CN113975400A - Method for preparing geniposide-phospholipid complex by using ultrasonic waves and application thereof - Google Patents
Method for preparing geniposide-phospholipid complex by using ultrasonic waves and application thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
- A61K47/544—Phospholipids
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/74—Rubiaceae (Madder family)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a method for preparing a geniposide-phospholipid complex by using ultrasonic waves and application thereof. The preparation method comprises the following steps: adding soybean lecithin into absolute ethyl alcohol, then adding a lactic acid solution and a hydrogen peroxide solution, heating and stirring, adjusting the pH value to be neutral, drying under reduced pressure, then adding a chitosan solution, stirring at room temperature, and freeze-drying to obtain modified soybean lecithin; adding geniposide and phospholipid compound containing modified soybean lecithin into a solvent, carrying out ultrasonic reaction, carrying out rotary evaporation after the ultrasonic reaction is finished, adding an inert organic solvent again, fully dissolving the phospholipid compound, carrying out suction filtration to remove uncomplexed geniposide, and carrying out rotary evaporation on the filtrate to obtain the geniposide-phospholipid compound. The compound provided by the invention enhances the lipid solubility of geniposide, improves the transmembrane transport performance of geniposide and improves the bioavailability of geniposide.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a method for preparing a geniposide-phospholipid complex by using ultrasonic waves and application thereof.
Background
Geniposide is an iridoid glucoside, is a main effective component of cape jasmine, and has a content of about 3-8% depending on the production area. Geniposide can be hydrolyzed to genipin by beta-glucosidase. Modern researches show that geniposide has obvious curative effects on diseases of digestive system, cardiovascular system and central nervous system, and has certain anti-inflammatory and soft tissue injury treating effects. Geniposide is widely applied to other fields besides medicine, such as plant yield increasing agents, biological detection agents and the like. However, because geniposide has strong water solubility, weak lipid solubility, poor membrane permeability and low bioavailability, its clinical application and development are greatly limited, and it is especially necessary to select a proper dosage form to improve its bioavailability.
Phospholipid complexes (PLCs) are relatively stable compounds or complexes of drugs and phospholipid molecules formed by charge transport. The preparation method can change the physicochemical property of parent drugs and improve the bioavailability, has simple preparation method and low cost, is gradually applied to the aspect of pharmaceutical preparations in recent years, and particularly obtains greater achievement in the aspect of researching traditional Chinese medicine phospholipid complexes. As a novel medicinal preparation, the phospholipid compound can obviously improve the lipid solubility of the medicament, enhance the medicament absorption, improve the medicament bioavailability, reduce the adverse reaction of the medicament and the like. The method has important theoretical and practical significance for exploring natural medicines in China, accelerating the modern research progress of the traditional Chinese medicine preparation and improving the industrial technical level and the clinical application quality of the traditional Chinese medicine. At present, the bioavailability of the geniposide phospholipid complex needs to be improved, and the drug loading rate is low.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for preparing geniposide-phospholipid complex by using ultrasonic waves.
The invention also aims to provide an application of the geniposide-phospholipid complex in repairing uric acid kidney injury (anti-inflammation), HKC is selected as a research object, and the release of nitric oxide is used as an evaluation index.
The technical scheme adopted by the invention for realizing the purpose is as follows:
the invention provides a method for preparing geniposide-phospholipid complex by using ultrasonic waves, which comprises the following steps:
(1) adding soybean lecithin into absolute ethyl alcohol, then adding a lactic acid solution and a hydrogen peroxide solution, heating to 65-70 ℃, stirring for 4-5h, adjusting the pH to be neutral, drying under reduced pressure, then adding a chitosan solution, stirring at room temperature, and freeze-drying to obtain modified soybean lecithin;
(2) adding geniposide and phospholipid compound containing modified soybean lecithin into a solvent, carrying out ultrasonic reaction, carrying out rotary evaporation after the ultrasonic reaction is finished, adding an inert organic solvent again, fully dissolving the phospholipid compound, carrying out suction filtration to remove uncomplexed geniposide, and carrying out rotary evaporation on the filtrate to obtain the geniposide-phospholipid compound.
