CN111939167A - Scutellarin-phospholipid complex, solid dispersion and microemulsion drug delivery system thereof, and preparation method and application thereof - Google Patents
Scutellarin-phospholipid complex, solid dispersion and microemulsion drug delivery system thereof, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a scutellarin-phospholipid complex, a solid dispersion and a microemulsion drug delivery system thereof, and a preparation method and application thereof. The preparation method of scutellarin-phospholipid complex comprises the steps of weighing scutellarin and phospholipid, dissolving the scutellarin and the phospholipid in a mixed solvent of tetrahydrofuran and other organic solvents, removing the mixed solvent under reduced pressure, adding the organic solvent, fully dissolving the phospholipid and the phospholipid complex in the mixed solvent, filtering, collecting filtrate, removing the organic solvent under reduced pressure, and drying at room temperature to obtain the scutellarin-phospholipid complex. The invention also comprises a scutellarin-phospholipid complex solid dispersion, a self-microemulsion drug delivery system, a preparation method and an application thereof. The invention has the advantages of good absorption, high bioavailability of the medicine, convenient administration and improved patient compliance, and is beneficial to the full play of the clinical curative effect of scutellarin. The preparation method of the scutellarin-phospholipid compound has high and stable compounding rate, stable preparation process and good reproducibility.
Description
Technical Field
The invention relates to the technical field of scutellarin-phospholipid complexes, in particular to a scutellarin-phospholipid complex, a solid dispersion and a microemulsion administration system thereof, and a preparation method and application thereof.
Background
Scutellarin (Scutellarin, DZ), CAS: 27740-01-8, also called scutellarin, 5, 6, 4' -trihydroxyflavone-7-O-glucuronide, is a flavonoid compound extracted and separated from dried whole herb Erigeron breviscapus (Vant.) hand-Mazz of Erigeron breviscapus (Compositae) of Erigeron genus. Has the functions of dispelling cold, relieving exterior syndrome, relaxing tendons, activating collaterals, promoting blood circulation, removing blood stasis, dispelling pathogenic wind and removing dampness, etc., is widely used for treating ischemic cardiovascular and cerebrovascular diseases clinically, such as cerebral embolism, paralysis after stroke, angina, myocardial infarction, coronary heart disease, etc., and has obvious curative effect. However, scutellarin is a drug with poor water solubility and fat solubility, and the oral bioavailability of Beagle dogs is only (0.40 +/-0.19)%. The common oral preparations such as tablets, granules and the like have poor absorption, low drug bioavailability, frequent administration times of injections, injection powder injections and the like, poor patient compliance and serious influence on the full play of the clinical curative effect. The existing preparation method of the scutellarin-phospholipid compound has low and unstable compounding rate, the compounding rate is as low as 30 percent, the preparation process is unstable, and the reproducibility is poor. Therefore, the existing scutellarin medicament has poor absorption, low medicament bioavailability, frequent administration times and poor patient administration compliance, and seriously influences the full play of the clinical curative effect of the scutellarin. The existing preparation method of the scutellarin-phospholipid compound has low and unstable compounding rate, unstable preparation process and poor reproducibility.
Disclosure of Invention
The invention aims to provide a scutellarin-phospholipid complex, a solid dispersion and a microemulsion drug delivery system thereof, and a preparation method and application thereof. The invention has the advantages of good absorption, high drug bioavailability, reduced administration frequency and improved patient compliance, and is beneficial to the full play of the clinical curative effect of scutellarin. The preparation method of the scutellarin-phospholipid compound has high and stable compounding rate, stable preparation process and good reproducibility.
The technical scheme of the invention is as follows: the scutellarin-phospholipid complex is prepared from the raw materials of scutellarin and phospholipid, wherein the mass ratio of the scutellarin to the phospholipid is 1: 2-5.
In the scutellarin-phospholipid complex, the raw materials of the scutellarin-phospholipid complex comprise scutellarin and phospholipid, and the mass ratio of the phospholipid scutellarin to the phospholipid is 1: 3.
The preparation method of the scutellarin-phospholipid complex comprises the steps of weighing scutellarin and phospholipid, dissolving the scutellarin and the phospholipid in a mixed solvent of tetrahydrofuran and other organic solvents, wherein the volume ratio of the tetrahydrofuran to the other organic solvents is 1:0.1-5, reacting for 0.5-5h at the reaction temperature of 20-60 ℃, removing the mixed solvent of the tetrahydrofuran and the other organic solvents under reduced pressure, adding the organic solvents, fully dissolving the phospholipid and the phospholipid complex in the mixed solvent, filtering, collecting filtrate, removing the organic solvents under reduced pressure, and drying at room temperature to obtain the scutellarin-phospholipid complex.
In the preparation method of the scutellarin-phospholipid complex, scutellarin and phospholipid are weighed, are dissolved in a mixed solvent of tetrahydrofuran and methanol, the volume ratio of tetrahydrofuran to methanol is 1:1, the mixture reacts for 2-3h at the reaction temperature of 30-40 ℃, the mixed solvent of tetrahydrofuran and methanol is removed under reduced pressure, dichloromethane is added, the phospholipid and the phospholipid complex are fully dissolved, the mixture is filtered, filtrate is collected, the dichloromethane is removed under reduced pressure, and the mixture is dried at room temperature to obtain the scutellarin-phospholipid complex.
In the preparation method of the scutellarin-phospholipid compound, the mass ratio of the scutellarin to the phospholipid is 1:3, the dosage of the scutellarin is 600mg, and the reaction is carried out at the reaction temperature of 30-40 ℃ for 2-3h and at the reaction temperature of 35 ℃ for 2.5 h.
The scutellarin-phospholipid compound is added with one or more pharmaceutically acceptable carriers or excipients to prepare the dripping pills for treating the cardiovascular and cerebrovascular diseases and other diseases.
