 100-400mg of Dicyclohexylcarbodiimide (DCC) and 10-30 mg of DMAP, stirring at room temperature for 5min, adding 250mg of capsaicin, stirring at room temperature for two hours, purifying the reaction solution by using a silica gel column, and obtaining dichloromethane-methanol (100: 0-90: 10V/V) as eluent. Obtaining light yellow viscous semisolid, namely the capsaicin-vitamin E prodrug.
The reaction formula is as follows:
the capsaicin-vitamin E prodrug self-assembly nanoparticles are formed by self-assembling the capsaicin-vitamin E prodrug in an aqueous solution, the average particle size of the capsaicin-vitamin E prodrug self-assembly nanoparticles is less than 200nm, the capsaicin-vitamin E prodrug self-assembly nanoparticles are uniformly distributed in a quasi-spherical shape, and the drug loading capacity can reach 8 mg/mL calculated by the capsaicin-1。
A method for preparing the capsaicin-vitamin E prodrug self-assembly nanoparticles is to dissolve the capsaicin-vitamin E prodrug in absolute ethyl alcohol, slowly drop the capsaicin-vitamin E prodrug into deionized water under the condition of stirring, and finally keep the final concentration of the ethyl alcohol to be less than 5 percent. Under the condition, the capsaicin-vitamin E prodrug is self-assembled to form liquid with blue glimmer, namely, the capsaicin-vitamin E prodrug self-assembly nanoparticle solution.
The capsaicin-vitamin E prodrug self-assembly nanoparticles are applied to preparation of a self-assembly nano drug delivery system.
The capsaicin-vitamin E prodrug self-assembly nanoparticles are applied to a drug delivery system.
The capsaicin-vitamin E prodrug self-assembly nanoparticles are applied to preparation of liver-protecting or blood fat-reducing medicines.
The capsaicin-vitamin E prodrug self-assembly nanoparticles can be used for preparing an injection for liver protection and a blood fat reduction drug, or can be used for preparing an injection for injection administration or a capsule or a tablet for oral administration.
Advantageous effects
The prepared capsaicin-vitamin E prodrug self-assembly nanoparticles have the average particle size of less than 200nm and are uniform in a similar spherical shapeThe distribution and drug loading can reach 8 mg/mL calculated by capsaicin-1. Is stable under acidic condition and is hydrolyzed gradually under the condition of pH7.4. The prodrug self-assembly nanoparticles can reduce gastrointestinal irritation of capsaicin, remarkably improve bioavailability of the capsaicin, increase targeting effect of the capsaicin in liver, and remarkably improve the anti-oxidation and blood fat reduction drug effects of the capsaicin.
Drawings
FIG. 1 is a mass spectrum of a capsaicin-vitamin E prodrug according to example 1 of the invention.
FIG. 2 is a diagram of the preparation of a capsaicin-vitamin E prodrug in example 113C-NMR spectrum.
FIG. 3 is a diagram of the capsaicin-vitamin E prodrug of example 11H-NMR spectrum.
Fig. 4 is a transmission electron microscope image of capsaicin-vitamin E prodrug self-assembled nanoparticles of embodiment 2.
FIG. 5 is the in vitro release profile of capsaicin-vitamin E prodrug self-assembled nanoparticles in different media in example 6 (A: water; B: pH1.2 hydrochloric acid solution; C: pH6.8 phosphate buffer solution; D: pH7.4 phosphate buffer solution).
FIG. 6 is a graph of the in vivo drug delivery curves of capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles from rats in example 7.
FIG. 7 is a graph of the in vivo administration of capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles in rats according to example 7 of the present invention.
Fig. 8 shows the tissue distribution of mice injected with capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles in example 8, and A, B, C shows the tissue distribution of mice injected with capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles 10, 30, and 60min later.
Fig. 9 shows the tissue distribution of the mice with the self-assembled nanoparticle of capsaicin and capsaicin-vitamin E prodrug in example 8 after oral administration, and A, B, C shows the tissue distribution after 0.5, 2 and 4 hours after oral administration.
