WO2018112728A1 - 辣椒碱-维生素e前药自组装纳米粒及其制法和用途 - Google Patents
辣椒碱-维生素e前药自组装纳米粒及其制法和用途 Download PDFInfo
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- WO2018112728A1 WO2018112728A1 PCT/CN2016/110972 CN2016110972W WO2018112728A1 WO 2018112728 A1 WO2018112728 A1 WO 2018112728A1 CN 2016110972 W CN2016110972 W CN 2016110972W WO 2018112728 A1 WO2018112728 A1 WO 2018112728A1
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- Prior art keywords
- capsaicin
- vitamin
- prodrug
- self
- assembled
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- 239000000651 prodrug Substances 0.000 title claims abstract description 124
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 229940088594 vitamin Drugs 0.000 title 1
- 239000011782 vitamin Substances 0.000 title 1
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Images
Classifications
-
- 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
-
- 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
-
- 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
Definitions
- the invention belongs to the field of new adjuvants and new dosage forms of pharmaceutical preparations, including the synthesis of capsaicin-vitamin E prodrugs and the construction of capsaicin-vitamin E prodrug self-assembled nanoparticles, and its application in drug delivery.
- Capsaicin is the main spicy ingredient in pepper.
- Capsicum is a Solsiaceae Capsicum herb native to South America.
- chili is spicy, hot, has the effect of warming and dispelling cold, appetizing and digestion. It is widely used in the treatment of vomiting, diarrhea, frostbite, cold stagnation and abdominal pain.
- pepper has the effects of digestion, insecticide, detoxification and so on.
- Modern pharmacological studies have shown that capsaicin is the main active ingredient of capsicum, and has a variety of pharmacological activities, such as anti-oxidation, anti-inflammatory, analgesic, hypolipidemic, anti-tumor, and has great development value.
- capsaicin has poor bioavailability due to its low water solubility, and capsaicin has great irritation, which seriously hinders its development and utilization as a food-borne drug.
- a self-assembling drug delivery system refers to a self-assembling drug or prodrug having a certain surface activity in an aqueous solution to form highly dispersed aggregates such as micelles and vesicles. Compared with the conventional nano-preparation method, it overcomes the problems of leakage, sudden release, excipient toxicity, etc., and has the advantages of stability, safety and high efficiency. Hydrophobic natural molecules, such as vitamin E, are modified to form hydrophobic drug molecules, forming a hydrophobic molecular structure at both ends, and then self-assembling into nanoparticles in water to increase biofilm permeability and improve bioavailability of drugs.
- capsaicin was combined with vitamin E by using dithiodiacetic acid to synthesize capsaicin-vitamin E prodrug, and capsaicin-vitamin E prodrug self-assembled nanoparticles were further prepared.
- dithiodiacetic acid to synthesize capsaicin-vitamin E prodrug
- capsaicin-vitamin E prodrug self-assembled nanoparticles were further prepared.
- One of the objects of the present invention is to provide a capsaicin-vitamin E prodrug and a preparation method.
- a second object of the present invention is to provide a capsaicin-vitamin E prodrug self-assembling nanoparticle and a preparation method thereof.
- the third object of the present invention is to provide a capsaicin-vitamin E prodrug self-assembling nanoparticle for use in preparing liver-protecting, hypolipidemic drugs and reducing the gastrointestinal irritation of capsaicin.
- a fourth object of the present invention is to provide a capsaicin-vitamin E prodrug self-assembling nanoparticle for use in a capsaicin injection, oral administration or topical drug system.
- a capsaicin-vitamin E prodrug which is a capsaicin-vitamin E prodrug formed by capsaicin as a parent drug and a captopril linked to a molecule of vitamin E by using thiodithiodiacetic acid, said pepper
- the structural formula of the base-vitamin E prodrug is as follows:
- a method of preparing the above-described capsaicin-vitamin E prodrug which comprises the steps of:
- Step 1 1 g of didithiodiacetic acid is dissolved in 10-20 mL of acetic anhydride, and stirred at room temperature for 3-4 hours. After the reaction is finished, it is rotary evaporated to dryness. The crude product is dissolved in 15-40 mL of dichloromethane, and 10-30 mg is added. Dimethylaminopyridine (DMAP), 500 mg of vitamin E, stirred at room temperature for 2 hours, and the reaction solution was purified with a silica gel column. The eluent was petroleum ether-ethyl acetate- glacial acetic acid (95:5:0.1-80:20:0.1) , V / V) to get S-VE.
- DMAP Dimethylaminopyridine
- Step 2 Take 500 mg of S-VE dissolved in dichloromethane, add 100-400 mg of dicyclohexylcarbodiimide (DCC) and 10-30 mg of DMAP, stir at room temperature for 5 min, add capsaicin 250 mg, stir at room temperature for two hours, the reaction solution Purified by a silica gel column, the eluent was dichloromethane-methanol (100:0 to 90:10 V/V). A light yellow viscous semi-solid, which is a capsaicin vitamin E prodrug.
- DCC dicyclohexylcarbodiimide
- a capsaicin-vitamin E prodrug self-assembling nanoparticle which is a capsaicin-vitamin E prodrug self-assembling nanoparticle assembled from an aqueous solution of the above-mentioned capsaicin-vitamin E prodrug, said pepper
- the average particle size of the self-assembled nanoparticles of alkali-vitamin E prodrugs is less than 200 nm, which is uniformly distributed in a spherical shape, and the drug loading can be up to 8 mg ⁇ mL -1 by capsaicin.
- a method for preparing the above-mentioned capsaicin-vitamin E prodrug self-assembling nanoparticles which is prepared by dissolving capsaicin-vitamin E prodrug in absolute ethanol and slowly dropping into deionized water under stirring, and finally maintaining The final concentration of ethanol is ⁇ 5%. Under these conditions, the capsaicin-vitamin E prodrug self-assembles to form a liquid with a blue shimmer, namely a capsaicin-vitamin E prodrug self-assembling nanoparticle solution.
- capsaicin-vitamin E prodrug self-assembled nanoparticles are used in the preparation of a self-assembled nano drug delivery system.
- capsaicin-vitamin E prodrug self-assembling nanoparticles are used for preparing liver-protecting or hypolipidemic drugs.