The raw materials of the scutellarin-phospholipid complex solid dispersion prepared from the scutellarin-phospholipid complex comprise a scutellarin-phospholipid complex and a solid dispersion carrier material, wherein the mass ratio of the scutellarin-phospholipid complex to the carrier material is 1:1-3, and the solid dispersion carrier material is PVP K17, PVP K30 or PEG 6000.
The preparation method of the scutellarin-phospholipid composite solid dispersion comprises the steps of dissolving the scutellarin-phospholipid composite and a carrier material of the solid dispersion in a mixed solvent of dichloromethane and ethanol, wherein the volume ratio of dichloromethane to ethanol is 1:0-2, removing the mixed solvent of dichloromethane and ethanol under reduced pressure at the water bath temperature of 30-58 ℃, drying at room temperature, and sieving.
In the preparation method of the scutellarin-phospholipid composite solid dispersion, the carrier material of the solid dispersion is PEG6000, the mass ratio of the scutellarin-phospholipid composite to the PEG6000 is 1:2, the volume ratio of dichloromethane to ethanol is 1:0, and the water bath temperature is 40 ℃.
The scutellarin-phospholipid complex solid dispersion is added with one or more pharmaceutically acceptable carriers or excipients to prepare the sustained-release capsules or sustained-release tablets for treating the cardiovascular and cerebrovascular diseases and other diseases, and the sustained-release capsules or sustained-release tablets can release the medicaments in the stomach, duodenum, colon and ileum.
The scutellarin-phospholipid composite microemulsion drug release system prepared from the scutellarin-phospholipid composite, the raw materials of the scutellarin-phospholipid complex microemulsion drug release system comprise a scutellarin-phospholipid complex, an oil phase, an emulsifier, an auxiliary emulsifier and distilled water/0.9% NaCl solution/5% glucose solution/buffer solution with the pH value of 6.8, the mass of the scutellarin-phospholipid complex is 3% -5% of the total mass of the scutellarin-phospholipid complex, the oil phase, the emulsifier and the auxiliary emulsifier, the mass ratio of the emulsifier to the auxiliary emulsifier is 1:1-9, the mass ratio of the oil phase to the emulsifier to the auxiliary emulsifier is 4:4-8, the addition amount of the distilled water/0.9% NaCl solution/5% glucose solution/buffer solution with the pH value of 6.8 is the amount of the microemulsion formed by the microemulsion release system.
In the microemulsion drug delivery system, the average particle diameter of the microemulsion drug delivery system is 33.34 + -0.45 nm, and the Zeta potential of the microemulsion drug delivery system is-8.99 + -0.90 mv.
In the scutellarin-phospholipid complex microemulsion drug release system, the oil phase is one or more of LCT, MCT, EO and IPM; the emulsifier is one or more of Kolliphor HS 15 and phospholipid; the auxiliary emulsifier is one or more of PEG 400, 1,2 propylene glycol, absolute ethyl alcohol or F-68, the mass ratio of the emulsifier to the auxiliary emulsifier is 1:6, the mass ratio of the oil phase to the sum of the emulsifier and the auxiliary emulsifier is 4:6, and the mass of the scutellarin-phospholipid complex is 5% of the total mass of the scutellarin-phospholipid complex, the oil phase, the emulsifier and the auxiliary emulsifier.
The preparation method of the scutellarin-phospholipid complex microemulsion drug delivery system comprises the steps of uniformly mixing the emulsifier and the co-emulsifier, mixing the scutellarin-phospholipid complex, the mixed emulsifier, the co-emulsifier and the oil phase, uniformly dissolving by ultrasonic waves, dropwise adding distilled water at 37 ℃, 0.9% NaCl solution, 5% glucose solution and buffer solution with the pH value of 6.8 in a constant-temperature water bath at 37 ℃ and the stirring speed of 500r/min, and preparing the microemulsion drug delivery system.
The preparation method of the scutellarin-phospholipid complex microemulsion drug delivery system comprises the steps of uniformly mixing the emulsifier and the co-emulsifier, mixing the scutellarin-phospholipid complex, the mixed emulsifier, the co-emulsifier and the oil phase, uniformly dissolving by ultrasonic, adjusting the pH to 7.5, and carrying out high-speed homogenization and/or high-pressure homogenization under the condition of 100MPa to prepare the microemulsion drug delivery system.
The scutellarin-phospholipid complex microemulsion drug release system is added with one or more pharmaceutically acceptable carriers or excipients to prepare an emulsion (comprising a submicron emulsion, a self-microemulsion or a nano emulsion of lipid microspheres), a tablet, an injection, a dropping pill, a capsule, a soft capsule or a freeze-dried powder injection for treating the cardiovascular and cerebrovascular diseases and other diseases, wherein the injection and the freeze-dried powder injection can be injected in muscles and blood vessels, and the capsule or the soft capsule is a sustained-release preparation which can release drugs in the stomach, the duodenum, the colon and the ileum.
