CN113975400B - Method for preparing geniposide-phospholipid complex by utilizing ultrasonic waves and application of geniposide-phospholipid complex - Google Patents
Method for preparing geniposide-phospholipid complex by utilizing ultrasonic waves and application of geniposide-phospholipid complex 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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- A61K31/7048—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
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- 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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- 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 utilizing ultrasonic waves and application thereof. The preparation method comprises the following steps: adding soybean lecithin into absolute ethyl alcohol, then adding lactic acid solution and hydrogen peroxide solution, heating and stirring, adjusting pH to be neutral, drying under reduced pressure, then adding chitosan solution, stirring at room temperature, and freeze-drying to obtain modified soybean lecithin; adding geniposide and a 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 fat 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 utilizing ultrasonic waves and application thereof.
Background
Geniposide (geniposide) is an iridoid glucoside, is a main medicinal component of fructus Gardeniae, and has a content of about 3% -8% according to the production area. Geniposide can be hydrolyzed to genipin by beta-glucosidase. Modern researches have shown that geniposide has remarkable curative effects on digestive system, cardiovascular system and central nervous system diseases, and in addition, geniposide has certain anti-inflammatory and soft tissue injury treatment effects. Geniposide is widely used in other fields besides medicines, such as plant yield increasing agents, biological detection agents and the like. However, geniposide has strong water solubility, weak fat solubility, poor membrane permeability and low bioavailability, so that the clinical application and development of geniposide are greatly limited, and the selection of a proper dosage form to improve the bioavailability is particularly necessary.
Phospholipid complexes (phospholipid complex, PLC) are relatively stable compounds or complexes formed by charge transfer of drugs and phospholipid molecules. The preparation method can change the physicochemical properties of the parent medicine, improve the bioavailability, is simple, has low cost, has gradually increased application in the aspect of medicine preparation in recent years, and particularly has achieved great achievement in the aspect of research of traditional Chinese medicine phospholipid complex. The phospholipid complex is used as a novel pharmaceutical preparation, can obviously improve the fat solubility of the medicine, enhance the absorption of the medicine, improve the bioavailability of the medicine, reduce adverse reactions of the medicine and the like. The method has important theoretical and practical significance for exploring natural medicines in China, accelerating the modern research progress of traditional Chinese medicine preparations and improving the technical level and clinical application quality of the traditional Chinese medicine industry. 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 a geniposide-phospholipid complex by utilizing ultrasonic waves.
Another object of the present invention is to provide an application of geniposide-phospholipid complex in repairing urinary acid kidney injury (anti-inflammatory), wherein HKC is selected as a study object, and release of nitric oxide is used as an evaluation index.
The technical scheme adopted by the invention for achieving the purpose is as follows:
the invention provides a method for preparing a geniposide-phospholipid complex by utilizing ultrasonic waves, which comprises the following steps:
(1) Adding soybean lecithin into absolute ethyl alcohol, then adding lactic acid solution and hydrogen peroxide solution, heating to 65-70 ℃, stirring for 4-5h, regulating pH to be neutral, drying under reduced pressure, then adding chitosan solution, stirring at room temperature, and freeze-drying to obtain modified soybean lecithin;
(2) Adding geniposide and a 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 1g:15-20mL; the addition amount of the lactic acid solution accounts for 1.5% 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 chitosan solution had a concentration of 15%.
Further, in the step (2), the phospholipid compound is prepared from 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 preparing medicines for repairing urinary acid kidney injury and resisting inflammation.
The compound provided by the invention is formed by compounding geniposide and phospholipid compound under the ultrasonic action in a hydrogen bond or Van der Waals force mode. The invention greatly improves the loading rate, the coincidence rate and the stability of the medicine by simply modifying the soybean lecithin.
The beneficial effects of the invention are as follows:
(1) The compound provided by the invention enhances the fat solubility of geniposide, improves the transmembrane transport performance of geniposide and improves the bioavailability of geniposide;
(2) Compared with the existing preparation method of the phospholipid complex solvent, the preparation method provided by the invention has better compounding rate and drug loading rate, and the obtained complex has better stability; the prepared geniposide-phospholipid complex obviously reduces the release amount of nitric oxide in cells in the aspect of repairing urinary acid kidney injury (anti-inflammation), which indicates that the complex can well repair kidney inflammation caused by hyperuricemia, and compared with geniposide, the activity of the complex is obviously improved.
