CN115252551A - Microemulsion and freeze-dried powder for paclitaxel injection and preparation method thereof - Google Patents
Microemulsion and freeze-dried powder for paclitaxel injection and preparation method thereof Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61P35/00—Antineoplastic agents
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to microemulsion and freeze-dried powder for paclitaxel injection and a preparation method thereof. The microemulsion for paclitaxel injection comprises the following components in parts by weight: 4-8 parts of paclitaxel, 235-300 parts of oil phase, 210-275 parts of surfactant, 70-90 parts of cosurfactant and 1900-2500 parts of solvent for injection, the product does not contain polyoxyethylene castor oil and has low toxicity, and the dosage of the surfactant and the cosurfactant is small, so that the toxic and side effects of chemotherapy on patients can be greatly reduced, and the anticancer effect and the cancer cure rate are enhanced; the microemulsion for paclitaxel injection has the particle size of 40-80 nm and good stability in blood plasma. The invention adopts the water drop method to prepare the microemulsion for paclitaxel injection, has simple and convenient production process, is suitable for large-scale production of pharmaceutical enterprises, and can greatly reduce the production cost and the medical expense of patients.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to microemulsion and freeze-dried powder for paclitaxel injection and a preparation method thereof.
Background
Paclitaxel (PTX for short) is a natural alkaloid with molecular formula C 47 H 51 NO 14 And the molecular weight is 853.91. Paclitaxel is a broad spectrum anticancer agent, has a wide therapeutic range, and is suitable for ovarian cancer, breast cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, kaposi's sarcoma, and late forms of acute leukemia. Paclitaxel has unique anti-tumor action mechanism, and can bind with tubulin in cells and promote its polymerization, and prevent tubulin dissociation, thereby blocking mitosis of cells at G2/M stage, and promoting apoptosis of tumor cells. However, the water solubility of paclitaxel is very small (<0.1 mug/mL) causing difficulty in administration, and is hardly effective in oral absorption, and is currently effective clinically only by administration by injection.
At present, taxol is sold in the market at home as a preparation taxol injection
The drug consists of Cremophor EL (polyoxyethylene castor oil) and 50 (v/v) of absolute ethyl alcohol, desensitization treatment is required before administration, renal toxicity, cardiac toxicity and the like are easily caused, and the toxic and side effects are very large. Chinese patent CN101612121A discloses a preparation method of a taxol microemulsion, which takes one or a mixture of two of refined corn oil, soybean oil and olive oil as an oil phase, one or a mixture of lecithin and poloxamer as an emulsifier, one or a mixture of anhydrous ethanol and propylene glycol as an auxiliary emulsifier, and water as a water phase to prepare the taxol or the derivative thereof self-emulsifying microemulsion.
Disclosure of Invention
The invention aims to provide a microemulsion for paclitaxel injection and a preparation method and application thereof aiming at the existing problems. The microemulsion for paclitaxel injection has good stability, can not separate out precipitate after dilution, can not separate out when passing through gastrointestinal tracts, has low toxicity, and is suitable for industrial production.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a microemulsion for paclitaxel injection, which comprises the following components in parts by weight: 4 to 8 portions of paclitaxel, 235 to 300 portions of oil phase, 210 to 275 portions of surfactant, 70 to 90 portions of cosurfactant and 1900 to 2500 portions of solvent for injection.
Preferably, the oil phase comprises one or more of castor oil, oleic acid, ethyl oleate, medium chain fatty acid glycerides, isopropyl myristate and vitamin E acetate.
Preferably, the surfactant comprises one or more of tween80, polyethylene glycol stearate, poloxamer 188 and soy lecithin.
Preferably, the co-surfactant comprises one or more of absolute ethanol, polyethylene glycol 400 and diethylene glycol monoethyl ether.
Preferably, the solvent for injection comprises one or more of water for injection, physiological saline for injection and glucose solution for injection.
Preferably, the particle size of the microemulsion for paclitaxel injection is 40-80 nm.
Preferably, the pH value of the microemulsion for paclitaxel injection is 4-6.
The invention also provides a preparation method of the microemulsion for paclitaxel injection, which comprises the following steps:
firstly mixing paclitaxel, partial surfactant and cosurfactant to obtain a mixed solution;
and secondly, mixing the mixed solution, the oil phase, the rest part of the surfactant and the injection solvent for the second time, and filtering to obtain the taxol microemulsion for injection.
Preferably, the time for the first mixing is 5 to 15min.
The invention also provides taxol microemulsion freeze-dried powder for injection, which is obtained by drying the taxol microemulsion for injection.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a microemulsion for paclitaxel injection, which comprises the following components in parts by weight: 4 to 8 portions of paclitaxel, 235 to 300 portions of oil phase, 210 to 275 portions of surfactant, 70 to 90 portions of cosurfactant and 1900 to 2500 portions of solvent for injection. The microemulsion for paclitaxel injection forms a homogeneous thermodynamic stable system, does not precipitate medicine after being diluted by water for injection, and can keep stable in blood.
Meanwhile, the surfactant and cosurfactant are less in dosage, and the prepared microemulsion for paclitaxel injection can greatly reduce the toxic and side effects of cancer chemotherapy on patients, enhance the anticancer curative effect of the cancer chemotherapy and enhance the cure rate of the cancer.
Furthermore, the surfactant comprises one or more of tween80, polyethylene glycol stearate, poloxamer 188 and soybean lecithin, the cosurfactant comprises one or more of absolute ethyl alcohol, polyethylene glycol 400 and diethylene glycol monoethyl ether, the surfactant and the cosurfactant with low toxicity are selected, the microemulsion does not contain polyoxyethylene castor oil, and the surfactant and the cosurfactant have low toxicity, so that the clinical toxic and side effects can be greatly reduced, and the curative effect of the medicine is improved.