FIG. 10 shows the pathological section with irritation to the gastrointestinal tract in example 9 of the present invention (A1-A4: pathological sections of control group stomach, duodenum, jejunum, and ileum; B1-B4: pathological sections of crude drug group stomach, duodenum, jejunum, and ileum; C1-C4: pathological sections of capsaicin-vitamin E prodrug self-assembled nanoparticles group stomach, duodenum, jejunum, and ileum)
FIG. 11 shows the effect of the self-assembled nanoparticles of capsaicin and capsaicin prodrug on the morphology of mouse liver tissue in example 11 (A-D: control group, model group, capsaicin-vitamin E prodrug self-assembled nanoparticles group)
Detailed Description
The examples set out below are intended to facilitate a better understanding of the invention by a person skilled in the art and are not intended to limit the invention in any way.
EXAMPLE 1 Synthesis of capsaicin-vitamin E prodrugs
1g of dithiodiglycolic acid is dissolved in 10mL of acetic anhydride, stirred at room temperature for 3-4 hours, and then rotated to evaporate to dryness at 60 ℃ after the reaction is finished. The crude product was dissolved in an appropriate amount of dichloromethane, 20mg of DMAP and 500mg of vitamin E were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column, and the eluent was petroleum ether-ethyl acetate-glacial acetic acid (95:5:0.1 to 80:20:0.1, V/V) to obtain about 800mg of S-VE. 500mg of S-VE is dissolved in a proper amount of dichloromethane, 200mg of DCC and 14mg of DMAP are added, stirring is carried out at room temperature for 5min, 250mg of capsaicin is added, and stirring is carried out at room temperature for two hours. Purifying the reaction solution by using a silica gel column, wherein the eluent is dichloromethane-methanol (100: 0-90: 10V/V), and obtaining about 500mg of light yellow viscous semisolid, namely the capsaicin-vitamin E prodrug.
The structure of the capsaicin-vitamin E prodrug in example 1 is verified by LC-MS (liquid chromatography-mass spectrometry) technology. The chromatographic conditions were as follows, column: waters Symmetry C18(150 mm. times.4.6 mm, 5 μm); the mobile phase was 0.01 formic acid (a) -methanol (B), eluting with a gradient. The gradient is 0-5 min, 70% B; 70-100% of B for 5-20 min; 100% B for 20-40 min. Detection wavelength: 280 nm; sample introduction amount: 10 mu L of the solution; ion trap mass spectrometer conditions: a shear Flow Rate of 35 arb; aux Gas Flow Rate 5 arb; i spray Voltage is 4.50 Kv; 325 ℃ C; 30V for Capillary Voltage; tube Lens 120V. The retention time Rt of the capsaicin-vitamin E prodrug is 31.47 min. The mass spectrum of the capsaicin-vitamin E prodrug is shown in figure 1. As can be seen from the figure, M/z 904.93 corresponds to [ M + Na ]]+M/z 1785.66 for [2M + Na]+Verifying that the molecular weight of the monomer compound is 881 and the molecular formula is C51H79NO7S2Consistent with the formula of the capsaicin prodrug.
The structure of the capsaicin-vitamin E prodrug from example 1 was determined by NMR.
The monomer component (20 mg) was weighed, dissolved in 0.6mL of deuterated chloroform, and detected by a nuclear magnetic resonance analyzer.13C-NMR、1The H-NMR spectrum is shown in FIG. 2 and FIG. 3.
13C-NMR(400MHz，CDCl3) The results were: δ is 173.2,168.2,167.2,182.1,178.9,140.5,138.5,137.8,137.1,127.5,125.6,123.5,122.8,121.1,118.5,111.3,74.6,53.2,42.1,40.5,39.0,36.9,35.2,33.9,32.0,31.1,29.8,28.6,25.6,25.2,24.9,22.3,21.5,21.0,20.0,13.0,12.1, 11.1. .