Drawings
FIG. 1 is an infrared spectrum characterization of geniposide-phospholipid complex;
wherein A: geniposide, B, phospholipid, C: physical mixture of geniposide and phospholipid, D: geniposide-phospholipid complex.
FIG. 2 is an XRD characterization of geniposide-phospholipid complexes;
wherein A: geniposide, B, phospholipid, C: physical mixture of geniposide and phospholipid, D: geniposide-phospholipid complex.
FIG. 3 is a DSC characterization of geniposide-phospholipid complexes;
a: geniposide, B, phospholipid, C: physical mixture of geniposide and phospholipid, D: geniposide-phospholipid complex.
FIG. 4 is an effect of geniposide-phospholipid complex on nitric oxide release from cells.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that the following detailed description of the present invention is given by way of specific examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples, and that the technology implemented based on the above description of the present invention falls within 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 materials used in the present invention may be purchased in conventional manners, and unless otherwise indicated, they may be used in conventional manners in the art or according to 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) 10 parts of soybean lecithin is added with 150mL of absolute ethyl alcohol, then 0.15 part of lactic acid solution (70% of mass concentration) and 0.3 part of hydrogen peroxide solution (35% of mass concentration) are added, the temperature is raised to 65 ℃, stirring is carried out for 4 hours, the pH is regulated to be neutral, drying is carried out under the condition of reduced pressure, then 1.5 parts of chitosan solution with 15% of concentration is added, stirring is carried out at room temperature, and freeze drying is carried out, thus obtaining the modified soybean lecithin;
(2) Accurately weighing geniposide 100 mg and a phospholipid compound (modified soybean lecithin and dipalmitoyl phosphatidylcholine according to a mass ratio of 1:0.2) 200 mg, adding into absolute ethyl alcohol 40 mL, performing ultrasonic treatment at 45 ℃ to enable reactants to be uniformly dispersed in absolute ethyl alcohol for reaction, performing rotary evaporation to remove a solvent after the reaction is finished after ultrasonic treatment at the ultrasonic frequency of 25 kHz and the power of 300W and ultrasonic treatment at the ultrasonic frequency of 2 h, adding petroleum ether 20mL to fully dissolve the obtained phospholipid compound, performing suction filtration to remove uncomplexed geniposide, and performing rotary evaporation on filtrate to obtain the light yellow waxy solid geniposide-phospholipid compound.
Comparative example 1 physical mixture Synthesis of geniposide-phospholipid
Accurately weighing geniposide 100 mg and phospholipid 200 mg, adding into absolute ethanol 40 mL, stirring for reaction at 45 ℃ in water bath for 2 h, removing solvent by rotary evaporation after the reaction is finished, adding petroleum ether 20mL for fully dissolving to obtain a phospholipid complex, filtering to remove uncomplexed geniposide, and rotary evaporating the filtrate to obtain a pale yellow waxy solid geniposide-phospholipid complex.
Effect examples
Measurement of drug-loading and complexing Rate of geniposide-phospholipid Complex
Preparation of geniposide standard curve
Chromatographic conditions: chromatographic column: diamond sil C18 column (250 mm X4.6 mm, 5 μm); column temperature: 25. the temperature is lower than the temperature; mobile phase: methanol-water (volume ratio 30:70); flow rate: 1.0 mL/min -1 The method comprises the steps of carrying out a first treatment on the surface of the Detection wavelength: 238 nm; sample injection amount: 10. mu L.
The experimental method comprises the following steps: precisely weighing geniposide 5 mg, placing in 50mL measuring flask, dissolving with methanol, and fixing volume to mass concentration of 100 mg.L -1 Stock solutions of geniposide. Precisely measuring the stock solution to prepare the stock solution with mass concentrations of 100.0, 50.0, 25.0, 12.5, 6.25 and 3.125.0 mg.L respectively -1 Passing the solution through a microporous filter membrane of 0.45 μm, collecting the filtrate, subjecting to sample injection analysis under chromatographic conditions, recording peak area, and linearly regressing the mass concentration with the peak area to obtain geniposide standard kojiA wire.