- the above-mentioned capsaicin-vitamin E prodrug self-assembling nanoparticles can be an injection for injection or a capsule or tablet for oral administration in preparing a liver-protecting and hypolipidemic drug.
- the prepared capsaicin-vitamin E prodrug self-assembled nanoparticles have an average particle size of less than 200 nm and are uniformly distributed in a spherical shape.
- the drug loading can be up to 8 mg ⁇ mL -1 by capsaicin. It is stable under acidic conditions and gradually hydrolyzed at pH 7.4.
- the prodrug self-assembling nanoparticles can reduce the gastrointestinal irritation of capsaicin, significantly improve the bioavailability of capsaicin, increase the targeting effect of capsaicin in the liver, and significantly increase the anti-oxidation and hypolipidemic effects of capsaicin. effect.
- Figure 1 is a mass spectrum of a capsaicin-vitamin E prodrug of Example 1 of the present invention.
- Example 2 is a 13 C-NMR chart of a capsaicin-vitamin E prodrug in Example 1 of the present invention.
- Figure 3 is a 1 H-NMR chart of a capsaicin-vitamin E prodrug in Example 1 of the present invention.
- Example 4 is a transmission electron micrograph of capsaicin-vitamin E prodrug self-assembled nanoparticles according to Example 2 of the present invention.
- Example 5 is an in vitro release curve of capsaicin-vitamin E prodrug self-assembled nanoparticles in different media according to Example 6 of the present invention (A: water; B: pH 1.2 hydrochloric acid solution; C: pH 6.8 phosphate buffer; D : pH 7.4 phosphate buffer).
- Figure 6 is a graph showing the incorporation of capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles into a drug in vivo in Example 7 of the present invention.
- Figure 7 is a graph showing the results of oral administration of capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticle rats in vivo in Example 7 of the present invention.
- Figure 8 is a view showing the distribution of the tissue of capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles after injection in Example 8 of the present invention, wherein A, B, and C are tissues after 10, 30, and 60 minutes of injection, respectively. Distribution.
- A, B, and C are tissues after oral administration for 0.5, 2, and 4 hours, respectively. Distribution.
- Figure 10 is a gastrointestinal tract pathological section in Example 9 of the present invention
- A1-A4 control stomach, duodenum, jejunum, ileum pathological section
- B1-B4 drug substance group stomach, duodenum
- jejunum ileal pathological section
- C1-C4 capsaicin-vitamin E prodrug self-assembled nanoparticle group stomach, duodenum, jejunum, ileum pathological section
- Figure 11 is a graph showing the effects of capsaicin and capsaicin prodrug self-assembled nanoparticle on the morphology of liver tissue in mice according to Example 11 of the present invention (AD: control group, model group, capsaicin group, capsaicin-vitamin E prodrug self-assembly) Nanoparticle group)
- 500 mg of S-VE was dissolved in an appropriate amount of dichloromethane, 200 mg of DCC, 14 mg of DMAP was added, and the mixture was stirred at room temperature for 5 min, and capsaicin 250 mg was added thereto, and the mixture was stirred at room temperature for two hours.
- the reaction solution was purified by a silica gel column, and the eluent was dichloromethane-methanol (100:0 to 90:10 V/V) to obtain about 500 mg of a pale yellow viscous semisolid, which is a capsaicin vitamin E prodrug.
- Example 1 The structure of the capsaicin-vitamin E prodrug in Example 1 was verified by LC/MS.
- the chromatographic conditions were as follows, column: Waters Symmetry C18 (150 mm ⁇ 4.6 mm, 5 ⁇ m); mobile phase was 0.01 formic acid (A)-methanol (B), gradient elution. The gradient is 0 to 5 min: 70% B; 5 to 20 min: 70% to 100% B; 20 to 40 min: 100% B.
- Detection wavelength 280 nm; injection amount: 10 ⁇ L; ion trap mass spectrometer conditions: Sheath Flow Rate: 35 arb; Aux Gas Flow Rate: 5 arb; I spray Voltage: 4.50 Kv; Capillary Temp: 325 ° C; Capillary Voltage: 30 V; Tube Lens: 120V.
- the mass spectrum of the capsaicin-vitamin E prodrug is shown in Figure 1.
- m/z 904.93 corresponds to [M+Na] +
- m/z 1785.66 corresponds to [2M+Na] +
- the molecular weight of the monomer compound is 881
- the molecular formula is C 51 H 79 NO 7 S 2
- the capsaicin prodrug formula is consistent.
- the capsaicin-vitamin E prodrug structure of Example 1 was determined by nuclear magnetic resonance.
- the preparation process is as follows: The capsaicin-vitamin E prodrug of Example 1 is dissolved in absolute ethanol and slowly dropped into deionized water under magnetic stirring (600-800 rpm). The final concentration of ethanol is ⁇ 5%. Under these conditions, capsaicin-vitamin E prodrugs self-assemble to form a liquid with blue gleam, ie capsaicin-vitamin E prodrug self-assembly Nanoparticle solution.
- Example 2 The morphology of capsaicin-vitamin E prodrug self-assembled nanoparticles in Example 2 was observed by transmission electron microscopy. Specifically, the capsaicin-vitamin E prodrug self-assembled nanoparticles were prepared, diluted with distilled water and dropped into copper mesh at room temperature. Dry underneath. The sample was dyed by adding a drop of 2% phosphotungstic acid, and dried at room temperature. The morphology was observed by transmission electron microscopy. Figure 4 shows the morphology of the self-assembled nanoparticles of the phytate-vitamin E prodrug, which is spherical.
- Example 4 Particle size distribution and zeta potential determination of capsaicin-vitamin E prodrug self-assembled nanoparticles
- the particle size distribution and zeta potential of the capsaicin-vitamin E prodrug self-assembled nanoparticles in Example 2 were determined by a laser particle size analyzer. Specifically, the capsaicin-vitamin E prodrug self-assembled nanoparticles were prepared, and diluted with distilled water. The particle size distribution and zeta potential were measured using a Brookhaven dynamic light scattering laser particle size analyzer. The average particle size was determined to be 159.12 ⁇ 1.55 nm, the polydispersity index was 0.16 ⁇ 0.04, and the zeta potential was -39.49 ⁇ 1.78 mV. This indicates that this self-assembled nanoparticle system is relatively stable.