1H-NMR(400MHz，CDCl3) The results were: δ 7.04(d, J ═ 8.0Hz,1H),6.93(d, J ═ 1.9Hz,1H), 6.90-6.80 (m,1H),5.71(s,1H), 5.48-5.23 (m,2H), 4.53-4.37 (m,2H),3.94(s,2H),3.90(s,2H),3.84(s,3H),2.61(t, J ═ 6.8Hz,2H), 2.32-2.20 (m,3H), 2.14-1.96 (m,12H), 1.90-1.75 (m,2H), 1.72-1.58 (m,9H), 1.48-1.38 (m,4H), 1.31-1.25 (m,9H), 1.20-1.11.11 (m,5H), 0.6, 6.82 (m, 6H), 6H, 0H).
Example 2 preparation of capsaicin-vitamin E prodrug self-assembled nanoparticles
The preparation process comprises the following steps: an appropriate amount of the capsaicin-vitamin E prodrug obtained in example 1 is dissolved in absolute ethanol and slowly dropped into deionized water under the condition of magnetic stirring (600-800 rpm). So that the final ethanol concentration is less than 5%. Under the condition, the capsaicin-vitamin E prodrug is self-assembled to form liquid with blue glimmer, namely, the capsaicin-vitamin E prodrug self-assembly nanoparticle solution.
Example 3 morphological Observation of capsaicin-vitamin E prodrug self-assembled nanoparticles
The morphology of the capsaicin-vitamin E prodrug self-assembled nanoparticles in the example 2 is observed through a transmission electron microscope, and specifically comprises the following steps: the capsaicin-vitamin E prodrug self-assembly nanoparticles are prepared, diluted by a proper amount of distilled water and then dripped to a copper net, and the nanoparticles are dried at room temperature. And then, a drop of 2% phosphotungstic acid is dripped to dye the sample, the sample is placed at room temperature for drying, and the morphological characteristics of the sample are observed by adopting a transmission electron microscope. FIG. 4 shows the self-assembled nanoparticle form of the capsaicin-vitamin E prodrug, which is in a sphere-like shape.
Example 4 capsaicin-vitamin E prodrug self-assembled nanoparticles particle size distribution and Zeta potential determination
The particle size distribution and Zeta potential of the capsaicin-vitamin E prodrug self-assembled nanoparticles in example 2 are measured by a laser particle size analyzer, and specifically are as follows: the capsaicin-vitamin E prodrug self-assembly nanoparticles are prepared, a proper amount of distilled water is added for dilution, and the particle size distribution and the Zeta potential of the nanoparticles are measured by using a Brookhaven dynamic light scattering laser particle size analyzer. The average particle diameter is 159.12 +/-1.55 nm, the polydispersity index is 0.16 +/-0.04 and the Zeta potential is-39.49 +/-1.78 mV. The self-assembled nanoparticle system is relatively stable.
Example 5 drug content test
The theoretical concentration of the preparation is 2 mg/mL-1、4mg·mL-1、8mg·mL-1The capsaicin-vitamin E prodrug self-assembly nanoparticles are prepared by respectively taking 2mL, diluting with double distilled water, filtering with a 0.8-micron microporous filter membrane, taking 0.1mL of diluent, diluting to 1mL with methanol, vortex mixing, and measuring the content of the capsaicin-vitamin E prodrug by an HPLC method, and the results show that the drug contents of the capsaicin-vitamin E prodrug self-assembly nanoparticles with three concentrations are respectively 1.93 +/-0.02 mg.mL-1，3.97±0.04mg·mL-1And 7.95. + -. 0.03 mg. mL-1。
Example 6 in vitro drug Release Profile study
The capsaicin-vitamin E prodrug self-assembly nanoparticles prepared in the preparation example 2 are packaged in a dialysis band (8000-. The drug release media are respectively: water, pH1.2 hydrochloric acid solution, pH6.8 phosphate buffer solution and pH7.4 phosphate buffer solution. In vitro drug release experiments were performed in a 37 + -1 deg.C water bath shaker. Sampling 1mL of the capsaicin-vitamin E prodrug at the specified time after lofting, adding a proper amount of methanol for dilution, and measuring the content of the capsaicin-vitamin E prodrug and the capsaicin by an HPLC method. The results are shown in FIG. 5. The result shows that the capsaicin-vitamin E prodrug self-assembly nanoparticles are stable in water and acidic conditions and slowly release capsaicin under neutral and slightly alkaline conditions.