Drug loading measurement: precisely weighing geniposide, preparing phospholipid complex, dissolving with appropriate amount of methanol, placing into 20mL measuring flask, and fixing volume with methanol. The solution was filtered through a 0.45 μm microporous filter membrane and the geniposide content was determined by chromatographic conditions.
Determination of the recombination rate: adding excessive petroleum ether into the phospholipid complex, fully dissolving, filtering and collecting filter residues to obtain uncomplexed geniposide, dissolving with a proper amount of methanol to a certain concentration, and determining the content of the geniposide by an HPLC method, wherein the calculation formula of the compounding rate is as follows: w= (m 0 -m 1 )/m 0 ×100%。
Wherein: m is m 0 Is the initial drug quality; m is m 1 Is the quality of uncomplexed medicine.
The specific detection 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, and the ultrasonic method is more suitable for preparing the phospholipid complex.
(II) determination of apparent oil-water partition coefficient of geniposide-phospholipid Complex
Accurately weighing an equivalent sample (calculated by geniposide), adding an oil phase (water supersaturated n-octanol), completely dissolving by ultrasonic, centrifuging at 4000r/min for 15 min to obtain an oil phase solution, quantitatively diluting, and carrying out sample injection measurement, wherein the concentration is recorded as Co. Precisely measuring 1 mL of the oil phase solution, placing into a 10 mL centrifuge tube, precisely adding 1 mL of water phase (n-octanol supersaturated water), placing into a constant-temperature water bath shaking table, shaking at 37 ℃ for 24 h, centrifuging, taking an upper oil phase, quantitatively diluting, and performing sample injection measurement, wherein the concentration is recorded as Cw. The oil-water distribution coefficient (P) is calculated as follows: p=co/Cw. The specific results are shown in Table 2.
TABLE 2
From table 2, it can be seen that lgp= -2.10 of geniposide shows that the water solubility of geniposide is particularly good, the fat solubility is poor, while lgP of the drug can achieve more ideal in vivo absorption at 1-4, lgP of the geniposide phospholipid complex prepared by the invention is increased to 1.05, which shows that after geniposide is prepared into a phospholipid complex, the lipophilicity of geniposide is improved to a certain extent, and the in vivo absorption of geniposide is hopefully improved, and the bioavailability of geniposide is improved.
(III) determination of geniposide-phospholipid Complex by Infrared, XRD and DSC
Taking a proper amount of geniposide, lecithin, physical mixture of geniposide and phospholipid, and geniposide-phospholipid complex, mixing with potassium bromide powder according to a mass ratio of 1:100, tabletting, and making into tablet at 4000-500cm -1 Where infrared spectroscopic analysis was performed (fig. 1); taking a proper amount of geniposide, lecithin, physical mixture of geniposide and phospholipid (solvent method) and geniposide phospholipid compound for analysis, wherein the test condition is Cu target (40 kV,40 mA), scanning step by 0.01 DEG/step, scanning range (2 theta) 5 DEG-50 DEG, and scanning speed 10 DEG/min (figure 2); the geniposide, lecithin, physical mixture of geniposide and phospholipid, and geniposide phospholipid complex were analyzed with an empty aluminum crucible as a reference and nitrogen as a shielding gas at a temperature ranging from 30 to 300 ℃ and a temperature rising rate of 10 ℃/min (fig. 3).
As seen in FIG. 1, genipin has a hydroxyl structure, at 3408 cm -1 There is a distinct absorption peak which appears equally in the physical mixture, but which disappears in the geniposide phospholipid complex, only at 3250-3500 cm -1 Showing a broad peak similar to that of phospholipids, indicating that the hydroxyl group of geniposide in the complex may have intermolecular forces with the phospholipids. In the complex, the stretching vibration peak 1243 and cm of the phosphorus-oxygen double bond at the polar end of the phospholipid -1 Substantially vanishing, whereas the hydrocarbon stretching vibration peak 2923 cm of the phospholipid nonpolar fatty chain -1 And 2853 cm -1 The polar ends of geniposide and phospholipid generate intermolecular acting force, so that a compound is formed.