Further, in the step (1), the feed-liquid ratio of the soybean lecithin to the absolute ethyl alcohol is 1 g: 15-20 mL; the addition amount of the lactic acid solution accounts for 1.5 percent of the mass of the soybean lecithin; the addition amount of the hydrogen peroxide solution accounts for 3-4% of the mass of the soybean lecithin; the concentration of the lactic acid solution is 70%; the concentration of the hydrogen peroxide solution was 35%.
Further, in the step (1), the mass ratio of the soybean lecithin to the chitosan is 1: 0.15; the concentration of the chitosan solution is 15%.
Further, in the step (2), the phospholipid compound is prepared by mixing modified soybean lecithin and dipalmitoyl phosphatidylcholine according to a mass ratio of 1: 0.2-0.3.
Further, in the step (2), the mass ratio of the geniposide to the phospholipid compound is 1:1-1:5, and the reaction concentration of the geniposide in the solvent is 0.5-5 mg/mL.
Further, the solvent is one or a mixture of two of tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, absolute ethyl alcohol, absolute methanol, ethyl acetate and isopropanol.
Further, in the step (2), the frequency of the ultrasonic reaction is 20-40 kHz, and the power is 200-500W; the ultrasonic reaction temperature is 20-60 ℃, and the reaction time is 1-5 h.
Further, in the step (2), the inert organic solvent is one or a mixture of two of dichloromethane, chloroform, petroleum ether, n-hexane and diethyl ether.
The invention also provides application of the geniposide-phospholipid complex in preparation of drugs for repairing uric acid kidney injury and resisting inflammation.
The compound provided by the invention is compounded by geniposide and phospholipid compound under the ultrasonic action through hydrogen bonds or van der Waals force and the like. The invention greatly improves the loading rate, the compliance rate and the stability of the medicament by simply modifying the soybean lecithin.
The invention has the beneficial effects that:
(1) the compound provided by the invention enhances the lipid solubility of geniposide, improves the transmembrane transport performance of geniposide and improves the bioavailability of geniposide;
(2) compared with the existing preparation method of phospholipid compound solvent, the preparation method provided by the invention has better compound rate and drug-loading rate, and the obtained compound has better stability; the prepared geniposide-phospholipid compound obviously reduces the release amount of nitric oxide in cells in the aspect of repairing uric acid kidney injury (anti-inflammation), and shows that the compound can well repair kidney inflammation caused by hyperuricemia, and compared with geniposide, the activity of the compound is obviously improved.
Drawings
FIG. 1 is an infrared characterization of geniposide-phospholipid complex;
wherein, A: geniposide, B: phospholipid, C: physical mixture of geniposide and phospholipids, D: geniposide-phospholipid complex.
FIG. 2 is an XRD characterization of geniposide-phospholipid complex;
wherein, A: geniposide, B: phospholipid, C: physical mixture of geniposide and phospholipids, D: geniposide-phospholipid complex.
FIG. 3 is a DSC characterization of geniposide-phospholipid complex;
a: geniposide, B: phospholipid, C: physical mixture of geniposide and phospholipids, D: geniposide-phospholipid complex.
FIG. 4 is a graph of the effect of geniposide-phospholipid complex on cellular nitric oxide release.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that the above-mentioned contents of the present invention are further described in detail by the following specific embodiments, but it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following embodiments, and all the technologies realized based on the above-mentioned contents of the present invention belong to the scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention.