Example 7 capsaicin-vitamin E prodrug self-assembling nanoparticle pharmacokinetic study
24 healthy male SD rats were randomly divided into 4 groups of 6 rats each. Respectively at a dose of 1.5 mg/kg-1The dosage of the drug is 50mg/kg-1Capsaicin or the capsaicin-vitamin E prodrug self-assembled nanoparticles of example 2 are administered orally. Blood was collected in the orbit at a predetermined time point of about 0.5mL, and plasma was isolated and the drug concentration of capsaicin in rat plasma was measured by HPLC.
Results of the injection administration are shown in fig. 6, and pharmacokinetic parameters were calculated as:
the results of oral administration are shown in fig. 7, and pharmacokinetic parameters were calculated:
the results show that after the capsaicin-vitamin E prodrug is injected into the self-assembled nanoparticles and orally administered, the blood concentration, AUC and C aremaxAre all remarkably improved, T is after oral administrationmaxThe self-assembly nanoparticles of the capsaicin-vitamin E prodrug are remarkably prolonged, so that the bioavailability of the capsaicin is remarkably improved, and the sustained-release effect is realized.
Example 8 capsaicin-vitamin E prodrug self-assembling nanoparticle tissue distribution study
30 healthy male Kunming mice were randomly divided into 4 groups of 5 mice each. Respectively at a dose of 1.5 mg/kg-1The dosage of the drug is 50mg/kg-1Capsaicin or the capsaicin-vitamin E prodrug self-assembled nanoparticles of example 2 are administered orally. At a given time point, the eyeball collects blood and each organ (heart, liver, spleen, lung, kidney, brain) is collected, and plasma or brain is separatedAfter the addition of the physiological saline for homogenization, the drug concentration of capsaicin in the plasma and organs of mice was measured by the HPLC method.
The results of injection administration are shown in fig. 8, and the results of oral administration are shown in fig. 9.
Example 9 capsaicin-vitamin E prodrug gastrointestinal irritation study
The 9 healthy male Kunming mice were randomly divided into three groups, blank, capsaicin and the capsaicin-vitamin E prodrug self-assembled nanoparticle group of example 2. Fasting was performed for 12 hours before administration and water was freely available. The control group is perfused with 4mL of distilled water, and the experimental group is perfused with 50mg/kg of distilled water-1The dosages of capsaicin and the capsaicin-vitamin E prodrug self-assembled nanoparticles of example 2 were administered orally, respectively. The mice were sacrificed 2 hours after administration, a small tissue of each of the whole stomach, duodenum, jejunum, and ileum was excised from the lower end of the cardia to the pylorus after dissection, and after slight rinsing with physiological saline, samples were collected and fixed in paraformaldehyde solution. And sequentially carrying out conventional dehydration and paraffin embedding, preparing pathological sections of gastric mucosa, duodenum, jejunum and ileum mucosa by a slicer, staining by hematoxylin-eosin, and observing under an optical microscope.