- capsaicin-vitamin E prodrug self-assembled nanoparticles with theoretical concentration of 2mg ⁇ mL -1 , 4mg ⁇ mL -1 , 8mg ⁇ mL -1 , take 2mL respectively, dilute with double distilled water and use 0.8 ⁇ m microporous filter Membrane filtration, 0.1 mL dilution was diluted to 1 mL with methanol, vortexed and mixed, and the content of capsaicin-vitamin E prodrug was determined by HPLC.
- the capsaicin-vitamin E prodrug self-assembled nanoparticles in Example 2 were prepared, and 1 mL of each was packaged in a dialysis belt (8000-14000 Da). The two ends were tightly packed and placed in an Erlenmeyer flask, and 100 mL of each drug release medium was separately added. .
- the drug release media were: water, pH 1.2 hydrochloric acid solution, pH 6.8 phosphate buffer and pH 7.4 phosphate buffer. In vitro drug release experiments were performed in a water bath shaker at 37 ⁇ 1 °C.
- capsaicin-vitamin E prodrug After sampling at a predetermined time, 1 mL was sampled, diluted with appropriate amount of methanol, and the content of capsaicin-vitamin E prodrug and capsaicin was determined by HPLC. The results are shown in Figure 5. The results show that the capsaicin-vitamin E prodrug self-assembled nanoparticles are stable under water and acidic conditions, in neutral alkaline strips. Capsaicin is slowly released under the condition.
- Capsaicin or Capsaicin-Vitamin E prodrug self-assembled nanoparticles in Example 2 were administered orally at a dose of 1.5 mg ⁇ kg -1 or 50 mg ⁇ kg -1 , respectively.
- blood was collected from the eyelids by about 0.5 mL, plasma was separated, and the drug concentration of capsaicin in the rat plasma was determined by HPLC.
- mice Thirty healthy male Kunming mice were randomly divided into 4 groups of 5 mice each.
- the capsaicin or the capsaicin-vitamin E prodrug self-assembled nanoparticles of Example 2 were orally administered by tail vein injection at a dose of 1.5 mg ⁇ kg -1 or 50 mg ⁇ kg -1 orally.
- the blood was collected from the eyeball and the organs (heart, liver, spleen, lung, kidney, brain) were taken.
- the plasma was separated or the physiological saline was added to homogenate.
- the plasma of the mouse and the peppers in each organ were determined by HPLC.
- the drug concentration of the base The capsaicin or the capsaicin-vitamin E prodrug self-assembled nanoparticles of Example 2 were orally administered by tail vein injection at a dose of 1.5 mg ⁇ kg -1 or 50 mg ⁇ kg -1 orally.
- the blood was collected from the eyeball and the organs (heart, liver, spleen, lung, kidney, brain) were taken
- mice Nine healthy male Kunming mice were randomly divided into three groups: blank group, capsaicin group and capsaicin-vitamin E prodrug self-assembled nanoparticle group in Example 2. Fasted for 12 hours before administration and free to drink water.
- the control group was intragastrically administered with 4 mL of distilled water, and the experimental group was orally administered with capsaicin and the capsaicin-vitamin E prodrug self-assembled nanoparticles of Example 2 at a dose of 50 mg ⁇ kg -1 .
- Two hours after the administration the mice were sacrificed. After dissection, a small piece of whole stomach, duodenum, jejunum and ileum was taken from the lower part of the cardia to the pylorus.
- Fig. 10 Pathological sections of gastric mucosa, duodenum, jejunum and ileum are shown in Fig. 10. It can be seen from the figure that the gastric mucosa in the pathological section of the gastric mucosa of the control group is intact, the gastric pits on the surface of the mucosa are clearly visible, and the glands in the mucosa are closely arranged. In the drug substance group, the area of gastric mucosal damage is large, the gastric pit is destroyed, a large number of epithelial cells are degenerated, shedding, erosion, gland structure disorder, and some are missing. Cell vacuolation is severe.
- the pathological sections of the capsaicin-vitamin E prodrug self-assembled nanoparticle group showed that the cells were arranged neatly, without obvious vacuoles, the nuclei were clearly visible, and the tissues were intact. It indicated that capsaicin raw materials have strong irritant to gastric mucosa and serious damage to stomach tissue.
- the capsaicin-vitamin E prodrug self-assembled nanoparticle group greatly reduced the damage to the mucosa.
- the duodenal, jejunal and ileal mucosa pathological sections showed intact intestinal mucosa, and the intestinal villi were intact and normal.
- the intestinal mucosal cells were pyknosis, the cells were vacuolated, and the intestinal villi were severely damaged.
- the degree of intestinal villus damage in the capsaicin-vitamin E prodrug self-assembled nanoparticles group was significantly reduced compared with the capsaicin group.
- mice Thirty mice were randomly divided into five groups of six each. They were blank group, model group, positive control group, capsaicin group and capsaicin-vitamin E prodrug self-assembled nanoparticle group in Example 2. The blank group and the model group were given normal saline daily, and the positive control group, the capsaicin group and the capsaicin-vitamin E prodrug self-assembled nanoparticle group were administered with vitamin C, capsaicin and capsaicin-vitamin E respectively. Drug self-assembling nanoparticles. Vitamin C drug The dosage was 50 mg/kg, and the dosage of capsaicin and its prodrug nano-preparation group was 5 mg/kg (calculated as capsaicin content). A total of 15 days were administered.
- mice On the 16th day, except for the blank group mice, the other groups of mice were intragastrically administered with 0.3% carbon tetrachloride sesame oil solution, and the intragastric dose was 5 mL/kg. The mice in the blank group were orally administered with the same dose of sesame oil solution. The mice were then weighed and sacrificed 24 hours later, blood and liver samples were collected, and four indicators of T-SOD, T-AOC, GSH-Px and MDA in plasma and liver were determined by kit.
- capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles on plasma GSH-Px, T-SOD, T-AOC and MDA contents in mice:
- capsaicin significantly reduced the amount of MDA in mouse plasma compared with the model group. Significantly increased T-SOD, GSH-Px and T-AOC activity in mouse plasma. Significantly increased the activity of GSH-Px in mouse plasma. The activity of T-SOD and T-AOC in plasma also increased, but there was no significant difference.
