CN111388466A - Pharmaceutical composition containing andrographolide and preparation thereof - Google Patents
Pharmaceutical composition containing andrographolide and preparation thereof Download PDFInfo
- Publication number
- CN111388466A CN111388466A CN201811652632.0A CN201811652632A CN111388466A CN 111388466 A CN111388466 A CN 111388466A CN 201811652632 A CN201811652632 A CN 201811652632A CN 111388466 A CN111388466 A CN 111388466A
- Authority
- CN
- China
- Prior art keywords
- andrographolide
- pharmaceutical composition
- cyclodextrin
- surfactant
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title claims abstract description 161
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 title claims abstract description 160
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 69
- 239000004094 surface-active agent Substances 0.000 claims abstract description 31
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000243 solution Substances 0.000 claims description 26
- 239000002202 Polyethylene glycol Substances 0.000 claims description 22
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 22
- 229920001223 polyethylene glycol Polymers 0.000 claims description 22
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 20
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 19
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- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 9
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- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 4
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
The invention discloses a pharmaceutical composition containing andrographolide, a preparation method and a preparation thereof. The pharmaceutical composition comprises a) andrographolide, b) cyclodextrin and c) surfactant, wherein the molar ratio of andrographolide to cyclodextrin is 1: 2-1: 5, and the mass percent of the surfactant is 0.1% -5%. The andrographolide-containing pharmaceutical composition has high ternary system solubility, and in-vitro characterization tests, cell tests and pharmacokinetic tests show that the pharmaceutical composition improves the in-vivo bioavailability of andrographolide, so that the clinical curative effect can be improved.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a pharmaceutical composition containing andrographolide and a preparation thereof.
Background
Andrographolide is the main effective component of andrographis paniculata of acanthaceae, has poor solubility in water, is generally called as bitter king, and has the effects of relieving fever, resisting inflammation, resisting virus, resisting platelet aggregation, protecting liver and benefiting gallbladder. Experiments show that the andrographolide has the effects of inhibiting and delaying the body temperature rise caused by the pneumococci or hemolytic streptococcus B, and has a certain anti-HIV effect. Andrographolide is mainly used for clinically treating bacillary dysentery, acute gastroenteritis, epidemic parotitis, tonsillitis, pharyngolaryngitis, upper respiratory infection, urinary infection and the like, and is widely applied as a traditional Chinese medicine antibiotic at present. The dosage forms recorded in the Chinese pharmacopoeia of 2015 edition include andrographolide dripping pills, andrographis tablets and andrographolide capsules. Andrographolide is also marketed in the form of injection, but in recent years, adverse reactions are reported to increase day by day, and rash, dizziness, gastrointestinal reactions, severe anaphylactic shock, acute renal failure and the like can occur frequently.
P-glycoprotein (P-gp) is widely distributed in the endothelial cells of the capillaries of liver, adrenal gland, intestinal mucosa, brain and testis, and has the function of reverse transport of drugs. Besides that andrographolide has low solubility in water and is easy to hydrolyze under weak alkaline conditions, andrographolide is easy to be discharged by P-glycoprotein and is subjected to first-pass metabolism, which is also an important reason for low bioavailability, and the production and application of andrographolide are greatly limited by the factors.
In recent years, there have been increasing reports of andrographolide, and many techniques have been applied to solve the problem of low bioavailability. Patent publication No. CN1568970A describes an andrographolide drop pill and its preparation method. The main technology is that the andrographolide crystal and polyethylene glycol mixture are prepared into solid dispersion with the mass ratio of 1:3, wherein the polyethylene glycol mixture is prepared by mixing polyethylene glycol 4000 and polyethylene glycol 6000 with the mass ratio of 1: 1. In addition, a film coating is also carried out in the process of preparing the andrographolide dropping pills to cover the bitter taste of the andrographolide. The formula is applied to the products on the market, but the solubility and dissolution test results are not seen.
Patent publication No. CN104557818A describes a method for extracting andrographolide, and herba Andrographitis extract containing andrographolide compounds and medicinal adjuvants are prepared into herba Andrographitis dripping pill and herba Andrographitis soft capsule. In order to improve the purity of andrographolide, a new crystal form of andrographolide is prepared and the drug effect of andrographolide is verified. This patent focuses on the extraction and preparation of a new form of andrographolide, and does not elucidate the results of improving its solubility and bioavailability.