Example 1
(1) Adding 10 parts of soybean lecithin into 150mL of absolute ethyl alcohol, then adding 0.15 part of lactic acid solution (with the mass concentration of 70%) and 0.3 part of hydrogen peroxide solution (with the mass concentration of 35%), heating to 65 ℃, stirring for 4 hours, adjusting the pH value to be neutral, drying under the reduced pressure condition, then adding 1.5 parts of chitosan solution with the concentration of 15%, stirring at room temperature, and freeze-drying to obtain modified soybean lecithin;
(2) accurately weighing 100 mg of geniposide and 200 mg of phospholipid compound (modified soybean lecithin and dipalmitoyl phosphatidylcholine are in a mass ratio of 1: 0.2) and adding into 40 mL of absolute ethyl alcohol, performing ultrasonic treatment at 45 ℃ to uniformly disperse reactants in the absolute ethyl alcohol for reaction, wherein the ultrasonic frequency is 25 kHz and the power is 300W, performing ultrasonic treatment for 2 hours, removing the solvent by rotary evaporation, adding 20mL of petroleum ether to fully dissolve the obtained phospholipid compound, performing suction filtration to remove uncomplexed geniposide, and performing rotary evaporation on the filtrate to obtain a light yellow waxy solid geniposide-phospholipid compound.
Comparative example 1 geniposide-phospholipid physical mixture Synthesis
Accurately weighing 100 mg of geniposide and 200 mg of phospholipid, adding the geniposide and the phospholipid into 40 mL of absolute ethyl alcohol, stirring and reacting for 2 h in a water bath at 45 ℃, after the reaction is finished, rotationally evaporating to remove the solvent, then adding 20mL of petroleum ether to fully dissolve the obtained phospholipid compound, then carrying out suction filtration to remove uncomplexed geniposide, and rotationally evaporating the filtrate to obtain the light yellow waxy solid geniposide-phospholipid compound.
Effects of the embodiment
Measurement of drug-loading rate and compound rate of geniposide-phospholipid compound
Preparation of geniposide standard curve
Chromatographic conditions are as follows: a chromatographic column: diamonsil C18 column (250 mm. times.4.6 mm, 5 μm); column temperature: 25 ℃; mobile phase: methanol-water (30: 70 by volume); flow rate: 1.0 mL·min-1(ii) a Detection wavelength: 238 nm; sample introduction amount: 10 μ L.
The experimental method comprises the following steps: precisely weighing geniposide 5 mg, placing in a 50mL measuring flask, dissolving with methanol, and fixing to volume to obtain 100 mg.L mass concentration-1Stock solutions of geniposide. Precisely measuring the stock solution to obtain the final product with mass concentrations of 100.0, 50.0, 25.0, 12.5, 6.25 and 3.125.0 mg.L-1The series of solutions are filtered through a 0.45 mu m microporous filter membrane, the subsequent filtrate is sampled and analyzed under the condition of the chromatographic strip, the peak area is recorded, and linear regression is carried out on the mass concentration by the peak area to obtain the geniposide standard curve.
And (3) measuring the drug loading capacity: precisely weighing geniposide, preparing a phospholipid compound, dissolving the compound in a proper amount of methanol, placing the dissolved compound in a 20mL measuring flask, and then adding methanol to the constant volume. The content of geniposide in the solution is measured by passing the solution through a 0.45 mu m microporous filter membrane according to the chromatographic conditions.
And (3) determination of the recombination rate: adding excessive petroleum ether into the phospholipid compound, fully dissolving, filtering and collecting filter residue to obtain uncomplexed geniposide, dissolving with appropriate amount of methanol to determined concentration, and measuring the geniposide content by HPLC method, wherein the calculation formula of the complexing rate is as follows: w = (m)0-m1)/m0×100%。
In the formula: m is0Is the initial amount of substance administered; m is1Is the quality of the drug which is not compounded.
The specific test results are shown in Table 1.
TABLE 1
As can be seen from Table 1, compared with the solvent method, the geniposide-phospholipid complex prepared by the method provided by the invention has the advantages that the drug loading rate and the complex rate of the complex are obviously improved, which indicates that the ultrasonic method is more suitable for preparing the phospholipid complex.