- capsaicin-vitamin E prodrug self-assembled nanoparticles significantly reduced MDA content in mouse plasma, and significantly increased T-SOD, GSH-Px and T-AOC activity in mouse plasma.
- capsaicin-vitamin E prodrug self-assembled nanoparticles were significantly different from those of capsaicin. It is indicated that the antioxidant effect of capsaicin-vitamin E prodrug self-assembled nanoparticles is significantly higher than that of capsaicin.
- mice Twenty-four mice were randomly divided into four groups of six each. They were blank group, model group, capsaicin group and capsaicin-vitamin E prodrug self-assembled nanoparticle group in Example 2. The blank group and the model group were given normal saline by gavage every day. At the same time, the capsaicin group and the capsaicin-vitamin E prodrug self-assembled nanoparticle group were intragastrically administered with capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles. The dose was 5 mg/kg for a total of 30 days. All groups of mice were fed a high-fat diet except for the blank group.
- each group of mice was subjected to eyeball blood collection, plasma was separated, and the liver was taken.
- the liver tissue fixed with paraformaldehyde was sequentially subjected to conventional dehydration and paraffin embedding, and pathological sections were prepared by a microtome. After staining with hematoxylin-eosin, the cells were observed under an optical microscope.
- the total plasma cholesterol, triglyceride, total bile acid, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol and triglyceride levels in the liver were determined by a kit, and the total fat content of the liver was determined.
- capsaicin and its capsaicin-vitamin E prodrug nanoforms on plasma total cholesterol, triglyceride, total bile acid, high density lipoprotein cholesterol, low density lipoprotein cholesterol:
- the triglyceride level in the plasma of the model group was significantly increased, the levels of cholesterol, total bile acid, and low-density lipoprotein were significantly increased, and the level of high-density lipoprotein was significantly decreased.
- Model group data It indicated that the high-fat diet had significant effects on the blood lipids of mice, and the mouse hyperlipidemia model was successfully established.
- the levels of cholesterol, triglyceride and low-density lipoprotein in the plasma of mice given capsaicin were significantly lower than those in the model group.
- the levels of high-density lipoprotein and bile acid increased and decreased compared with the model group. Without reaching a significant difference.
- the levels of cholesterol, triglyceride, low-density lipoprotein and bile acid in the capsaicin-vitamin E prodrug self-assembled nanoparticle group were significantly lower than those in the model group (p ⁇ 0.01), which was significant compared with the CAP group.