Compared with the prior art, the scutellarin is prepared into the scutellarin-phospholipid compound, and the scutellarin-phospholipid compound can enhance the fat solubility and the water solubility of the scutellarin, so that the membrane permeability of the scutellarin is improved, the permeability of the scutellarin at each absorption part is improved, the intestinal absorption speed of the scutellarin is improved, the administration frequency is reduced, the absorption of the medicament in the gastrointestinal tract is increased, the medicament taking compliance of a patient is improved, and the bioavailability and the curative effect of the medicament are improved. Scutellarin in the scutellarin-phospholipid composite solid dispersion is highly dispersed in a solid dispersion carrier, and a water-soluble carrier can increase the scutellarin-dissolution rate, so that the accumulative dissolution rate of the scutellarin is greatly improved, the absorption of the scutellarin is further improved, and the accumulative dissolution rate of the scutellarin is about 99.4%. The absorption of the scutellarin-phospholipid complex and the scutellarin-phospholipid complex solid dispersion in each intestinal section of the intestinal tract all accord with a zero-order absorption kinetic model, and compared with the scutellarin, the absorption rate constants Ka of the scutellarin-phospholipid complex and the scutellarin-phospholipid complex solid dispersion in each intestinal section of the intestinal tract are obviously improved, and the scutellarin-phospholipid complex solid dispersion is absorbed most strongly in duodenum. The scutellarin-phospholipid complex microemulsion drug delivery system also has targeting property and low cytotoxicity, can greatly reduce the drug delivery dose and the drug delivery frequency, reduce the side effect of the drug and further improve the drug delivery compliance of patients. The preparation method of the scutellarin-phospholipid compound has the advantages of 98 percent of compounding rate, stable process and good reproducibility. In the preparation of the scutellarin-phospholipid compound, tetrahydrofuran and methanol in a volume ratio of 1:1 are used as a mixed solvent, so that the compounding rate and stability of the scutellarin and the phospholipid compound can be improved. The preparation process of the scutellarin-phospholipid composite solid dispersion is stable and has good reproducibility. The scutellarin-phospholipid complex microemulsion drug delivery system has the advantages of stable preparation process and good repeatability. The invention applies the scutellarin-phospholipid compound, the solid dispersion and the microemulsion drug delivery system thereof to the preparation of the drugs for treating cardiovascular and cerebrovascular diseases and other diseases, has good drug absorption, high drug bioavailability, reduced drug delivery times and improved drug delivery compliance of patients, and is beneficial to the full play of the clinical curative effect of the scutellarin. The preparation method of the scutellarin-phospholipid compound has high and stable compounding rate, stable preparation process and good reproducibility.
Detailed Description
The present invention is further illustrated by the following examples, which are not to be construed as limiting the invention.
Example 1.
DZ-PC (scutellarin-phospholipid complex)
The raw materials of the scutellarin-phospholipid compound comprise scutellarin and phospholipid, and the mass ratio of the phospholipid scutellarin to the phospholipid is 1: 3.
Characterization of DZ-PC as described above
FT-IR
Taking DZ, PC, DZ-PC-MIX (DZ quality)25% of component), 4 parts of DZ-PC, and scanning by a Fourier transform infrared spectrometer. Scanning range 400-4000cm-1Resolution of 0.09cm-1Wave number precision of 0.09cm-1Detectors DTGS/MCT/A and InGaAs, beam splitters KBr and CaF, using KBr pellets (2 g dose).
FT-IR results
The FT-IR detection result of DZ, PC, DZ-PC-MIX and DZ-PC shows. DZ-PC at 3030--1The absorption peak and the stretching vibration of aromatic hydrogen on a benzene ring, the stretching vibration of a skeleton of the benzene ring and the C-H out-of-plane bending vibration of the mono-substituted benzene appear. At the same time at 1700cm-1The stretching vibration characteristic absorption peak of the carbonyl of DZ appears, and no new chemical bond is generated in the preparation process of DZ-PC.
XRD
DZ, PC, DZ-PC-MIX (DZ mass fraction 25%), DZ-PC, and XRD was used to examine the dispersion of the drug in the material. The test conditions are Cu target, tube voltage 40kV, current 30mA, scanning speed 4 degree/min, and scanning range 0-80 ℃.
XRD results
The X-ray diffraction pattern showed that when the DZ content was consistent, 1 distinct characteristic diffraction peak was present near 25.642 ° (d 3.4711) for DZ, soybean phospholipid was an amorphous substance, and 1 discrete peak appeared, and the characteristic diffraction peak of DZ disappeared after the complex was prepared. Indicating that the drug is dispersed in the carrier material in an amorphous state.
Preparation of DZ-PC (scutellarin-phospholipid complex).
Weighing a certain amount of DZ (scutellarin) and PC (phospholipid) to dissolve in 20mL of mixed solvent of tetrahydrofuran and methanol (1:1), reacting at a certain temperature for a certain time, removing the organic solvent under reduced pressure, adding a proper amount of DCM (dichloromethane), fully dissolving the phospholipid and phospholipid compound in the mixture, filtering, collecting filtrate, removing DCM under reduced pressure, and drying at room temperature to obtain DZ-PC. Meanwhile, the precipitate on the filter membrane is collected, dried and weighed, and the compounding rate of the DZ is calculated.
And (3) optimizing the process of the orthogonal experiment of DZ-PC. The compound rate is used as an evaluation index, 3 factors with obvious influence on preparation, such as the feed ratio, the reaction temperature and the dosage, are selected as an investigation object to investigate the preparation process and the prescription, and the optimal process conditions are preferably selected. The factors and level design are shown in table 1.
Table 1 factors and levels
Single-factor experiment optimization process of DZ-PC
Investigation of DZ and PC feed ratio
According to the orthogonal experiment result, the compound rate is used as an evaluation index, the feeding ratio is set to be 1:3, 1:2 and 1:5, and the feeding ratio of DZ and PC is further examined.
Investigation of reaction time
According to the previous experimental result, taking the recombination rate as an evaluation index, setting three reaction times of 2h, 2.5h and 3h for investigation.
Verification experiment
According to the optimal process obtained by orthogonal test and single-factor test results, 3 batches of samples are repeatedly prepared, and the recombination rate is calculated.
The DZ-PC preparation process preferably results. From the results, the influence of each factor on the quality of DZ-PC is sequentially the feed ratio (A), the water bath temperature (B) and the feed amount (C). The visual analysis result shows that the optimum prescription process is that the feeding ratio is 1:3, the reaction temperature is 35 ℃, the feeding amount is 600mg, and the variance analysis result shows that A, B has significant statistical significance. After the factors such as production requirements are expanded after the synthesis, the optimal formula process is selected with the material feeding ratio of 1:3, the reaction temperature of 35 ℃ and the material feeding amount of 600 mg.