Pathological sections of gastric mucosa, duodenum, jejunum and ileum are shown in fig. 10. As can be seen, the pathological section of the gastric mucosa of the rat in the control group has a perfect tissue structure of the gastric mucosa, the gastric fovea on the surface of the mucosa is clearly visible, and the arrangement of the gland bodies in the mucosa is close and regular. The injury area of the gastric mucosa in the raw material medicine is large, the stomach fovea is damaged, a large amount of epithelial cells are degenerated, shed and eroded, and the gland structure is disordered and has some defects. Cells were severely vacuolated. Pathological section images of the capsaicin-vitamin E prodrug self-assembly nanoparticle group show that cells are arranged orderly, no obvious vacuole exists, cell nuclei are clear and visible, and tissues are intact. The capsaicin raw material medicine has stronger stimulation to gastric mucosa and serious damage to gastric tissues. And the damage of the capsaicin-vitamin E prodrug self-assembled nanoparticle group to the mucosa is greatly reduced. In the pathological section images of duodenum, jejunum and ileum mucosa of the rats in the control group, the tissue structure of the intestinal mucosa is intact, the intestinal villus structure is intact, and the shape is normal. In the capsaicin group, intestinal mucosa cells are solidified and contracted, cells are seriously vacuolated, and intestinal villi are seriously damaged; the extent of intestinal villus structure damage in the capsaicin-vitamin E prodrug self-assembled nanoparticle group is greatly reduced compared to the capsaicin group.
Example 10 study of antioxidant Activity of capsaicin-vitamin E prodrug self-assembled nanoparticles
30 mice were randomly divided into five groups of 6 mice each. Blank, model, positive control, capsaicin and the capsaicin-vitamin E prodrug self-assembled nanoparticle of example 2, respectively. The blank group and the model group are respectively administered with physiological saline by intragastric gavage, and simultaneously, the positive control group, the capsaicin group and the capsaicin-vitamin E prodrug self-assembly nanoparticle group are respectively administered with vitamin C, capsaicin and capsaicin-vitamin E prodrug self-assembly nanoparticles by intragastric gavage. The dose of vitamin C is 50mg/kg, and the dose of capsaicin and the prodrug thereof in the nano preparation group is 5mg/kg (calculated by the content of the capsaicin). The administration was carried out for a total of 15 days. On day 16, except the blank group of mice, the other groups of mice were intragastrically administered with a 0.3% solution of carbon tetrachloride in sesame oil at a intragastric dose of 5 mL/kg. The blank mice were gavaged with an equal dose of sesame oil solution. The mice were then weighed and sacrificed 24 hours later, blood and liver samples were collected and four indices of T-SOD, T-AOC, GSH-Px and MDA in plasma and liver were determined with the kit.
The influence of capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles on the content of GSH-Px, T-SOD, T-AOC and MDA in the blood plasma of a mouse:
αp<0.05, compared to model set
βp<0.01, compared to model set
γp<0.05, compared to capsaicin group
The influence of the capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles on the GSH-Px, T-SOD, T-AOC and MDA contents of mouse livers:
αp<0.05, compared to model set
βp<0.01, compared to model set
γp<0.05, compared to capsaicin group
As can be seen from the two tables, compared with the model group, the capsaicin obviously reduces the MDA content in the plasma of the mice and obviously improves the T-SOD, GSH-Px and T-AOC activity in the plasma of the mice. The activity of GSH-Px in the plasma of the mice is obviously improved. There was also a tendency for the activity of T-SOD and T-AOC in plasma to increase without significant difference. Compared with a model group, the capsaicin-vitamin E prodrug self-assembly nanoparticles remarkably reduce the content of MDA in the plasma of a mouse, and remarkably improve the activity of T-SOD, GSH-Px and T-AOC in the plasma of the mouse. Meanwhile, the capsaicin-vitamin E prodrug has significant differences from capsaicin bulk drugs in T-SOD and MDA values of plasma, liver T-SOD, GSH-Px and MDA values of self-assembled nanoparticles. The anti-oxidation effect of the capsaicin-vitamin E prodrug self-assembly nanoparticles is remarkably improved compared with that of capsaicin raw material medicaments.