- the decrease was (p ⁇ 0.05) and the bile acid level was significantly reduced relative to the CAP group.
- High-density lipoprotein levels were significantly elevated relative to the model group (p ⁇ 0.05).
- the results showed that the hypolipidemic effect of capsaicin-vitamin E prodrug self-assembled nanoparticles on hyperlipidemia mice was significantly higher than that of capsaicin.
- capsaicin-vitamin E prodrug self-assembled nanoparticles significantly increase the effect of capsaicin on reducing liver lipids in mice with high fat diet, and the effect of lowering cholesterol and triglyceride levels in mouse liver. Significantly increased.
- liver tissue of the normal control group has clear hepatic lobule structure, normal liver cells, no hepatocyte swelling and steatosis, necrosis, and no lipid droplets in the cytoplasm. Diffuse hepatic steatosis occurred in the liver of the model group, the hepatocytes became larger, and there were more lipid droplets, which had more obvious damage to the liver. After 30 days of administration of capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles, the liver damage of the high-fat diet to mice was improved to some extent.
- capsaicin raw material group In the capsaicin raw material group, hepatocyte swelling in the liver tissue was alleviated, and there was still more lipid drip in the cytoplasm. The lipid droplets were smaller in size and lower in density than the model group. The liver cell degeneration of the capsaicin-vitamin E prodrug self-assembled nanoparticle group was greatly reduced, the cell boundary was clear, and the cytoplasmic fat droplet episodes were less. This indicates that capsaicin and capsaicin-vitamin E prodrug self-assembled nanoparticles can improve the liver damage of mice fed with high fat diet, and the effect of capsaicin-vitamin E prodrug self-assembled nanoparticles is better than that of capsaicin. More obvious.
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Abstract
制备一种辣椒碱-维生素E前药自组装纳米给药系统，其利用亚二硫基二乙酸将辣椒碱与维生素E相连，制备辣椒碱-维生素E前药(Cap-SVE)。在此基础上，进一步制备辣椒碱-维生素E前药自组装纳米粒(Cap-SVE NPs)。该前药自组装纳米粒具有一些特征：平均粒径小于200nm，呈类球形均匀分布，载药量以辣椒碱计算可达8mg·mL-1。在酸性条件下较稳定，在pH7.4条件下逐渐水解。该前药自组装纳米粒可降低辣椒碱的胃肠道刺激性，显著提高辣椒碱的生物利用度，增加辣椒碱在肝脏的靶向作用，并显著提高辣椒碱的抗氧化与降血脂的药效。稳定性好，安全性高，具有较大的市场前景。
Description
本发明属于药物制剂新辅料和新剂型领域，包括辣椒碱-维生素E前药的合成及辣椒碱-维生素E前药自组装纳米粒的构建，以及其在药物传递中的应用。
辣椒碱(Capsaicin，Cap)，为辣椒中的主要辛辣成分。辣椒为茄科(Solanaceae)辣椒属(Capsicum)草本植物，原产于南美洲。辣椒味辛，性热，具有温中散寒，开胃消食的功效。被广泛应用于治疗呕吐，泻痢，冻疮，寒滞腹痛等疾病。此外，辣椒还有消食、杀虫、解毒等功效。现代药理学研究表明，辣椒碱为辣椒的主要活性成分，具有多种药理活性，如抗氧化、抗炎、镇痛、降血脂、抗肿瘤，具有极大的开发价值。然而，辣椒碱由于其较低的水溶性而导致生物利用度较差，且辣椒碱具有较大的刺激性，严重阻碍了其作为食源性药物的开发利用。
自组装药物传递系统是指具有一定表面活性的药物或前药在水溶液中自组装形成胶束、囊泡等高度分散的聚集体。相比于常规纳米制剂手段，克服了渗漏、突释、辅料毒性等问题，具有稳定、安全、高效等优势。将疏水性天然分子，如维生素E等，修饰疏水性的药物分子，形成两端疏水的小分子结构，进而在水中自组装成纳米颗粒，以起到增加生物膜渗透性、提高药物的生物利用度、降低药物的刺激性等作用，为制备前药自组装纳米颗粒的策略之一。二硫键由于其自身的柔性结构，所连接的药物与亲脂基团易于在水中发生自组装而形成相对稳定的纳米颗粒。