Patent publication No. CN108042512A discloses an andrographolide-loaded core-shell alginate/polyacrylamide microsphere, and a preparation method and application thereof. The andrographolide polymer microspheres prepared by the invention can be used for loading a large amount of andrographolide, and have the advantages of high encapsulation rate, controllable size, capability of masking bitter taste, increase of clinical application range and the like. However, the invention does not carry out in vivo and in vitro bioavailability research experiments and does not show that the bioavailability of the compound is obviously improved.
The invention discloses a soft capsule preparation of andrographolide and its preparing method, which comprises preparing clathrate from andrographolide and β -cyclodextrin at a ratio of 1:3, and preparing soft capsule by pressing method, wherein the product can fully cover the bad smell of andrographolide and improve its bioavailability, and has little adverse reaction.
In order to solve the problem of low bioavailability of andrographolide, researches in these years mainly focus on solving the problems that andrographolide is low in water solubility and andrographolide is easy to hydrolyze under a weak alkaline condition, and no one has studied about solving the problems that andrographolide is easy to be discharged by P glycoprotein and metabolized in the first pass.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing andrographolide, which has good solubility and high bioavailability.
The second purpose of the invention is to provide an andrographolide preparation, which comprises a pharmaceutical composition of andrographolide with good solubility and high bioavailability.
In order to achieve the above object, the present invention provides the following technical solutions.
One aspect of the present invention provides a pharmaceutical composition containing andrographolide, comprising: a) andrographolide, b) cyclodextrin and c) surfactant, wherein the molar ratio of andrographolide to cyclodextrin is 1: 2-1: 5, and the mass percent of the surfactant is 0.1% -5%.
Furthermore, the pharmaceutical composition containing andrographolide, disclosed by the invention, has the molar ratio of andrographolide to cyclodextrin of 1: 2-1: 3, and the surfactant accounts for 0.1% -1% of the pharmaceutical composition.
Furthermore, the pharmaceutical composition containing andrographolide, provided by the invention, is characterized in that the cyclodextrin is one or more selected from α -cyclodextrin, β -cyclodextrin, gamma-cyclodextrin, hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin or sulfobutyl- β -cyclodextrin.
Furthermore, the pharmaceutical composition containing andrographolide, provided by the invention, is characterized in that the surfactant is one or more selected from sodium dodecyl sulfate, sodium hexadecyl sulfate, tween 60, tween 80, benzyl S10, benzyl S20, vitamin E-polyethylene glycol succinate, poloxamer P188, poloxamer P407 and polyoxyethylene castor oil E L.
Furthermore, in the pharmaceutical composition containing andrographolide, the cyclodextrin is gamma-cyclodextrin.
Furthermore, in the andrographolide-containing pharmaceutical composition, the surfactant is one or more of tween 80, vitamin E-polyethylene glycol succinate, poloxamer P407 and polyoxyethylene castor oil E L.
Furthermore, in the pharmaceutical composition containing andrographolide, the surfactant is vitamin E-polyethylene glycol succinate.
Furthermore, the mole ratio of the andrographolide to the cyclodextrin in the pharmaceutical composition containing andrographolide is 1: 2.
Furthermore, in the pharmaceutical composition containing andrographolide, the surfactant accounts for 1% of the pharmaceutical composition by mass.
In another aspect of the present invention, there is provided a method for preparing the ternary system pharmaceutical composition containing andrographolide, comprising the steps of: adding solvent into andrographolide, cyclodextrin and surfactant, mixing the above components, reacting, and removing solvent to obtain dry medicinal composition.
Further, the solvent comprises: one or more of water, methanol, ethanol, acetone and dichloromethane.
Further, the method for removing the solvent comprises one or more of a drying method, a vacuum drying method, a freeze drying method, a spray drying method and a rotary evaporation method.