Determination of apparent oil-water distribution coefficient of geniposide-phospholipid complex
Accurately weighing an equivalent sample (calculated by geniposide), adding an oil phase (n-octanol supersaturated with water), performing ultrasonic treatment to completely dissolve the sample, centrifuging the solution at 4000r/min for 15 min to obtain an oil phase solution, quantitatively diluting the solution, and performing sample injection measurement to obtain the concentration of Co. Respectively and precisely measuring 1 mL of the oil phase solution, placing the oil phase solution in a 10 mL centrifuge tube, precisely adding 1 mL of a water phase (water supersaturated with n-octanol), placing the water phase solution in a constant-temperature water bath shaking table, shaking for 24 hours at 37 ℃, centrifuging, taking an upper oil phase, quantitatively diluting, and carrying out sample injection measurement, wherein the concentration is recorded as Cw. The oil-water distribution coefficient (P) is calculated according to the following formula: p = Co/Cw. The specific results are shown in Table 2.
TABLE 2
As can be seen from Table 2, lgP = -2.10 of geniposide, which indicates that the geniposide has particularly good water solubility and poor fat solubility, and the lgP of the drug can be absorbed in vivo more ideally at 1-4.
Determination of infrared, XRD and DSC of geniposide-phospholipid Complex
Mixing appropriate amount of geniposide, lecithin, physical mixture of geniposide and phospholipid, and geniposide-phospholipid complex with potassium bromide powder at a mass ratio of 1:100, tabletting, and adding water at 4000-500cm-1Infrared spectroscopy (fig. 1); taking a proper amount of geniposide, lecithin, a physical mixture of geniposide and phospholipid (a solvent method) and a geniposide-phospholipid complex for analysis, wherein the test condition is Cu target (40 kV and 40 mA), the scanning angle is 0.01 degrees per step, the scanning range (2 theta) is 5 degrees to 50 degrees, and the scanning speed is 10 degrees per min (figure 2); an empty aluminum crucible is used as a reference substance, nitrogen is used as protective gas, the temperature rising range is 30-300 ℃, the temperature rising speed is 10 ℃/min, and geniposide, lecithin, a physical mixture of geniposide and phospholipid and a geniposide phospholipid compound are analyzed (figure 3).
As shown in figure 1, geniposide has hydroxyl structure at 3408 cm -1Has a distinct absorption peak which appears in the physical mixture, but disappears in the geniposide phospholipid complex only at 3250-3500 cm-1Shows a broad peak similar to that of phospholipid, indicating that the hydroxyl group of geniposide in the complex may have intermolecular forces with phospholipid. In the compound, the stretching vibration peak 1243 cm of phosphorus-oxygen double bond at the polar end of phospholipid -1Basically disappears, and the hydrocarbon stretching vibration peak of phospholipid nonpolar aliphatic chain is 2923 cm -1And 2853 cm -1No change occurs, which indicates that geniposide and the polar end of phospholipid generate intermolecular force to form a compound.
From figure 2, geniposide is a crystal compound and has an obvious crystal diffraction peak, phospholipid is basically amorphous and has a diffraction peak only at a small angle, the diffraction pattern of a physical mixture is the combination of the geniposide and the phospholipid diffraction peak, which indicates that the crystal form of the drug cannot be changed by simple physical mixing, and after a compound is formed, the diffraction peak of the geniposide completely disappears, which indicates that the drug is highly dispersed in the phospholipid in an amorphous or molecular state, so that the crystal form is changed.
As seen from FIG. 3, geniposide has a sharp characteristic endothermic peak at 164.1 ℃, and the physical mixture also has a peak at 164.1 ℃, which are the same, indicating that the geniposide crystal form is not changed by the physical mixture. The characteristic peak of geniposide in the phospholipid compound disappears, a slow endothermic peak appears at 128.6 ℃, and the geniposide is presumed to change the crystal form after forming the phospholipid compound, which is probably because geniposide and polar group part of phospholipid generate intermolecular interaction, the phospholipid wraps the geniposide, and the geniposide is highly dispersed in the phospholipid. There are many fluctuations on the DSC curve of phospholipids, and it is likely that different components show different caloric changes under different temperature conditions.