因此，结合辣椒碱的结构特点，利用亚二硫基二乙酸将辣椒碱与维生素E相连，合成辣椒碱-维生素E前药，并进一步制备辣椒碱-维生素E前药自组装纳米粒。从而降低辣椒碱的胃肠道刺激性，提高辣椒碱的生物利用度，增加辣椒碱在肝脏的靶向作用，以提高辣椒碱的抗氧化与降血脂的药效作用。
发明内容
本发明的目的之一是，提供辣椒碱-维生素E前药及制备方法。
本发明的目的之二是，提供辣椒碱-维生素E前药自组装纳米粒及制备方法。
本发明的目的之三是，提供辣椒碱-维生素E前药自组装纳米粒在制备保肝、降血脂药物及降低辣椒碱胃肠道刺激性方面的应用。
本发明的目的之四是，提供辣椒碱-维生素E前药自组装纳米粒在辣椒碱注射给药、口服给药或局部给药药物系统中的应用。
本发明的技术方案如下：
一种辣椒碱-维生素E前药，它是以辣椒碱为母药，以亚二硫基二乙酸将辣椒碱与一分子维生素E相连而形成的辣椒碱-维生素E前药，所述的辣椒碱-维生素E前药的结构式如下：
一种制备上述的辣椒碱-维生素E前药的方法，它包括下列步骤：
步骤1、将1g亚二硫基二乙酸溶于10～20mL乙酸酐，室温搅拌3-4小时，反应结束后旋转蒸发至干，粗品溶于15～40mL二氯甲烷，加入10～30mg 4-二甲氨基吡啶(DMAP)、500mg维生素E，室温下搅拌2小时，反应液用硅胶柱纯化，洗脱液为石油醚-乙酸乙酯-冰乙酸(95:5:0.1～80:20:0.1，V/V)得S-VE。
步骤2、取500mg S-VE溶于二氯甲烷，加入100～400mg二环己基碳二亚胺(DCC)和10～30mg DMAP，室温搅拌5min，加入辣椒碱250mg，室温搅拌两小时，反应液用硅胶柱纯化，洗脱液为二氯甲烷-甲醇(100:0～90:10V/V)。得浅黄色粘稠半固体，即为辣椒碱维生素E前药。
反应式如下：
一种辣椒碱-维生素E前药自组装纳米粒，它是由上述的辣椒碱-维生素E前药在水溶液中自组装而成的辣椒碱-维生素E前药自组装纳米粒，所述的辣椒碱-维生素E前药自组装纳米粒平均粒径小于200nm，呈类球形均匀分布，载药量以辣椒碱计算可达8mg·mL-1。
一种制备上述的辣椒碱-维生素E前药自组装纳米粒的方法，它是将辣椒碱-维生素E前药溶于无水乙醇中，于搅拌条件下，缓慢滴入去离子水中，最终保持乙醇终浓度＜5％。在此条件下，辣椒碱-维生素E前药自组装形成具有蓝色微光的液体，即辣椒碱-维生素E前药自组装纳米粒溶液。
上述的辣椒碱-维生素E前药自组装纳米粒在制备自组装纳米药物传递系统中的应用。
上述的辣椒碱-维生素E前药自组装纳米粒在药物传递系统中的应用。
上述的辣椒碱-维生素E前药自组装纳米粒在制备保肝或降血脂药物中的应用。
上述的辣椒碱-维生素E前药自组装纳米粒在制备保肝及降血脂药物可以是注射给药的针剂或口服给药的胶囊或片剂。
制备的辣椒碱-维生素E前药自组装纳米粒平均粒径小于200nm，呈类球形均匀分布，载药量以辣椒碱计算可达8mg·mL-1。在酸性条件下较稳定，在pH 7.4条件下逐渐
水解。该前药自组装纳米粒可降低辣椒碱的胃肠道刺激性，显著提高辣椒碱的生物利用度，增加辣椒碱在肝脏的靶向作用，并显著提高辣椒碱的抗氧化与降血脂的药效。
图1为本发明实施例1的辣椒碱-维生素E前药的质谱图。
图2为本发明实施例1中辣椒碱-维生素E前药的13C-NMR谱图。
图3为本发明实施例1中辣椒碱-维生素E前药的1H-NMR谱图。
图4为本发明实施例2的辣椒碱-维生素E前药自组装纳米粒的透射电镜图。
图5为本发明实施例6中不同介质中辣椒碱-维生素E前药自组装纳米粒体外释药曲线(A：水；B：pH 1.2盐酸溶液；C：pH6.8磷酸盐缓冲液；D：pH7.4磷酸盐缓冲液)。
图6为本发明实施例7中辣椒碱与辣椒碱-维生素E前药自组装纳米粒大鼠注射给药体内药时曲线。
图7为本发明实施例7中辣椒碱与辣椒碱-维生素E前药自组装纳米粒大鼠口服给药体内药时曲线。
图8为本发明实施例8中辣椒碱与辣椒碱-维生素E前药自组装纳米粒小鼠注射给药后组织分布情况，A、B、C分别为注射给药10、30、60min后组织分布情况。
图9为本发明实施例8中辣椒碱与辣椒碱-维生素E前药自组装纳米粒小鼠口服给药后组织分布情况，A、B、C分别为口服给药0.5、2、4h后组织分布情况。
图10为本发明实施例9中的胃肠道刺激性病理切片(A1-A4：对照组胃、十二指肠、空肠、回肠病理切片；B1-B4：原料药组胃、十二指肠、空肠、回肠病理切片；C1-C4：辣椒碱-维生素E前药自组装纳米粒组胃、十二指肠、空肠、回肠病理切片)
图11为本发明实施例11的辣椒碱、辣椒碱前药自组装纳米对小鼠肝脏组织形态学的影响(A-D:对照组、模型组、辣椒碱组、辣椒碱-维生素E前药自组装纳米粒组)
以下所列实施例有助于本领域技术人员更好地理解本发明，但不以任何方式限制本发明。
实施例1.辣椒碱-维生素E前药的合成
取1g亚二硫基二乙酸溶于10mL乙酸酐，室温搅拌3-4小时，反应结束后于60℃旋转蒸发至干。粗品溶于适量二氯甲烷，加入20mg DMAP，500mg维生素E，室温
下搅拌2小时。反应液用硅胶柱纯化，洗脱液为石油醚-乙酸乙酯-冰乙酸(95:5:0.1～80:20:0.1，V/V)，得约800mg S-VE。取500mg S-VE溶于适量二氯甲烷，加入200mg DCC，14mg DMAP，室温搅拌5min，加入辣椒碱250mg，室温搅拌两小时。反应液用硅胶柱纯化，洗脱液为二氯甲烷-甲醇(100:0～90:10V/V)，得约500mg浅黄色粘稠半固体，即为辣椒碱维生素E前药。
采用液质联用技术验证实施例1中辣椒碱-维生素E前药结构。色谱条件如下，色谱柱：Waters Symmetry C18(150mm×4.6mm，5μm)；流动相为0.01甲酸(A)-甲醇(B)，梯度洗脱。梯度为0～5min:70％B；5～20min:70％～100％B；20～40min:100％B。检测波长：280nm；进样量：10μL；离子阱质谱联用仪条件：Sheath Flow Rate:35arb；Aux Gas Flow Rate:5arb；I spray Voltage:4.50Kv；Capillary Temp:325℃；Capillary Voltage:30V；Tube Lens:120V。辣椒碱-维生素E前药的保留时间Rt＝31.47min。辣椒碱-维生素E前药的质谱图见图1。由图可知，m/z 904.93对应[M+Na]+，m/z 1785.66对应[2M+Na]+，验证该单体化合物的分子量为881，分子式为C51H79NO7S2，与辣椒碱前药分子式相符合。
采用核磁共振确定实施例1中辣椒碱-维生素E前药结构。
称取单体成分20mg，用0.6mL氘代氯仿溶解，使用核磁共振分析仪检测。13C-NMR、1H-NMR谱图见图2、图3。