Further, the preparation method of the ternary system pharmaceutical composition containing andrographolide comprises the following steps:
a) dissolving a surfactant in a solvent, and stirring the solution into a uniform mixed solution by using ultrasonic or magnetic force;
b) adding cyclodextrin into solution containing surfactant, dissolving, adding andrographolide into the mixed solution, and mixing the above components to obtain andrographolide mixed solution;
c) removing the solvent to obtain a dried finished product.
Furthermore, the method for removing the solvent is a drying method, and the andrographolide mixed solution is dried at 50 ℃ to obtain a final finished product;
furthermore, the method for removing the solvent is a vacuum drying method, and the andrographolide mixed solution is placed in a vacuum drying oven for drying to obtain a final finished product;
furthermore, the method for removing the solvent is a freeze-drying method, and the andrographolide mixed solution is subjected to freeze-drying to obtain a final finished product;
furthermore, the method for removing the solvent is a rotary evaporation method, and the mixed solution of andrographolide is volatilized at 65 ℃ to remove the solvent, so as to obtain the final product.
In another aspect of the present invention, a pharmaceutical preparation is provided, which comprises the aforementioned pharmaceutical composition containing andrographolide and a pharmaceutically acceptable carrier.
Further, the formulation may be any one of tablets, capsules, dripping pills, granules, concentrated pills, suspensions, solutions, emulsions, syrups and elixirs.
Further, pharmaceutically acceptable carriers in the preparation include various diluents, excipients, fillers, emulsifiers, binders, lubricants, disintegrants, antioxidants, and the like, which are conventional in the pharmaceutical field.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reasons for the low bioavailability of andrographolide include the following: firstly, andrographolide has low solubility in water, secondly andrographolide is easy to hydrolyze under the alkalescent condition, thirdly, andrographolide is easy to be discharged by P glycoprotein at the tail end of the intestine and to be metabolized in the first pass, etc.
One of the common methods of increasing the solubility of compounds is to form a molecular composite from a poorly soluble compound with a carrier molecular cavity to increase solubility. The invention adopts the addition of cyclodextrin to achieve the purpose of improving the solubility of andrographolide, and surfactant is added on the basis to form a ternary system pharmaceutical composition. The surfactants of the invention have the effect of inhibiting the efflux of P-glycoprotein, and after the surfactants are added, the efflux rate of andrographolide by P-glycoprotein is obviously reduced, thereby improving the bioavailability of andrographolide. In vitro characterization tests, cell tests and pharmacokinetic tests in the examples all show that the ternary system pharmaceutical composition provided by the invention effectively improves in vivo and in vitro bioavailability of andrographolide, and can improve clinical treatment effects.
Drawings
FIG. 1 phase solubility curves for the andrographolide-cyclodextrin system of example 1.
Figure 2 is a graph of the solubility of the andrographolide-cyclodextrin system of example 2.
FIG. 3 is a schematic diagram of the molecular dynamics simulation of the andrographolide-cyclodextrin system of example 3.
Figure 4. results of MDCK-MDR1 cytotoxicity of andrographolide- γ -cyclodextrin-surfactant ternary system in example 4.
FIG. 5 shows the result of cellular uptake of MDCK-MDR1 in the ternary system of andrographolide-gamma-cyclodextrin-surfactant of example 5.
FIG. 6 shows the results of the MDCK-MDR1 cell transmembrane transport experiment in the ternary system of andrographolide-gamma-cyclodextrin-surfactant in example 6.
Figure 7 is a solubility chart of the highly soluble andrographolide formulation of example 7.
Figure 8 is a graph of the percentage in vitro cumulative release versus time for the highly soluble andrographolide formulation of example 7.
Figure 9 is a DSC of the highly soluble andrographolide formulation of the present invention from example 7.
FIG. 10 is a Fourier transform infrared spectrum of the highly soluble andrographolide formulation of example 7.
FIG. 11 is the plasma concentration-time curve of rats prescribed with andrographolide of the present invention having high solubility in example 7.