(IV) test for Activity to repair Kidney injury (anti-inflammatory)
The HKC cells were plated in 96-well cell culture plates at 40000 cells per well, cultured with RPMI1640 containing 10% fetal bovine serum for 5-6 hours, added with diluted phospholipid complex, aspirin was selected as a positive control, and then the amount of nitric oxide released was measured with a nitric oxide kit.
Nitric oxide is involved in a variety of inflammatory signal transduction, interacts with a variety of inflammatory factors, is produced at each stage of the inflammatory response process, is closely related to inflammation in excess production, and inhibition of nitric oxide production is a direct indicator of anti-inflammatory activity. As can be seen from FIG. 4, the level of nitric oxide in the cells of the model group was significantly increased compared to the blank group, indicating that the cells produced a severe inflammatory response; the content of the cellular nitric oxide treated by aspirin is obviously reduced, and concentration dependence is shown; the high, medium and low dosage of the medicine can obviously inhibit the generation of nitric oxide, and the effect is equivalent to that of a positive control.
Claims (9)
1. A method for preparing geniposide-phospholipid complex by using ultrasonic waves is characterized by comprising the following steps:
(1) adding soybean lecithin into absolute ethyl alcohol, then adding a lactic acid solution and a hydrogen peroxide solution, heating to 65-70 ℃, stirring for 4-5h, adjusting the pH to be neutral, drying under reduced pressure, then adding a chitosan solution, stirring at room temperature, and freeze-drying to obtain modified soybean lecithin;
(2) adding geniposide and phospholipid compound containing modified soybean lecithin into a solvent, carrying out ultrasonic reaction, carrying out rotary evaporation after the ultrasonic reaction is finished, adding an inert organic solvent again, fully dissolving the phospholipid compound, carrying out suction filtration to remove uncomplexed geniposide, and carrying out rotary evaporation on the filtrate to obtain the geniposide-phospholipid compound.
2. The method according to claim 1, wherein in the step (1), the feed-liquid ratio of the soybean lecithin to the absolute ethyl alcohol is 1 g: 15-20 mL; the addition amount of the lactic acid solution accounts for 1.5 percent of the mass of the soybean lecithin; the addition amount of the hydrogen peroxide solution accounts for 3-4% of the mass of the soybean lecithin; the concentration of the lactic acid solution is 70%; the concentration of the hydrogen peroxide solution was 35%.
3. The method according to claim 1 or 2, wherein in the step (1), the mass ratio of the soybean lecithin to the chitosan is 1: 0.15; the concentration of the chitosan solution is 15%.
4. The method according to claim 1, wherein in the step (2), the phospholipid compound is prepared from modified soybean lecithin and dipalmitoyl phosphatidylcholine in a mass ratio of 1: 0.2-0.3.
5. The method according to any one of claims 1 to 4, wherein in the step (2), the mass ratio of the geniposide to the phospholipid complex is 1:1-1:5, and the reaction concentration of the geniposide in the solvent is 0.5-5 mg/mL.
6. The method according to claim 5, wherein the solvent is one or a mixture of two of tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, absolute ethanol, absolute methanol, ethyl acetate and isopropanol.
7. The method as claimed in claim 1, wherein in the step (2), the frequency of the ultrasonic reaction is 20-40 kHz, and the power is 200-500W; the ultrasonic reaction temperature is 20-60 ℃, and the reaction time is 1-5 h.
8. The method according to claim 1, wherein in the step (2), the inert organic solvent is one or a mixture of two of dichloromethane, chloroform, petroleum ether, n-hexane and diethyl ether.
9. Use of geniposide-phospholipid complex according to any one of claims 1-8 in the preparation of a medicament for repairing uric acid kidney injury and anti-inflammatory treatment.
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| CHANDER PARKASH DORA，ET AL.: "Improved oral bioavailability and therapeutic efficacy of erlotinib through molecular complexation with phospholipid" * |
| 吴桐 等: "栀子苷磷脂复合物的制备与评价" * |
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