Example 11 study of lipid-lowering Activity of capsaicin-vitamin E prodrug self-assembled nanoparticles
The 24 mice were randomly divided into four groups of 6 mice each. Blank, model, capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticle groups of example 2, respectively. The blank group and the model group are respectively administered with physiological saline by intragastric gavage, and meanwhile, the capsaicin group and the capsaicin-vitamin E prodrug self-assembly nanoparticle group are respectively administered with capsaicin and the capsaicin-vitamin E prodrug self-assembly nanoparticles by intragastric gavage. The administration dose was 5mg/kg for 30 days. All mice in each group were fed high-fat diet except the blank group. On day 31 of the experiment, after the mice in each group had fasted for 12 hours, the mice in each group were subjected to eyeball bleeding, plasma was separated, and livers were taken. The liver tissue fixed by paraformaldehyde is sequentially subjected to conventional dehydration and paraffin embedding, a pathological section is prepared by a microtome, and the pathological section is observed under an optical microscope after hematoxylin-eosin staining. The kit is used for measuring the content of total cholesterol, triglyceride, total bile acid, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in the plasma of the mouse, the content of total cholesterol and triglyceride in the liver and the total fat content in the liver.
The effect of capsaicin and its capsaicin-vitamin E prodrug nano-preparation on the content of plasma total cholesterol, triglyceride, total bile acid, high density lipoprotein cholesterol, low density lipoprotein cholesterol:
αp<0.05, compared to model set
βp<0.01, compared to model set
γp<0.05, compared to capsaicin group
As can be seen from the above table, compared with the blank group, the plasma triglyceride level in the model group is significantly increased, the cholesterol, total bile acid and low-density lipoprotein level are significantly increased, and the high-density lipoprotein level is significantly decreased. The data of the model groups show that high-fat diet has obvious influence on various indexes of the blood fat of the mouse, and the mouse hyperlipidemia model is successfully established. The levels of cholesterol, triglyceride and low-density lipoprotein in the plasma of mice given the capsaicin raw material drug are remarkably reduced compared with the model group, and the levels of high-density lipoprotein and bile acid respectively have the tendency of rising and falling compared with the model group without reaching the remarkable difference. Mice administered the capsaicin-vitamin E prodrug self-assembled nanoparticle group had very significantly reduced levels of cholesterol, triglycerides, low density lipoprotein, bile acids relative to the model group (p < 0.01), significantly reduced levels relative to the CAP group (p < 0.05), and very significantly reduced levels of bile acids relative to the CAP group. High density lipoprotein levels were significantly elevated relative to the model group (p < 0.05). The result shows that the blood fat reducing effect of the capsaicin-vitamin E prodrug self-assembled nanoparticles on the hyperlipidemic mice is obviously higher than that of capsaicin raw material medicaments.
Effect of capsaicin and its prodrugs on total liver weight and total fat content in high-fat diet mice 30 days after dosing:
αp<0.05, compared to model set
βp<0.01, compared to model set
γp<0.05, compared to capsaicin group
Effect of capsaicin and its prodrugs on liver total cholesterol and triglyceride levels in high-fat diet mice 30 days after administration:
αp<0.05, compared to model set
βp<0.01, compared to model set
γp<0.05, compared to capsaicin group
The table shows that the capsaicin-vitamin E prodrug self-assembly nanoparticles significantly improve the effect of capsaicin on reducing liver lipid of mice with high-fat diet, and significantly improve the effect of reducing the levels of cholesterol and triglyceride in the livers of the mice.
The morphological characteristics of mouse liver tissues after administration of high fat diet and capsaicin-vitamin E prodrug self-assembled nanoparticles are shown in fig. 11.