Detailed Description
The inventor of the invention creatively discovers the andrographolide-cyclodextrin-surfactant ternary system pharmaceutical composition through a large amount of experimental researches aiming at the defects of the prior art. Compared with andrographolide bulk drugs, the solubility of the ternary pharmaceutical composition is greatly improved, and the dissolution rate and the cumulative dissolution rate of andrographolide are remarkably improved. In addition, MDCK-MDR1 cell model tests show that the pharmaceutical composition containing andrographolide can improve the absorption of andrographolide in MDCK-MDR1 cell models and remarkably reduce the efflux of P glycoprotein, so that the bioavailability of rats in vivo is improved.
Example 1 Cyclodextrin species investigation
A phase solubility curve was prepared by preparing solutions of different types of cyclodextrin (α -cyclodextrin, β -cyclodextrin, γ -cyclodextrin, hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin and sulfobutyl- β -cyclodextrin) at concentrations of 0mM, 1.5mM, 3mM, 6mM, 9mM, 12mM, 15mM, each 1m L, adding andrographolide 5mg, respectively, and performing a phase solubility test, and after sufficient dissolution, determining the concentration of andrographolide dissolved in the solution, using the molar concentration of cyclodextrin as abscissa and the aqueous solubility of andrographolide as ordinate.
The detection method comprises detecting with high performance liquid chromatography under the conditions of Eclipse XDB C18 column (250mm × 4.6.6 mm, 5 μm), protective column Eclipse XDB C18 column (12.5mm × 4.6.6 mm, 5 μm), mobile phase methanol-water (1: 1), column temperature of 30 deg.C, detection wavelength of 225nm, and flow rate of 1.0m L min-1The sample injection amount is 10u L. the detection result is shown in figure 1.
The experimental result shows that the andrographolide has better solubility in gamma-cyclodextrin, methyl- β -cyclodextrin and hydroxypropyl- β -cyclodextrin sulfobutyl- β -cyclodextrin, and has the best solubility in the gamma-cyclodextrin.
Example 2 Andrographolide to Cyclodextrin molar ratio examination
Preparing andrographolide-cyclodextrin inclusion compounds with molar concentrations of 1: 1 and 1:2, wherein the detailed formula and formulation are shown in table 1. precisely weighing 25mg of each inclusion compound, respectively adding into 5m L of water, and measuring the concentration of andrographolide dissolved in the solution after the inclusion compound is fully dissolved.
Table 1 recipe ingredients table
The detection method comprises detecting with high performance liquid chromatography under the conditions of Eclipse XDB C18 column (250mm × 4.6.6 mm, 5 μm), protective column Eclipse XDB C18 column (12.5mm × 4.6.6 mm, 5 μm), mobile phase methanol-water (1: 1), column temperature of 30 deg.C, detection wavelength of 225nm, and flow rate of 1.0m L. min-1The sample injection amount is 10u L. the detection result is shown in FIG. 2.
The experimental result shows that the molar ratio of andrographolide to cyclodextrin is 1: the effect is better at 2 days.
Example 3 simulation experiment of molecular dynamics of andrographolide-cyclodextrin system
The invention provides a molecular dynamics simulation method for interaction between andrographolide and gamma-cyclodextrin, hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin and sulfobutyl- β -cyclodextrin, which intuitively presents the state and interaction of molecules between andrographolide and various cyclodextrins.
Firstly, using Discovery Studio 2016 to construct molecular structures of andrographolide and different cyclodextrins, and then constructing two different insertion forms of andrographolide according to AutoDock Tools and AutoDock Vina as initial structures of molecular dynamics simulation. Placing different initial structures in the container respectivelyIn the water box of (1), heating to 310K after energy minimizationA molecular dynamics simulation experiment of 50ns resulted in the most stable structure of andrographolide-cyclodextrin inclusion compound, and the results are shown in FIG. 3.
The experimental results show that the inclusion compound formed by inserting the lactone ring into the cavity of the gamma-cyclodextrin is the most stable when the andrographolide and the gamma-cyclodextrin form the inclusion compound, and the inclusion compound formed by inserting the decalin ring into the cavity of the cyclodextrin is the most stable in other cyclodextrins.