As seen from figure 2, geniposide is a crystalline compound with obvious crystal diffraction peaks, phospholipids are basically amorphous, diffraction peaks exist only at small angles, the diffraction pattern of a physical mixture is a combination of geniposide and phospholipid diffraction peaks, the simple physical mixture indicates that the crystal form of the medicine cannot be changed, and after a compound is formed, the diffraction peaks of the geniposide completely disappear, which indicates that the medicine is highly dispersed in the phospholipid in an amorphous or molecular state, so that the crystal form is changed.
From fig. 3, geniposide has a sharp characteristic endothermic peak at 164.1 ℃ while the physical mixture also peaks at 164.1 ℃, both of which are identical, indicating that physical mixing did not cause the genipin Ping Ganjing form to change. The characteristic peak of geniposide in the phospholipid complex disappears, and a gentle endothermic peak appears at 128.6 ℃, and it is presumed that the crystal form is changed after geniposide forms the phospholipid complex, probably due to intermolecular interactions between geniposide and polar groups of phospholipid, the phospholipid encapsulates the geniposide, and the geniposide is highly dispersed in the phospholipid. While there are multiple fluctuations in the phospholipid DSC curve, it is possible that different components exhibit different caloric changes under different temperature conditions.
(IV) Activity test for repairing renal injury (anti-inflammatory)
HKC cells were plated in 96-well cell culture plates at 40000 cells per well, incubated with RPMI1640 containing 10% fetal bovine serum for 5-6 hours, diluted phospholipid complex was added, aspirin was selected as a positive control, and nitric oxide release was determined using a nitric oxide kit.
Nitric oxide is involved in various inflammatory signal transduction, interacts with various inflammatory factors, is produced at each stage of the inflammatory reaction process, and is closely related to inflammation, while inhibition of nitric oxide production is a direct indicator of anti-inflammatory activity. As can be seen from fig. 4, the model group cells showed a significant increase in nitric oxide content compared to the blank group, indicating that the cells produced a severe inflammatory response; the content of nitric oxide in cells treated by aspirin is obviously reduced, and the concentration dependence is shown; the high, medium and low doses of the medicine can obviously inhibit the generation of nitric oxide, and the effect is equivalent to that of a positive control.
Claims (6)
1. A method for preparing geniposide-phospholipid complex by using ultrasonic waves, which is characterized by comprising the following steps:
(1) Adding soybean lecithin into absolute ethyl alcohol, then adding lactic acid solution and hydrogen peroxide solution, heating to 65-70 ℃, stirring for 4-5h, regulating pH to be neutral, drying under reduced pressure, then adding chitosan solution, stirring at room temperature, and freeze-drying to obtain modified soybean lecithin;
(2) Adding geniposide and a phospholipid compound containing modified soybean lecithin into a solvent, carrying out ultrasonic reaction, rotationally evaporating after the ultrasonic reaction is finished, adding an inert organic solvent again, fully dissolving the phospholipid compound, filtering to remove uncomplexed geniposide, and rotationally evaporating a filtrate to obtain a geniposide-phospholipid compound;
in the step (2), the phospholipid compound is prepared from modified soybean lecithin and dipalmitoyl phosphatidylcholine according to the mass ratio of 1: 0.2-0.3; 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; 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.
2. The method of claim 1, wherein in step (1), the ratio of soybean lecithin to absolute ethanol is 1g:15-20mL; the addition amount of the lactic acid solution accounts for 1.5% 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, wherein in the step (1), the mass ratio of the soybean lecithin to the chitosan is 1:0.15; the chitosan solution had a concentration of 15%.
4. The method of claim 1, wherein in step (2), the solvent to which the geniposide and the phospholipid complex containing modified soybean lecithin are added is one or a mixture of two of tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, absolute ethanol, absolute methanol, ethyl acetate, and isopropanol.
5. 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.
6. Use of a geniposide-phospholipid complex prepared by the method for preparing a geniposide-phospholipid complex as defined in any one of claims 1-5 in the preparation of a medicament for repairing urinary acid kidney injury and anti-inflammatory.
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| Title |
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| Chander Parkash Dora，et al..Improved oral bioavailability and therapeutic efficacy of erlotinib through molecular complexation with phospholipid.International Journal of Pharmaceutics.2017,第534卷第1-13页. * |
| 吴桐 等.栀子苷磷脂复合物的制备与评价.中国药剂学杂志.2019,第17卷(第1期),第1-11页. * |
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