Single factor test results. The single factor experiment result shows that the influence of the feed ratio (1:3-1:4) on the recombination rate is small. Comprehensively considering factors such as cost saving and the like, and selecting a feeding ratio of 1: 3; the results show that the reaction time has little influence on the recombination rate. Comprehensively considering the factors of saving cost and the like, and the reaction time is 2.5 h.
And verifying the experimental result. The optimal preparation process of the DZ-PC comprises the steps of feeding the DZ to the PC in a ratio of 1:3, controlling the water bath temperature to be 35 ℃, feeding the medicine amount to be 600mg, and controlling the reaction time to be 2.5 hours, wherein 3 batches of DZ-PC prepared according to the optimal formula have the average compound rate (98.72 +/-0.42)%, and the RSD less than 5.0%, which indicates that the optimal preparation process is stable and has good reproducibility.
Is prepared from scutellarin-phospholipid complex by optimal preparation process.
Adding breviscapine B-phospholipid complex 240g into corresponding adjuvant for preparing dripping pill. Making into 1200 dripping pills, each dripping pill contains scutellarin 50 mg. Can be used for treating cardiovascular and cerebrovascular diseases or other diseases, and is administered orally 1-8 times per day 1-4 times per day.
Example 2.
DZ-PC-SD (Breviscapine B-phospholipid complex solid dispersion)
The raw materials of the scutellarin-phospholipid composite solid dispersion comprise a scutellarin-phospholipid composite (prepared by an optimal preparation process) and a solid dispersion carrier material, wherein the mass ratio of the scutellarin-phospholipid composite to the carrier material is 1:2, and the solid dispersion carrier material is PEG 6000.
And (3) preparing DZ-PC-SD. The DZ-PC-SD is prepared by a solvent method. Precisely weighing appropriate amount of DZ-PC (prepared by using scutellarin-phospholipid complex as the best preparation process) and carrier material, dissolving in appropriate amount of organic solvent, removing organic solvent under reduced pressure, drying at room temperature, and sieving to obtain DZ-PC-SD.
And (4) the prescription and the process investigation of DZ-PC-SD.
Examination of DZ-PC to PVP K17 ratio
The three reactions with the cumulative dissolution rate as an evaluation index and with the set ratios of 1:1, 1:2 and 1:3 were investigated.
Examination of DZ-PC to PVP K30 ratio
The three reactions with the cumulative dissolution rate as an evaluation index and with the set ratios of 1:1, 1:2 and 1:3 were investigated.
Investigation of DZ-PC to PEG6000 ratio
The three reactions with the cumulative dissolution rate as an evaluation index and with the set ratios of 1:1, 1:2 and 1:3 were investigated.
Investigation of solvent species
The accumulated dissolution rate is used as an evaluation index, and the types of the solvents are dichloromethane: ethanol 1:0, dichloromethane: ethanol 1:1 and dichloromethane: ethanol 1:2 for investigation respectively.
Investigation of solvent volume
The cumulative dissolution rate was used as an evaluation index, and the solvent volumes were set to 10mL, 20mL, and 30mL, respectively, for examination.
Investigation of Water bath temperature during Rotary Evaporation
The cumulative dissolution rate is used as an evaluation index, and three temperatures of 30 ℃, 40 ℃ and 58 ℃ are set for investigation.
Results of DZ-PC and PVP K17 ratio investigation
The result of the single-factor experiment shows that DZ-PC and PVP K17(1:1-1:3) have larger influence on the cumulative dissolution rate. The cumulative dissolution rate of DZ at 240min when DZ-PC is PVP K171:1 is 100%.
Results of DZ-PC and PVP K30 ratio investigation
The result of the single-factor experiment shows that DZ-PC and PVP K30(1:1-1:3) have larger influence on the cumulative dissolution rate. The cumulative dissolution rate of DZ at 240min when the ratio of DZ-PC to PVP K301:1 is 86%.
Results of DZ-PC and PEG6000 ratio investigation
The single factor experiment result shows that DZ-PC and PEG6000(1:1-1:3) have larger influence on the accumulative dissolution rate. The cumulative dissolution rate of DZ at 240min when DZ-PC is PEG60001:2 is 100%.
The DZ-PC-SD is prepared by selecting DZ-PC, PEG60001:2 and the like according to the comprehensive consideration of factors such as the fluidity of the DZ-PC-SD.
Investigation result of solvent species
The single factor experiment result shows that the influence of the solvent type on the accumulative dissolution rate is large. The cumulative dissolution rate of DZ was maximal at 240min when DCM was used as ethanol 1:0.
Investigation result of solvent volume
The results of the single factor experiment show that the volume of the solvent (10mL-30mL) has a greater influence on the cumulative dissolution rate. The cumulative dissolution rate of 240min DZ was 100% when the solvent volume was 10 mL.
Investigation of Water bath temperature during Rotary Evaporation
The single factor experiment result shows that the influence of the water bath temperature (30-58 ℃) on the accumulative dissolution rate is small. At each evaporation water bath temperature, the cumulative dissolution rate of DZ at 240min is close to 100%.
Considering the factors of DZ-PC-SD mobility and the like, the temperature of a water bath during rotary evaporation of the solvent is selected to be 40 ℃, and 10mL of DCM is used for preparing the DZ-PC-SD.
Verification of the results of the experiment
The optimal preparation process of the DZ-PC-SD comprises the steps of preparing DZ-PC, PEG60001:2 and DCM 10mL, carrying out rotary evaporation on the solvent at the water bath temperature of 40 ℃, and preparing 3 batches of DZ-PC-SD according to the optimal process, wherein the average accumulative dissolution rate of the DZ-PC-SD is (99.35 +/-1.14)%) for 240 min. RSD is less than 5.0%, which shows that the optimized preparation process is stable and has good reproducibility.