EXAMPLE 4 MDCK-MDR1 cytotoxicity assay of Andrographolide-gamma-cyclodextrin-surfactant ternary System
The operation method comprises the step of inoculating the MDCK-MDR1 cells into a 96-well plate in a suspension manner, wherein the inoculation density is 1 × 104Per well, outermost round 100. mu. L PBS was added to prevent edge effects placing cells in 5% CO2After 24 hours of culture in an incubator at 37 ℃, old culture solution is aspirated, 100 mu L (see table 2) of fresh culture solution with the prescribed concentration is added, the cells after adding the drugs are put back into the incubator for 3 hours, the old culture solution is aspirated, 100 mu L of fresh culture solution (containing 10 mu L of thiazole blue and no serum) is added, the cells are taken out after 2 hours of incubation, 100 mu L DMSO is added after the culture solution is aspirated, the OD value is measured at 530nm wavelength by using an enzyme-labeling instrument after 3 minutes of low-speed shaking, the survival rate of the cells is calculated, and the result is shown in figure 4.
TABLE 2 culture solution preparation recipe
The experimental result shows that the cell survival rate of the andrographolide-gamma-cyclodextrin-surfactant ternary system pharmaceutical composition is equivalent to that of the andrographolide-gamma-cyclodextrin composition and the andrographolide bulk drug, the increase of the surfactant does not increase the cytotoxicity of the pharmaceutical composition, and the concentrations of the selected drugs and the auxiliary materials are within a safe range.
EXAMPLE 5 MDCK-MDR1 cellular uptake assay of Andrographolide-gamma-cyclodextrin-surfactant ternary System
The operation method comprises the step of inoculating the MDCK-MDR1 cells into a 6-well plate in a suspension manner, wherein the inoculation density is 5 × 105Per well. Placing the cells inAt 5% CO2Culturing overnight in an incubator at 37 ℃, removing old culture solution by suction, adding fresh culture solution with the prescribed concentration of 2m L (see table 3), putting the cells after adding the drugs back into the incubator for culturing for 90 minutes, removing old culture solution by suction, immediately washing the cells with cold PBS three times, removing andrographolide on the surfaces of the cells, adding 200 mu L Triton X-100 to lyse the cells for 30 minutes, collecting the cells, performing ultrasonic treatment for 10 minutes, centrifuging the cells, taking supernatant, and analyzing the content of andrographolide in the cells by using high performance liquid chromatography, wherein the results are shown in figure 5.
TABLE 3 recipe for culture solution preparation
The experimental result shows that the cell uptake concentration of the andrographolide-gamma-cyclodextrin-surfactant ternary system pharmaceutical composition is obviously higher than that of the commercially available dropping pill, the andrographolide-gamma-cyclodextrin composition and the andrographolide bulk drug, wherein the cell uptake concentration of the andrographolide-gamma-cyclodextrin-vitamin E-polyethylene glycol succinate ternary system pharmaceutical composition is the highest and is about 1.6 times that of the commercially available dropping pill.
Example 6 transmembrane transport assay of Andrographolide-gamma-cyclodextrin-vitamin E-polyethylene glycol succinate ternary System in MDCK-MDR1 cells
The operation method comprises the steps of inoculating MDCK-MDR1 cells in a Transwell chamber in a suspension manner, wherein the inoculation density is 5 × 105Per well. Place the cells in 5% CO2After 7 days of incubation at 37 ℃ in an incubator, the cells were washed twice with HBSS buffer solution at 37 ℃ and pH7.4, and allowed to equilibrate for 30 minutes in the incubator, after the old buffer was aspirated, 1.5m L HBSS buffer solution (see Table 4) was added to the inside of the Transwell cell and 2.6m L HBSS buffer solution was added to the bottom side of the Transwell cell for the A L-BP end, 2.6m L HBSS buffer solution (see Table 4) was added to the bottom side of the Transwell cell and 1.5m L HBSS buffer solution was added to the inside of the Transwell cell for the BP-A L end, and the cells were returned to the incubatorAnd at 15, 30, 45, 60, 90 and 120 minutes, 1m L solution was taken from the non-drug-added end and the same volume of HBSS buffer was added back and returned to the incubator, and the solution was analyzed for the rate of cell absorption and efflux by HPLC, as shown in FIG. 6.