13C-NMR(400MHz，CDCl3)结果为：δ＝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)结果为：δ7.04(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(m,5H),0.98(d,J＝6.6Hz,6H),0.92–0.82(m,12H)。
实施例2.辣椒碱-维生素E前药自组装纳米粒的制备
制备工艺如下：取实施例1中辣椒碱-维生素E前药适量溶于无水乙醇中，于磁力搅拌(600-800rpm)条件下，缓慢滴入去离子水中。使得乙醇终浓度＜5％。在此条件下，辣椒碱-维生素E前药自组装形成具有蓝色微光的液体，即辣椒碱-维生素E前药自组装
纳米粒溶液。
实施例3.辣椒碱-维生素E前药自组装纳米粒的形态观察
通过透射电子显微镜观察实施例2中辣椒碱-维生素E前药自组装纳米粒形态，具体为：制备辣椒碱-维生素E前药自组装纳米粒，以适量蒸馏水稀释后滴至铜网，于室温下晾干。再滴加一滴2％磷钨酸对样品进行染色，于室温放置干燥，采用透射电镜观察其形态特征。图4为椒碱-维生素E前药自组装纳米粒形态，呈类球形。
实施例4.辣椒碱-维生素E前药自组装纳米粒粒径分布及Zeta电位测定
通过激光粒度分析仪测定实施例2中辣椒碱-维生素E前药自组装纳米粒的粒径分布及Zeta电位，具体为：制备辣椒碱-维生素E前药自组装纳米粒，加入适量蒸馏水稀释，使用Brookhaven动态光散射激光粒度分析仪测定其粒径分布与Zeta电位。经测定，其平均粒径为159.12±1.55nm，多分散性指数为0.16±0.04，Zeta电位为-39.49±1.78mV。表明此自组装纳米粒体系相对稳定。
实施例5.含药量考察
配制理论浓度为2mg·mL-1、4mg·mL-1、8mg·mL-1的辣椒碱-维生素E前药自组装纳米粒，分别取2mL，以双蒸水稀释后使用0.8μm微孔滤膜过滤，取0.1mL稀释液以甲醇稀释至1mL，涡旋混合后以HPLC法测定辣椒碱-维生素E前药的含量，结果显示，三种浓度的辣椒碱-维生素E前药自组装纳米粒含药量分别为1.93±0.02mg·mL-1，3.97±0.04mg·mL-1和7.95±0.03mg·mL-1。
实施例6.体外释药特性考察
配制实施例2中辣椒碱-维生素E前药自组装纳米粒，分别取1mL封装于透析带(8000-14000Da)中，两端扎紧后置于锥形瓶中，分别加入100mL各释药介质。释药介质分别为：水、pH 1.2盐酸溶液、pH 6.8磷酸盐缓冲液和pH 7.4磷酸盐缓冲液。于37±1℃的水浴振荡器中进行体外释药实验。于放样后规定时间分别取样1mL，加入适量甲醇稀释后，以HPLC法测定辣椒碱-维生素E前药及辣椒碱的含量。结果见图5。结果表明，辣椒碱-维生素E前药自组装纳米粒在水及酸性条件下稳定，在中性偏碱性条
件下缓慢释放出辣椒碱。
实施例7.辣椒碱-维生素E前药自组装纳米粒药代动力学研究
24只健康雄性SD大鼠随机分为4组，每组6只大鼠。分别按1.5mg·kg-1的剂量尾静脉注射或按50mg·kg-1口服给药辣椒碱或实施例2中的辣椒碱-维生素E前药自组装纳米粒。于规定时间点眼眶采血约0.5mL，分离获得血浆，以HPLC法测定大鼠血浆中辣椒碱的药物浓度。
注射给药结果如图6，计算得药动学参数：
口服给药结果如图7，计算得药动学参数：
结果表明，辣椒碱-维生素E前药自组装纳米粒注射及口服给药后，血药浓度、AUC及Cmax均显著提高，口服给药后Tmax显著延长，表明辣椒碱-维生素E前药自组装纳米粒显著提高了辣椒碱的生物利用度，并具有缓释作用。
实施例8.辣椒碱-维生素E前药自组装纳米粒组织分布研究
30只健康雄性昆明小鼠随机分为4组，每组5只小鼠。分别按1.5mg·kg-1的剂量
尾静脉注射或按50mg·kg-1口服给药辣椒碱或实施例2中的辣椒碱-维生素E前药自组装纳米粒。于规定时间点处死，眼球采血并取各脏器(心、肝、脾、肺、肾、脑)，分离血浆或加入生理盐水匀浆后，以HPLC法测定小鼠血浆及各脏器中辣椒碱的药物浓度。
注射给药结果如图8，口服给药结果如图9。
实施例9.辣椒碱-维生素E前药胃肠道刺激性研究
9只健康雄性昆明种小鼠随机分为三组，分别为空白组、辣椒碱组和实施例2中的辣椒碱-维生素E前药自组装纳米粒组。给药前禁食12小时，自由饮水。对照组灌胃4mL蒸馏水，实验组按50mg·kg-1的剂量分别口服辣椒碱和实施例2中的辣椒碱-维生素E前药自组装纳米粒。给药2小时后处死小鼠，解剖后从贲门下端到幽门截取全胃、十二指肠、空肠、回肠各一小块组织，生理盐水轻微漂洗后，收集样品并放置于多聚甲醛溶液中固定。依次进行常规脱水和石蜡包埋，切片机制备胃黏膜、十二指肠、空肠、回肠粘膜病理切片，经苏木精-伊红染色后于光学显微镜下观察。
胃粘膜、十二指肠、空肠、回肠病理切片如图10。由图可见，对照组大鼠胃黏膜病理切片图中胃黏膜组织结构完好，黏膜表面胃小凹清晰可见，粘膜内腺体排列紧密规则。原料药组中胃黏膜损伤面积较大，胃小凹破坏，大量上皮细胞变性、脱落、糜烂，腺体结构紊乱，有的缺失。细胞空泡化严重。辣椒碱-维生素E前药自组装纳米粒组的病理切片图均显示细胞排列整齐，无明显空泡，细胞核清晰可见，组织完好。说明辣椒碱原料药对胃黏膜有较强的刺激性，对胃部组织损伤严重。而辣椒碱-维生素E前药自组装纳米粒组对粘膜的损伤大大降低。对照组大鼠十二指肠、空肠、回肠黏膜病理切片图中肠黏膜组织结构完好，肠绒毛结构完整，形态正常。辣椒碱组中肠黏膜细胞固缩，细胞空泡化严重，肠绒毛破损严重；辣椒碱-维生素E前药自组装纳米粒组的肠绒毛结构损伤程度相比于辣椒碱组大大减轻。
实施例10.辣椒碱-维生素E前药自组装纳米粒抗氧化活性研究
30只小鼠随机分为五组，每组6只。分别为空白组，模型组，阳性对照组，辣椒碱组和实施例2中的辣椒碱-维生素E前药自组装纳米粒组。空白组和模型组每天灌胃给予生理盐水，同时，阳性对照组、辣椒碱组和辣椒碱-维生素E前药自组装纳米粒组分别灌胃给予维生素C、辣椒碱和辣椒碱-维生素E前药自组装纳米粒。维生素C给药剂
量为50mg/kg，辣椒碱及其前药纳米制剂组给药剂量均为5mg/kg(以辣椒碱含量计算)。共给药15天。于第16天，除空白组小鼠外，其余各组小鼠均灌胃给予0.3％的四氯化碳麻油溶液，灌胃剂量为5mL/kg。空白组小鼠灌胃给予同等剂量的麻油溶液。小鼠随后进行体重称量并于24小时后处死，收集血液和肝脏样品，并以试剂盒测定血浆及肝脏中T-SOD、T-AOC、GSH-Px和MDA四个指标。
辣椒碱和辣椒碱-维生素E前药自组装纳米粒对小鼠血浆GSH-Px,T-SOD,T-AOC和MDA含量的影响：
αp<0.05,相比于模型组
βp<0.01,相比于模型组
γp<0.05,相比于辣椒碱组