Is prepared from DZ-PC-SD by optimal preparation method. Adding corresponding auxiliary materials for preparing the sustained-release capsule into the DZ-PC-SD720g, wherein the sustained-release capsule can release medicines in duodenum, colon and ileum. 1200 sustained-release capsules are prepared, and each sustained-release capsule contains 50mg of scutellarin. Can be used for treating cardiovascular and cerebrovascular diseases or other diseases, and is administered orally 1-6 times per day 1-6 times.
The DZ-PC-SD tablet prepared by the optimal preparation process is used as a raw material. Adding corresponding auxiliary materials for preparing the sustained-release tablet into DZ-PC-SD720g, wherein the sustained-release tablet can release medicines in duodenum, colon and ileum. Making into 1200 sustained release tablets, each tablet contains scutellarin 50 mg. Can be administered orally 1-6 tablets each time 1-6 times a day for treating cardiovascular and cerebrovascular diseases or other diseases.
Example 3.
Study of intestinal absorption
Solution preparation
Tyrode buffer [49 ]: weighing 8.0g of sodium chloride, 0.20g of potassium chloride, 1.00g of sodium bicarbonate, 0.05g of sodium dihydrogen phosphate, 0.10g of magnesium chloride and 1.10g of glucose, adding distilled water to dissolve, uniformly mixing with 0.20g of calcium chloride dissolved in another beaker, and adding distilled water to a constant volume of 1L to obtain the calcium chloride.
Preparation of control solutions: precisely weighing 10.0mg of DZ reference substance, placing in a 50mL measuring flask, adding Tyrode buffer solution to dilute to scale, shaking up, and performing ultrasonic treatment for 10min to obtain a DZ reference substance stock solution with the concentration of 0.2 mg/mL-1.
Preparation of a test solution: taking a proper amount of DZ, DZ-PC and DZ-PC-SD, adding a proper amount of Tyrode buffer solution, and preparing a test solution with a certain concentration.
Absorption test in rat small intestine
SD rats, male and female halves, body weight (240 + -20) g, were randomly divided into 4 groups of 6 rats per group by body weight. Rats fasted for 12h before the test were weighed, sacrificed by cervical spine amputation, and skin and muscle were cut along the ventral midline and the ventral white line, respectively. The excised intestine was rinsed in Tyrode buffer at 0 ℃ until no intestinal contents were present. Carefully turning over the tube with a gavage needle, ligating the turned section of intestine into a small bag, fastening one end of the small bag, placing the small bag into a four-cavity organ bath system of 10mL Tyrode buffer solution with constant temperature of 37 ℃, fixing the open end of an intestinal tube on the four-cavity organ bath, and supplying oxygen. About 0.5mL of Tyrode buffer was injected into the intestinal tube to equilibrate for 5min, and then the Tyrode buffer was changed to the test solution. 0.5mL of the enterocyst was sampled at 15, 30, 45, 60, 90 and 120min, respectively, while the same isothermal volume of Tyrode buffer was supplemented. Placing the mixture into a 5mL measuring flask, adding Tyrode buffer solution to the constant volume to a scale, taking the subsequent filtrate, measuring A at 334nm, and calculating the cumulative absorption amount (Q) of the intestinal sac. After the test is finished, the intestinal canal is longitudinally split, the intestinal canal is naturally spread on filter paper to measure the length and the width, the absorption area A is recorded, the accumulated absorption quantity Q of the drug is subjected to correlation regression analysis on the time t, and the obtained slope is divided by the absorption surface area to obtain the drug intestinal absorption rate constant (Ka). And performing t-test analysis on the data by using Excel software.
2.10.3DZ, DZ-PC, DZ-PC-SD (PEG6000) and DZ-PC-SD (PVP K17) were examined for absorption characteristics in different intestinal sections of rats
The duodenum, jejunum and ileum of the rat were cut and placed in the test solutions, respectively, and the procedure was performed according to the method under item 2.10.2. Drawing a Q-t curve, and respectively fitting by adopting three models, namely: the present invention relates to a model of zero-order release (Q ═ Kt + C), a second-order release (ln (1-Q) ═ Kt + C), and a Higuchi (Q ═ Kt1/2+ C), where Q is the cumulative uptake, t is the release time (h), K is the release kinetic constant, and C is a constant. The fitting of the curve is determined according to the correlation coefficient (r 2).
Ka comparison of DZ, DZ-PC, DZ-PC-SD (PEG6000) and DZ-PC-SD (PVP K17) in different intestinal sections
Statistical analyses were performed for Ka in different intestinal sections for DZ, DZ-PC, DZ-PC-SD (PEG6000) and DZ-PC-SD (PVP K17).
The results show that DZ, DZ-PC, DZ-PC-SD (PEG6000) and DZ-PC-SD (PVP K17) are absorbed at different parts of rat intestinal tract. And respectively carrying out curve fitting on the absorption of DZ, DZ-PC, DZ-PC-SD (PEG6000) and DZ-PC-SD (PVP K17) in different intestinal sections by adopting a zero-order kinetic model, a first-order kinetic model and a Higuchi model, wherein the closer the correlation coefficient r is to 1, the better the fitting effect is, and the absorption of DZ, DZ-PC, DZ-PC-SD (PEG6000) and DZ-PC-SD (PVP K17) in different intestinal sections accords with the zero-order absorption kinetic model.
The results showed that DZ-PC, DZ-PC-SD (PEG6000) (except jejunum) and DZ-PC-SD (PVP K17) were very significantly different in Ka (P < 0.01) for each intestinal segment compared to DZ. The absorption in duodenum is strongest with DZ-PC-SD (PEG 6000).
Example 4.