TABLE 4 prescription of buffer solution
The experimental result shows that the cellular absorption rate of the andrographolide medicinal composition is equivalent to that of andrographolide dropping pills and andrographolide bulk drugs; however, the cell efflux rate of the andrographolide medicinal composition is obviously less than that of andrographolide dropping pills and andrographolide bulk drugs.
Example 7 preparation of a ternary pharmaceutical composition of andrographolide-gamma-cyclodextrin-vitamin E-polyethylene glycol succinate
(1) Prescription of andrographolide pharmaceutical composition
Andrographolide 2.00g
14.81g of gamma-cyclodextrin
Vitamin E-polyethylene glycol succinate 0.17g
(2) The preparation method comprises the steps of weighing the vitamin E-polyethylene glycol succinate with the prescription amount, dissolving the vitamin E-polyethylene glycol succinate in a small amount of water (about 20m L), weighing the gamma-cyclodextrin with the prescription amount, placing the gamma-cyclodextrin into a mortar, adding the vitamin E-polyethylene glycol succinate aqueous solution, stirring to dissolve the cyclodextrin, adding the andrographolide with the prescription amount into the mortar, fully grinding for 2 hours to be pasty, and drying in vacuum to obtain the final product.
EXAMPLE 8 in vitro characterization and in vivo bioavailability assay of Andrographolide-gamma-cyclodextrin-vitamin E-polyethylene glycol succinate ternary pharmaceutical composition
Experiment 1: solubility test of pharmaceutical composition containing andrographolide
Accurately weighing andrographolide 25mg, grinding to obtain andrographolide-gamma-cyclodextrin composition 210mg and andrographolide-containing pharmaceutical composition 212.1mg (both equivalent to andrographolide 25mg) prepared in example 7, dissolving in 5m L deionized water, shaking in a constant temperature shaking box at 37 deg.C for 48 hr, after complete dissolution, centrifuging to obtain supernatant, filtering with 0.45 μm microporous membrane, discarding the primary filtrate, detecting the sample solution with high performance liquid chromatography at wavelength of 225nm, and calculating andrographolide solubility by external standard method, with the results shown in FIG. 7.
Experiment 2: solubility experiment of pharmaceutical composition containing andrographolide and in-vitro dissolution experiment of andrographolide-gamma-cyclodextrin
According to the second method for measuring the release rate under the item 0931 in the fourth part of the Chinese pharmacopoeia 2015 edition, four different mediums (0.1 mol/L hydrochloric acid solution, phosphate buffer solution with pH6.8, water and 1% sodium dodecyl sulfate solution) are selected as release mediums, the volume of the release mediums is 1000m L, the temperature is controlled at (37 +/-0.5) DEG C, and the rotating speed is 75 r.min-1Taking 5m L of solution at 5min, 10 min, 15 min, 20 min, 30 min, 45 min and 60min, filtering with a 0.45 μm microporous membrane, discarding the primary filtrate, taking the secondary filtrate for later use, immediately supplementing 5m L of blank medium solution, detecting at 225nm by high performance liquid chromatography, and calculating the dissolution rate of andrographolide at different time points by external standard method, as shown in FIG. 8 (A: 0.1 mol/L hydrochloric acid, B: pH6.8 phosphate buffer, C: water, D: 1% sodium dodecyl sulfate solution).
Experiment 3: differential scanning calorimetry detection experiment of pharmaceutical composition containing andrographolide
Andrographolide, gamma-cyclodextrin, tocopheryl polyethylene glycol succinate, physical mixture of the formulation and andrographolide formulation (i.e. the pharmaceutical composition containing andrographolide prepared in example 7) were prepared in parallel, and the sample was analyzed using a differential scanning calorimeter model DSC-60, and the sample (about 3mg) was precisely weighed, and the DSC analysis conditions were set as follows: the scanning range is 30-250 ℃, and the heating rate is 10 ℃ min-1The scanning environment is a nitrogen environment, and the result is shown in FIG. 9。
Experiment 4: fourier transform infrared spectrum detection experiment for pharmaceutical composition containing andrographolide
Andrographolide, gamma-cyclodextrin, vitamin E-polyethylene glycol succinate, a physical mixture of the formulations and andrographolide formulation (i.e. the pharmaceutical composition containing andrographolide prepared in example 7) were prepared in parallel, the samples were analyzed using a fourier infrared spectrometer, and the sample powder and KBr were co-ground and pressed into thin sheets for infrared scanning analysis. The scanning range is 400-4000cm-1Scanning speed of 2cm-1The results are shown in FIG. 10.