As can be seen, the liver lobule structure of the liver tissue sample of the normal control group is clear, the liver cells are normal, the liver cells have no swelling, fatty degeneration and necrosis, and no lipid drop is seen in cytoplasm. Diffuse hepatocyte steatosis appears in the liver of a mouse in a model group, the hepatocyte becomes large, more lipid droplets exist, and the damage effect on the liver is obvious. After the capsaicin and the capsaicin-vitamin E prodrug self-assembly nanoparticles are administrated for 30 days, the damage of high-fat feed to the liver of a mouse can be improved to a certain extent. The capsaicin raw material medicine has the advantages that the liver tissue hepatocyte swelling is reduced, more lipid drops are still deposited in cytoplasm, and the volume and the density of the lipid drops are smaller than those of a model group. The degeneration of liver cells of the capsaicin-vitamin E prodrug self-assembly nanoparticle group is greatly reduced, the cell boundary is clear, and the intracytoplasmic fat drops are less highly concentrated. Therefore, the capsaicin and the capsaicin-vitamin E prodrug self-assembly nanoparticles can improve liver injury of high-fat feed to mice, and the improvement effect of the capsaicin-vitamin E prodrug self-assembly nanoparticles is more obvious than that of capsaicin raw material medicines.
Claims (6)
1. A capsaicin-vitamin E prodrug, comprising: the capsaicin-vitamin E prodrug is formed by taking capsaicin as a parent drug and connecting the capsaicin with a molecule of vitamin E by dithiodiglycolic acid, and the structural formula of the capsaicin-vitamin E prodrug is as follows:
2. a process for preparing the capsaicin-vitamin E prodrug according to claim 1, comprising the steps of:
step 1, dissolving 1g of dithiodiglycolic acid in 10-20 mL of acetic anhydride, stirring at room temperature for 3-4 hours, carrying out rotary evaporation to dryness after the reaction is finished, dissolving a crude product in 15-40 mL of dichloromethane, adding 10-30 mg of 4-Dimethylaminopyridine (DMAP) and 500mg of vitamin E, stirring at room temperature for 2 hours, purifying a reaction solution by using a silica gel column, and eluting with a petroleum ether-ethyl acetate-glacial acetic acid mixed solvent, wherein the volume ratio is as follows: petroleum ether: ethyl acetate: glacial acetic acid is 95:5: 0.1-80: 20:0.1 to obtain S-VE;
step 2, dissolving 500mg of S-VE in dichloromethane, adding 100-400mg of Dicyclohexylcarbodiimide (DCC) and 10-30 mg of DMAP, stirring for 5min at room temperature, adding 250mg of capsaicin, stirring for two hours at room temperature, purifying the reaction solution by using a silica gel column, wherein the eluent is a dichloromethane-methanol mixed solvent, and the volume ratio is as follows: dichloromethane: and (3) obtaining light yellow viscous semisolid by using methanol as 100:0-90:10, namely the capsaicin-vitamin E prodrug.
3. A capsaicin-vitamin E prodrug self-assembly nanoparticle is characterized in that: the capsaicin-vitamin E prodrug self-assembly nanoparticles are formed by self-assembling the capsaicin-vitamin E prodrug in an aqueous solution according to claim 1, the average particle size of the capsaicin-vitamin E prodrug self-assembly nanoparticles is less than 200nm, the capsaicin-vitamin E prodrug self-assembly nanoparticles are uniformly distributed in a quasi-spherical shape, and the drug loading is 8 mg/mL calculated by the capsaicin-1。
4. A method of making the capsaicin-vitamin E prodrug self-assembled nanoparticles of claim 3, wherein: dissolving a capsaicin-vitamin E prodrug in absolute ethyl alcohol, slowly dripping the capsaicin-vitamin E prodrug into deionized water under the stirring condition, and finally keeping the final concentration of the ethyl alcohol to be less than 5 percent, wherein the capsaicin-vitamin E prodrug is self-assembled to form liquid with blue glimmer, namely the capsaicin-vitamin E prodrug self-assembled nanoparticle solution.
5. The use of the capsaicin-vitamin E prodrug self-assembled nanoparticles as claimed in claim 3 in the preparation of a liver-protecting or blood lipid-lowering drug.
6. The use of the capsaicin-vitamin E prodrug self-assembled nanoparticles according to claim 5, in the preparation of a liver-protecting or blood fat-reducing medicament, wherein: the medicine is injection for injection or capsule or tablet for oral administration.
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| CN107072966A (en) | 2017-08-18 |
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