Microemulsion drug release system of scutellarin-phospholipid complex
The raw materials of the scutellarin-phospholipid complex microemulsion drug delivery system comprise a scutellarin-phospholipid complex (50mg, wherein the scutellarin-phospholipid complex is prepared by an optimal preparation process), an oil phase, an emulsifier, an auxiliary emulsifier and a buffer solution with the pH value of 6.8, wherein the mass of the scutellarin-phospholipid complex is 5% of the total mass of the scutellarin-phospholipid complex, the oil phase, the emulsifier and the auxiliary emulsifier, the mass ratio of the emulsifier to the auxiliary emulsifier is 1:6, the mass ratio of the oil phase to the mass ratio of the emulsifier to the auxiliary emulsifier is 4:6, the addition amount of the buffer solution with the pH value of 6.8 is 10mL, and the oil phase is ethyl oleate; the emulsifier is Kollip hor HS 15; the coemulsifier is 1,2 propylene glycol or absolute ethyl alcohol. The average particle diameter of the microemulsion drug delivery system of scutellarin-phospholipid complex is 33.34 + -0.45 nm, and the Zeta potential of the microemulsion drug delivery system of scutellarin-phospholipid complex is-8.99 + -0.90 mv.
Preparation of scutellarin-phospholipid complex microemulsion drug delivery system (DZ-PC-SMEDDS is short for short).
Drawing of pseudo ternary phase diagram
Fixing DZ-PC (scutellarin-phospholipid complex prepared by optimal preparation process) at 30mg, mixing emulsifier and co-emulsifier at 37 deg.C, mixing with oil phase at a ratio of 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, and 9:1 (total weight of fixing system is 1.0g), and adding distilled water at the same temperature dropwise for emulsification to obtain a uniform system. The quality of the distilled water added when the microemulsion turns from clear to turbid and then turns from turbid to clear or with opalescence is recorded. Km is taken as one peak, and oil phase and distilled water are taken as the other two peaks. A pseudo-ternary phase diagram was plotted using orgin 7.5.
Investigation of solubility of different oil phases and emulsifying effect of emulsifier
According to the investigation of the dissolution situation of the medicine in the oil phase, LCT, MCT, EO and IPM are selected as the oil phase, HS-15 and lecithin are selected as the emulsifier. Fixing ethanol as co-emulsifier, emulsifier-co-emulsifier (Km) is 1:1, oil-co-emulsifier (Km) is 1:9, weighing the components in proportion, mixing uniformly, dripping distilled water at 37 +/-0.5 ℃, stirring in a constant-temperature water bath at 100rpm at 37 ℃, observing the milk forming effect of different formulas, and carrying out primary screening on the milk forming condition. The results show that the solubility of DZ-PC in different oils is EO > MCT > IPM > LCT. The result shows that the dissolution conditions of DZ-PC in different coemulsifiers are Tween-80 > EL-35 > HS 15 > F-68 > lecithin, and because the relative solubility advantages of Tween-80 and EL-35 are not particularly outstanding, the toxicity is relatively high and unsafe relative to intravenous injection, HS-15 with a large HLB value is selected as the emulsifier in the research.
Examination of Co-emulsifier
According to the research result of the emulsifier, the fixed oil phase is EO, the emulsifier is HS-15, Km is 1:1, and the influence of the co-emulsifier which is absolute ethyl alcohol, 1,2 propylene glycol and PEG 400 on the area size of the formed micro-emulsion area is respectively researched. The result shows that the dissolution conditions of DZ-PC in different coemulsifiers are ethanol > 1,2 propylene glycol > polyethylene glycol > isopropanol > glycerol, and the upper layer is still turbid after centrifugation due to the higher viscosity of glycerol and is discarded.
Effect of Km on DZ-PC-SMEDDS
EO is used as an oil phase, HS-15 is used as an emulsifier, ethanol is used as an auxiliary emulsifier, distilled water at 37 +/-0.5 ℃ is dripped for emulsification, an emulsifier solution is used as one vertex, the oil phase and the distilled water are used as the other two vertices to draw a pseudo-ternary phase diagram, and the influence of Km on an emulsification region is examined when Km is respectively 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1 and 1: 2.
The results show that the emulsifying difficulty of different oil phases is IPM & gt EO & gt MCT & gt LCT by taking HS-15 as an emulsifier; and (3) combining a solubility investigation experiment, so that EO is selected as an oil phase and HS-15 is selected as an emulsifier.
Investigation of maximum drug Loading
Precisely weighing 4 parts of emulsifier, co-emulsifier and oil phase according to the prescription amount, placing the mixture into a centrifugal tube, wherein the total mass is 1g, adding DZ-PC according to the concentration of 30, 40, 50 and 60mg/g, and ultrasonically dissolving and uniformly mixing until the medicine is completely dissolved. Dropwise adding water into the microemulsion, observing the microemulsion forming condition in the water, and inspecting the influence of the addition amount of DZ-PC on the microemulsion particle size and the emulsion forming effect.
The results show that when Km 4:6, Km 6:1 and Km 4:6, the maximum drug loading was 50mg and the area of the microemulsion region was the largest.
Verification test of optimal prescription
According to the screening of the emulsifier, the co-emulsifier and the oil phase, a pseudo ternary phase diagram is combined, the optimal formula is determined to be 50mg of DZ-PC, the oil phase is EO, the emulsifier is HS-15, the co-emulsifier is 1, 2-propylene glycol, Km is 6:1, the oil phase Km is 4:6, three batches of DZ-PC-SMEDDS are prepared by the same method, and are stirred in 10mL of buffer solution with pH6.8 at the temperature of 25 ℃ at the stirring speed of 500rpm to prepare uniform, yellow and clear solution.