Experiment 5: in vivo pharmacokinetics experiment of pharmaceutical composition containing andrographolide for rats
Andrographolide, commercially available andrographolide drops and andrographolide formulations (i.e. the pharmaceutical composition containing andrographolide prepared in example 7) were prepared in parallel for comparative experiments, 18 healthy SD male rats, weighing 250 ± 20 mg, were provided by the animal center of the health institute of australia university, fasted for 12 hours a day before the experiment, water was freely drunk, the animals were randomly divided into three groups of 6 animals each, andrographolide bulk drug, andrographolide drop pill and andrographolide formulation were administered separately, single dose administration was performed, dose was 40mg/kg BW. three groups of rats were each drenched with andrographolide bulk drug, andrographolide drop pill and andrographolide formulation, 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24 hours after administration, jugular vein blood was taken at 300 μ L, the plasma was transferred to heparin coated, centrifuged at 5000rpm for 5min, separated, placed at-80 ℃ and stored, ready to use, time points of plasma concentration was determined by hplc, blood concentration calculation, and the results are shown in the centrifuge tube 11.
Table 5 shows the pharmacokinetic parameters of the andrographolide-containing pharmaceutical composition of the present invention in rats, where API is andrographolide bulk drug, DP is andrographolide dropping pill, and AG-CD is high-solubility andrographolide formula, i.e. the andrographolide-containing pharmaceutical composition prepared in example 7 of the present invention.
TABLE 5 measurement results of pharmacokinetic parameters
The experiments are combined, the andrographolide-containing pharmaceutical composition has high solubility, the in vitro dissolution rate of the andrographolide-containing pharmaceutical composition is obviously superior to that of the commercially available andrographolide dropping pills, and DSC experiments show that the andrographolide-containing pharmaceutical composition is not simply and physically mixed with materials in a formula, but forms a new composition. The in vivo pharmacokinetic experiment of the rats shows that the pharmaceutical composition containing andrographolide has short peak reaching time of blood concentration and quick absorption; the area under the blood concentration-time curve (AUC) is about 1.6 times of that of the andrographolide dropping pills sold in the market, and the bioavailability is obviously improved.
EXAMPLE 9 preparation of tablets of pharmaceutical composition of Andrographolide
In this example, a wet granulation tabletting method is adopted, and the specific operations are as follows: according to the preparation method of the andrographolide pharmaceutical composition in embodiment 8, andrographolide, gamma-cyclodextrin and vitamin E-polyethylene glycol succinate are prepared into the andrographolide pharmaceutical composition, the andrographolide pharmaceutical composition is uniformly mixed with microcrystalline cellulose and hypromellose, 50% ethanol is used as a wetting agent to be added into mixed powder to prepare a soft material, the soft material is granulated through a 40-mesh nylon sieve, the soft material is dried at 50-60 ℃, the dried granules are screened through a 40-mesh sieve to be granulated, the granulated granules are uniformly mixed with magnesium stearate, and a single-punch tablet press is used for tabletting. The specification of the tablet is phi 10mm, and the tabletting pressure is 4-5 kN. The amounts of the drugs and adjuvants are shown in table 6.
TABLE 6 Andrographolide tablet formulation
Andrographolide | 0.5g |
Gamma-cyclodextrin | 3.7g |
Vitamin E-polyethylene glycol succinate | 0.043g |
Microcrystalline cellulose | 4.25g |
Hydroxypropyl methylcellulose | 0.85g |
Magnesium stearate | Appropriate amount (1%) |
Pressing | 20 pieces |
Example 10 preparation of Andrographolide pharmaceutical composition capsules
According to the preparation method of the andrographolide pharmaceutical composition in example 8, andrographolide, gamma-cyclodextrin and vitamin E-polyethylene glycol succinate are prepared into an andrographolide pharmaceutical composition, and the pharmaceutical powder is sieved by a 40-mesh sieve and then directly filled into a No. 2 capsule. The amounts of the drugs and adjuvants are shown in table 7.