辣椒碱和辣椒碱-维生素E前药自组装纳米粒对小鼠肝脏GSH-Px,T-SOD,T-AOC和MDA含量的影响：
αp<0.05,相比于模型组
βp<0.01,相比于模型组
γp<0.05,相比于辣椒碱组
由以上两表可以看出，与模型组相比，辣椒碱显著降低了小鼠血浆中MDA的含量，
显著提高了小鼠血浆中T-SOD、GSH-Px和的T-AOC活性。显著提高了小鼠血浆中GSH-Px的活性。血浆中T-SOD和T-AOC的活性亦有升高趋势，而无显著性差异。与模型组相比，辣椒碱-维生素E前药自组装纳米粒显著降低了小鼠血浆中MDA的含量，显著提高小鼠血浆中T-SOD、GSH-Px和的T-AOC活性。同时，辣椒碱-维生素E前药自组装纳米粒血浆T-SOD、MDA值，肝脏T-SOD、GSH-Px和MDA值与辣椒碱原料药存在显著性差异。表明辣椒碱-维生素E前药自组装纳米粒的抗氧化作用相比于辣椒碱原料药显著提高。
实施例11.辣椒碱-维生素E前药自组装纳米粒降血脂活性研究
24只小鼠随机分为四组，每组6只。分别为空白组，模型组，辣椒碱组和实施例2中的辣椒碱-维生素E前药自组装纳米粒组。空白组和模型组每天灌胃给予生理盐水，同时，辣椒碱组和辣椒碱-维生素E前药自组装纳米粒组分别灌胃给予辣椒碱和辣椒碱-维生素E前药自组装纳米粒。给药剂量为5mg/kg，共给药30天。各组小鼠除空白组外，均喂食高脂饲料。实验第31天，各组小鼠禁食12小时后，各组小鼠进行眼球取血，分离血浆，并取肝脏。将以多聚甲醛固定后的肝组织依次进行常规脱水和石蜡包埋，切片机制备病理切片，经苏木精-伊红染色后于光学显微镜下观察。以试剂盒测定小鼠血浆总胆固醇、甘油三酯、总胆汁酸、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇的含量、肝脏中总胆固醇和甘油三酯的含量，并测定肝脏总脂肪含量。
辣椒碱及其辣椒碱-维生素E前药纳米制剂对血浆总胆固醇、甘油三酯、总胆汁酸、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇的含量的影响：
αp<0.05,相比于模型组
βp<0.01,相比于模型组
γp<0.05,相比于辣椒碱组
由上表可知，与空白组相比，模型组血浆中的甘油三酯水平显著升高，胆固醇、总胆汁酸、低密度脂蛋白水平极显著升高，高密度脂蛋白水平显著降低。模型组数据
表明高脂饮食对于小鼠的血脂各项指标影响显著，小鼠高血脂模型建立成功。给予辣椒碱原料药的小鼠血浆中胆固醇、甘油三酯、低密度脂蛋白水平相比于模型组极显著下降，高密度脂蛋白与胆汁酸水平相比于模型组分别有上升与下降的趋势，而没有达到显著性差异。给予辣椒碱-维生素E前药自组装纳米粒组的小鼠，其胆固醇、甘油三酯、低密度脂蛋白、胆汁酸水平相对于模型组极显著降低(p＜0.01)，相对于CAP组显著降低(p＜0.05)，且胆汁酸水平相对于CAP组极显著降低。高密度脂蛋白水平相对于模型组显著升高(p＜0.05)。结果表明，辣椒碱-维生素E前药自组装纳米粒对高脂血症小鼠的降血脂作用显著高于辣椒碱原料药。
给药30天后，辣椒碱及其前药对高脂饮食小鼠的肝脏总重及总脂肪含量的影响：
αp<0.05,相比于模型组
βp<0.01,相比于模型组
γp<0.05,相比于辣椒碱组
给药30天后，辣椒碱及其前药对高脂饮食小鼠的肝脏总胆固醇与甘油三酯水平的影响：
αp<0.05,相比于模型组
βp<0.01,相比于模型组
γp<0.05,相比于辣椒碱组
由上表可知，辣椒碱-维生素E前药自组装纳米粒显著提高辣椒碱对于高脂饮食的小鼠的降低肝脏脂质的作用，且对小鼠肝脏中胆固醇、甘油三酯水平的降低效果显著提高。
给予高脂饮食和辣椒碱及辣椒碱-维生素E前药自组装纳米粒后，小鼠肝脏组织形态学特征见图11。
由图可见，正常对照组肝组织样品肝小叶结构清楚，肝细胞正常，无肝细胞肿胀和脂肪变性、坏死，胞浆内未见脂滴。模型组小鼠肝脏中出现了弥漫性肝细胞脂肪变性，肝细胞变大，存在较多脂滴，对肝脏的损伤作用较为明显。辣椒碱及辣椒碱-维生素E前药自组装纳米粒给药30天后，均能在一定程度上改善高脂饲料对小鼠肝脏的损伤。辣椒碱原料药组肝脏组织肝细胞肿胀减轻，胞质内仍有较多脂滴沉着，脂滴与模型组比较体积稍小，密度较低。而给予辣椒碱-维生素E前药自组装纳米粒组的肝脏细胞变性大大降低，细胞界限清晰，胞质内脂肪滴剧集较少。由此表明，辣椒碱及辣椒碱-维生素E前药自组装纳米粒均能改善高脂饲料对小鼠的肝损伤，且辣椒碱-维生素E前药自组装纳米粒改善作用较辣椒碱原料药更为明显。
Claims (8)
- 一种辣椒碱-维生素E前药，其特征是：它是以辣椒碱为母药，以亚二硫基二乙酸将辣椒碱与一分子维生素E相连而形成的辣椒碱-维生素E前药，所述的辣椒碱-维生素E前药的结构式如下：
- 一种制备权利要求1所述的辣椒碱-维生素E前药的方法，其特征是它包括下列步骤：步骤1、将1g亚二硫基二乙酸溶于10～20mL乙酸酐，室温搅拌3-4小时，反应结束后旋转蒸发至干，粗品溶于15～40mL二氯甲烷，加入10～30mg 4-二甲氨基吡啶(DMAP)、500mg维生素E，室温下搅拌2小时，反应液用硅胶柱纯化，洗脱液为石油醚-乙酸乙酯-冰乙酸(95:5:0.1～80:20:0.1，V/V)得S-VE；步骤2、取500mg S-VE溶于二氯甲烷，加入100-400mg二环己基碳二亚胺(DCC)和10～30mg DMAP，室温搅拌5min，加入辣椒碱250mg，室温搅拌两小时，反应液用硅胶柱纯化，洗脱液为二氯甲烷-甲醇(100:0-90:10V/V)，得浅黄色粘稠半固体，即为辣椒碱维生素E前药。
- 一种辣椒碱-维生素E前药自组装纳米粒，其特征是：它是由权利要求1所述的辣椒碱-维生素E前药在水溶液中自组装而成的辣椒碱-维生素E前药自组装纳米粒，所述的辣椒碱-维生素E前药自组装纳米粒平均粒径小于200nm，呈类球形均匀分布，载药量以辣椒碱计算达8mg·mL-1。
- 一种制备权利要求3所述的辣椒碱-维生素E前药自组装纳米粒的方法，其特征是：它是将辣椒碱-维生素E前药溶于无水乙醇中，于搅拌条件下，缓慢滴入去离子水 中，最终保持乙醇终浓度＜5％，辣椒碱-维生素E前药自组装形成具有蓝色微光的液体，即辣椒碱-维生素E前药自组装纳米粒溶液。
- 权利要求3所述的辣椒碱-维生素E前药自组装纳米粒在制备自组装纳米药物传递系统中的应用。
- 权利要求3所述的辣椒碱-维生素E前药自组装纳米粒在药物传递系统中的应用。
- 权利要求3所述的辣椒碱-维生素E前药自组装纳米粒在制备保肝或降血脂药物中的应用。
- 根据权利要求7所述的辣椒碱-维生素E前药自组装纳米粒在制备保肝及降血脂药物，其特征是：所述药物是注射给药的针剂或口服给药的胶囊或片剂。
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