A preparation method of DZ-PC-SMEDDS. According to the optimal formula, an emulsifier and a co-emulsifier are uniformly mixed, a scutellarin-phospholipid complex, the mixed emulsifier, the mixed co-emulsifier and an oil phase are uniformly dissolved by ultrasonic waves, and 10mL of 37 ℃ distilled water, 0.9% NaCl solution, 5% glucose solution and a buffer solution with the pH value of 6.8 are dropwise added into a thermostatic water bath at 37 ℃ and the stirring speed of 500r/min to prepare a microemulsion drug release system.
DZ-PC-SMEDDS dripping pills are prepared by using DZ-PC-SMEDDS prepared by an optimal process as a raw material. Adding corresponding adjuvants for preparing dripping pill into 220g of DZ-PC-SMEDDS. Making into 2000 dripping pills, each dripping pill contains scutellarin 5 mg. Can be administered orally 6-8 times per time (1-6 times per day) for treating cardiovascular and cerebrovascular diseases.
DZ-PC-SMEDDS slow-release capsules prepared by using DZ-PC-SMEDDS prepared by an optimal process as a raw material. Adding corresponding auxiliary materials for preparing the slow-release capsule into the DZ-PC-SMEDDS220g, wherein the slow-release capsule can release medicines in duodenum, colon and ileum. 2000 sustained-release capsules are prepared, and each sustained-release capsule contains 5mg of scutellarin. Can be used for treating cardiovascular and cerebrovascular diseases or other diseases, and is administered orally 6-8 times per day 1-6 times per day.
The DZ-PC-SMEDDS slow-release soft capsule is prepared by taking DZ-PC-SMEDDS prepared by an optimal process as a raw material. And adding corresponding auxiliary materials for preparing the slow-release soft capsule into 220g of DZ-PC-SMEDDS, wherein the slow-release soft capsule can release medicines in duodenum, colon and ileum. 2000 sustained-release soft capsules are prepared, and each sustained-release soft capsule contains 5mg of scutellarin. Can be used for treating cardiovascular and cerebrovascular diseases or other diseases, and is administered orally 6-8 times per day 1-6 times per day.
DZ-PC-SMEDDS slow-release freeze-dried powder prepared by taking DZ-PC-SMEDDS prepared by an optimal process as a raw material. Adding corresponding auxiliary materials for preparing the sustained-release freeze-dried powder into the DZ-PC-SMEDDS1100g, wherein the sustained-release freeze-dried powder can release medicines in duodenum, colon and ileum. Preparing into 400 pieces of sustained-release lyophilized powder, each containing 3g of scutellarin 12.5 mg. Can be used for treating cardiovascular and cerebrovascular diseases or other diseases by injection 1-2 times per time and 1-3 times per day.
Example 5.
A preparation method of DZ-PC-SMEDDS. Uniformly mixing 12% of PC with the mass fraction of 75% and 0.6% of F-68, adding 50mg of scutellarin-phospholipid complex, 10% of a mixture of LCT and MCT (wherein the mass ratio of LCT to MCT is 1:3), 0.5% of oleic acid and 2.5% of glycerol, uniformly mixing, adding 100mL of distilled water, adjusting the pH to 7.5, and homogenizing at high speed and/or high pressure for 6 times under the condition of 100MPa to prepare the microemulsion drug delivery system.
Example 6.
HUVECs in logarithmic growth phase were used for toxicity test, and DZ, DZ-PC-MESSDS and blank group were set. DZ (0.1-6.5 mg. L)-1)，DZ-PC-SMEDDS(15-530mg·L-1) DZ, DZ-PC-MESSDS, blank groups 8 groups each. The cell viability of HUVECs was determined by MTT method.
Results of DZ-PC-SMEDDS in vitro cytotoxicity experiments.
The relative survival rate (RGR) calculation and cytotoxicity evaluation criteria were referred to IS0210932-5 cytotoxicity assay, and cytotoxicity grading was performed using a 5-point method: grade 0, RGR is more than or equal to 100%, grade 1: RGR between 75% and 99%, grade 2: RGR between 50% and 74%, grade 3: RGR between 25% and 49%, grade 3: grade 4 is between 1% and 24%, grade 5: RGR < 1%. Grades 0 and 1 are considered to be non-cytotoxic, grade 2 is mild cytotoxic, grades 3 and 4 are moderate cytotoxic, and grade 5 is overt cytotoxic.
Cell viability ═ A sample/A control X100%
Sample A: the absorbance of the cells cultured by the DZ, the auxiliary material group and the DZ-PC-SMEDDS is measured; control A: absorbance was measured for normal chaperone cells.
Respectively cultured with DZ and DZ-PC-SMEDDS suspension at different concentrations for 24h, and the DZ is shown to be 0.2-6.4 mg.L-1(corresponding to 16.4-525 mg. L)-1The amount of DZ contained in DZ-PC-SMEDDS) was rated 0 on a cytotoxicity scale, the drug was considered to be non-toxic to cells; the in vitro cytotoxicity of the DZ-PC-SMEDDS and the auxiliary material group is dose-dependent, and the relative proliferation rate of cells of each group is gradually reduced along with the increase of the administration concentration. The concentration of DZ-PC-SMEDDS is 262.5, 525 mg.L-1In time, compared with a normal control group, the cytotoxicity scores are all 4, obvious cytotoxicity is shown, and the obvious difference is achieved. The concentration of the auxiliary materials is less than or equal to 64.8 mg.L-1Compared with the control group, the composition has no significant difference, is considered to have no toxicity to cells in the concentration range, and is assisted byThe concentration of the material group is not less than 129.7 mg.L-1(equivalent to 131.2 mg. multidot.L)-1DZ-PC-SMEDDS contains adjuvant concentration), obvious cytotoxicity is shown. The values of DZ-PC-SMEDDS and the auxiliary material group IC50 are 221.7 +/-5.89 and 184.7 +/-5.48 mg.L respectively calculated by GraphPadprism software-1The IC50 value of the auxiliary material group is lower than that of DZ-PC-SMEDDS, and the cytotoxicity of the auxiliary material group is higher than that of the SMEDDS containing the same amount of DZ, which indicates that the toxicity of the auxiliary material is reduced after the DZ is prepared into the SMEDDS.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof, and it should be understood that various changes and modifications can be effected therein by one skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. Scutellarin-phospholipid complex, which is characterized in that: the raw materials of the scutellarin-phospholipid compound comprise scutellarin and phospholipid, and the mass ratio of the scutellarin to the phospholipid is 1: 2-5.