TABLE 7 Andrographolide Capsule prescription
Andrographolide | 0.5g |
Gamma-cyclodextrin | 3.7g |
Vitamin E-polyethylene glycol succinate | 0.043g |
The above-mentioned embodiments, objects, technical solutions and advantageous results of the present invention are further described in detail, it should be understood that the above-mentioned embodiments are only examples of the present invention and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A pharmaceutical composition containing andrographolide, wherein the pharmaceutical composition comprises: a) andrographolide, b) cyclodextrin and c) surfactant, wherein the molar ratio of andrographolide to cyclodextrin is 1: 2-1: 5, and the surfactant accounts for 0.1% -5% of the pharmaceutical composition by mass.
2. The pharmaceutical composition of claim 1, wherein the molar ratio of the andrographolide to the cyclodextrin is 1: 2-1: 3, and the surfactant accounts for 0.1% -1% of the pharmaceutical composition by mass.
3. The pharmaceutical composition of claim 2, wherein the cyclodextrin is selected from one or more of α -cyclodextrin, β -cyclodextrin, γ -cyclodextrin, hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin or sulfobutyl- β -cyclodextrin.
4. The pharmaceutical composition of claim 1, wherein the surfactant is selected from one or more of sodium lauryl sulfate, sodium cetyl sulfate, tween 60, tween 80, benzyl S10, benzyl S20, vitamin E-polyethylene glycol succinate, poloxamer P188, poloxamer P407, and polyoxyethylene castor oil E L.
5. The pharmaceutical composition of claim 3, wherein the cyclodextrin is γ -cyclodextrin.
6. The pharmaceutical composition of claim 4, wherein the surfactant is one or more selected from the group consisting of Tween 80, vitamin E-polyethylene glycol succinate, poloxamer P407 and polyoxyethylated castor oil E L.
7. The pharmaceutical composition of claim 6, wherein the surfactant is vitamin E-polyethylene glycol succinate.
8. The pharmaceutical composition of claim 2, wherein the molar ratio of andrographolide to cyclodextrin is 1: 2.
9. The pharmaceutical composition of claim 2, wherein the surfactant is present in an amount of 1% by weight of the pharmaceutical composition.
10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in the form of any one of tablets, capsules, pills, granules, pellets, suspensions, solutions, emulsions, syrups or elixirs.
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CN114913927A (en) * | 2021-02-08 | 2022-08-16 | 欧阳德方 | Method for developing pharmaceutical composition and predicting and evaluating pharmaceutical composition |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102343096A (en) * | 2010-07-26 | 2012-02-08 | 香港城市大学 | Andrographolide cyclodextrin inclusion compound, preparation method and application thereof |
CN106377500A (en) * | 2016-11-22 | 2017-02-08 | 南京中医药大学 | Andrographolide nano suspension and preparation method thereof |
-
2018
- 2018-12-28 CN CN201811652632.0A patent/CN111388466A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102343096A (en) * | 2010-07-26 | 2012-02-08 | 香港城市大学 | Andrographolide cyclodextrin inclusion compound, preparation method and application thereof |
CN106377500A (en) * | 2016-11-22 | 2017-02-08 | 南京中医药大学 | Andrographolide nano suspension and preparation method thereof |
Non-Patent Citations (2)
Title |
---|
HONGZHI QIAO等: "Fabrication and in vitro/in vivo evaluation of amorphous andrographolide nanosuspensions stabilized by D-α-tocopheryl polyethylene glycol 1000 succinate/sodium lauryl sulfate", 《INTERNATIONAL JOURNAL OF NANOMEDICINE》 * |
PING DU等: "Nanonization of andrographolide by a wet milling method:the effects of vitamin E TPGS and oral bioavailability enhancement", 《RSC ADVANCES》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114913927A (en) * | 2021-02-08 | 2022-08-16 | 欧阳德方 | Method for developing pharmaceutical composition and predicting and evaluating pharmaceutical composition |
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