2. The method for preparing scutellarin-phospholipid complex according to claim 1, wherein the method comprises the following steps: weighing scutellarin and phospholipid, dissolving the scutellarin and the phospholipid in a mixed solvent of tetrahydrofuran and other organic solvents, wherein the volume ratio of the tetrahydrofuran to the other organic solvents is 1:0.1-8, reacting for 0.5-5h at the reaction temperature of 20-60 ℃, removing the mixed solvent of the tetrahydrofuran and the other organic solvents under reduced pressure, adding the organic solvents, fully dissolving the phospholipid and phospholipid complex in the mixed solvent, filtering, collecting filtrate, removing the organic solvents under reduced pressure, and drying at room temperature to obtain the scutellarin-phospholipid complex.
3. Use of scutellarin-phospholipid complex according to any one of claims 1 to 2 in the preparation of medicaments for treating cardiovascular and cerebrovascular diseases and other diseases, wherein: adding one or more pharmaceutically acceptable carriers or excipients into scutellarin-phospholipid complex, and making into dripping pill for treating cardiovascular disease, cerebrovascular disease and other diseases.
4. Scutellarin-phospholipid complex solid dispersion prepared from scutellarin-phospholipid complex according to any one of claims 1 to 2, wherein: the raw materials of the scutellarin-phospholipid composite solid dispersion comprise a scutellarin-phospholipid composite and a solid dispersion carrier material, wherein the mass ratio of the scutellarin-phospholipid composite to the carrier material is 1:1-3, and the solid dispersion carrier material is PVP K17, PVP K30 or PEG 6000.
5. The method for preparing a scutellarin-phospholipid complex solid dispersion according to claim 4, wherein: dissolving scutellarin-phospholipid complex and carrier material of solid dispersion in mixed solvent of dichloromethane and ethanol at a volume ratio of dichloromethane to ethanol of 1:0-2, removing the mixed solvent of dichloromethane and ethanol under reduced pressure at water bath temperature of 30-58 deg.C, drying at room temperature, and sieving.
6. The use of scutellarin-phospholipid complex solid dispersion according to any one of claims 4 to 5 in the preparation of medicaments for treating cardiovascular and cerebrovascular diseases and other diseases, wherein the solid dispersion comprises the following components in percentage by weight: adding one or more pharmaceutically acceptable carriers or excipients into the scutellarin-phospholipid composite solid dispersion to prepare a sustained-release capsule or a sustained-release tablet for treating cardiovascular and cerebrovascular diseases and other diseases, wherein the sustained-release capsule or the sustained-release tablet can release medicines in stomach, duodenum, colon and ileum.
7. A microemulsion-phospholipid delivery system prepared from scutellarin-phospholipid complex according to any one of claims 1-2, which is characterized in that: the raw materials of the scutellarin-phospholipid complex microemulsion drug delivery system comprise a scutellarin-phospholipid complex, an oil phase, an emulsifier, an auxiliary emulsifier and distilled water/0.9% NaCl solution/5% glucose solution/buffer solution with the pH value of 6.8, wherein the mass of the scutellarin-phospholipid complex is 3% -5% of the total mass of the scutellarin-phospholipid complex, the oil phase, the emulsifier and the auxiliary emulsifier, the mass ratio of the emulsifier to the auxiliary emulsifier is 1:1-9, the mass ratio of the oil phase to the total mass of the emulsifier and the auxiliary emulsifier is 4:4-8, and the addition amount of the distilled water/0.9% NaCl solution/5% glucose solution/buffer solution with the pH value of 6.8 is the amount for forming the microemulsion drug delivery system.
8. The preparation method of scutellarin-phospholipid complex microemulsion drug delivery system according to claim 7, which is characterized in that: mixing emulsifier and co-emulsifier uniformly, mixing scutellarin-phospholipid complex, mixed emulsifier, co-emulsifier and oil phase, dissolving uniformly by ultrasonic wave, adding distilled water at 37 deg.C/0.9% NaCl solution/5% glucose solution/buffer solution with pH of 6.8 dropwise in 37 deg.C constant temperature water bath at stirring speed of 500r/min, and making into microemulsion drug delivery system.
9. The preparation method of scutellarin-phospholipid complex microemulsion drug delivery system according to claim 7, which is characterized in that: mixing emulsifier and co-emulsifier uniformly, mixing scutellarin-phospholipid complex, mixed emulsifier, co-emulsifier and oil phase, dissolving uniformly by ultrasonic wave, adjusting pH to 7.5, homogenizing at high speed and/or high pressure under 100MPa, and making into microemulsion drug delivery system.
10. The use of scutellarin-phospholipid complex microemulsion drug delivery system according to any one of claims 7-9 in the preparation of drugs for treating cardiovascular and cerebrovascular diseases and other diseases, which is characterized in that: the microemulsion releasing system of scutellarin-phospholipid complex is taken, and one or more pharmaceutically acceptable carriers or excipients are added to prepare emulsion, tablets, injection, dripping pills, capsules, soft capsules or freeze-dried powder injection for treating cardiovascular and cerebrovascular diseases and other diseases, wherein the capsules or soft capsules are slow release preparations which can release medicines in stomach, duodenum, colon and ileum.
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