The particle size of the microemulsion for paclitaxel injection is 40-80 nm. The microemulsion is a thermodynamically stable dispersion system consisting of an oil phase, a water phase, a surfactant and a cosurfactant according to a certain proportion, the whole system is a transparent or semitransparent oil-water mixing system, the drug absorption can be promoted, the drug curative effect can be enhanced, and the microemulsion has good application prospects in the aspects of preventing and treating tumors, inhibiting the discharge of p-glycoprotein, reducing the occurrence of multidrug resistance, targeting drug delivery and the like.
The invention also provides a preparation method of the microemulsion for paclitaxel injection, which is simple and suitable for industrial production of pharmaceutical enterprises, can greatly reduce the production cost of products and greatly reduce the medical expense of patients, and has huge market prospect and social value.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required in the embodiments will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a graph showing the particle size distribution of a microemulsion for paclitaxel injection (PTX-ME) of example 1 and a microemulsion for paclitaxel injection (Blank-ME) of comparative example 1, wherein A is the particle size distribution of the Blank microemulsion, B is the particle size distribution of the microemulsion for paclitaxel injection (PTX-ME), and C is the Zeta potential of the Blank microemulsion and the microemulsion for paclitaxel injection (PTX-ME);
FIG. 2 is a transmission electron microscopy scan of the microemulsion for paclitaxel injection of example 1;
FIG. 3 shows a microemulsion and paclitaxel injection for paclitaxel injection in example 1
And Free paclitaxel (Free-PTX) in vitro release profiles;
FIG. 4 is a graph showing the results of in vitro anti-cell proliferation assay in test example 2, wherein A is the results of cell proliferation after MCF-7 breast cancer cells were administered for 24 hours, B is the results of cell proliferation after MCF-7 breast cancer cells were administered for 48 hours, C is the results of cell proliferation after MDA-MB-231 breast cancer cells were administered for 24 hours, and D is the results of cell proliferation after MDA-MB-231 breast cancer cells were administered for 48 hours;
FIG. 5 is a graph showing the tumor growth inhibition experiment in test example 2, in which A is physiological saline, a commercially available preparation
Microemulsion (PTX-ME) administration for paclitaxel injectionThe change of the post-tumor volume is shown in the figure, B is the tumor tissue diagram of each administration group at the end of the experiment;
FIG. 6 shows the microemulsion for paclitaxel injection and the commercial formulation in test example 2
The experimental picture of the tumor-bearing nude mouse tissue distribution.
Detailed Description
The invention provides a microemulsion for paclitaxel injection, which comprises the following components in parts by weight: 4 to 8 portions of paclitaxel, 235 to 300 portions of oil phase, 210 to 275 portions of surfactant, 70 to 90 portions of cosurfactant and 1900 to 2500 portions of solvent for injection.
In the present invention, unless otherwise specified, all the raw materials used are commercially available in the art.
In the present invention, the microemulsion for paclitaxel injection preferably comprises 4 to 5 parts by weight of paclitaxel.
In the present invention, the microemulsion for paclitaxel injection preferably comprises 250 to 285 parts by weight of an oil phase. In the invention, the oil phase has the functions of increasing the solubility of the drug (paclitaxel), enabling drug molecules to exist in oil drops, increasing the stability of the drug and forming an O/W type homogeneous phase thermodynamic stable system.
In the present invention, the oil phase preferably includes one or more of castor oil, oleic acid, ethyl oleate, medium-chain fatty glyceride (Labrafac lipophile WL 1349), isopropyl myristate and vitamin E acetate, more preferably includes ethyl oleate and vitamin E acetate, and the mass ratio of ethyl oleate to vitamin E acetate is preferably 1.5-1.6.
In the present invention, the microemulsion for paclitaxel injection preferably comprises 230 to 270 parts by weight of a surfactant. In the present invention, the surfactant functions to increase the solubility of the drug and reduce the interfacial tension on the surface of the emulsion droplets.
In the invention, the surfactant preferably comprises one or more of Tween80 (Tween 80), polyethylene glycol stearate, poloxamer 188 (P188) and soybean lecithin, more preferably comprises polyethylene glycol stearate, soybean lecithin and poloxamer 188, and the mass ratio of the polyethylene glycol stearate, the soybean lecithin and the poloxamer 188 is preferably 3-3.5. In a specific embodiment of the present invention, the polyethylene glycol stearate is preferably polyethylene glycol-15 hydroxystearate (Solutol HS 15).
In the invention, the microemulsion for paclitaxel injection preferably comprises 80 to 90 parts by weight of cosurfactant. In the present invention, the cosurfactant acts to increase the solubility of the drug, forming a stable microemulsion.
In the present invention, the co-surfactant preferably includes one or more of anhydrous ethanol, polyethylene glycol 400 (PEG 400), and diethylene glycol monoethyl ether (transcutol HP), and more preferably diethylene glycol monoethyl ether (transcutol HP).
In the present invention, the microemulsion for paclitaxel injection preferably comprises 1900 to 2000 parts by weight of the solvent for injection.
In the present invention, the solvent for injection preferably includes one or more of water for injection, physiological saline for injection, and glucose solution for injection, and more preferably water for injection.
In the invention, the particle size of the microemulsion for paclitaxel injection is preferably 40-80 nm, and more preferably 50nm; the shape is preferably spherical or spheroidal, and the size is uniform and the distribution is uniform.
In the invention, the microemulsion for paclitaxel injection is preferably O/W type microemulsion with clear transparent and bluish opalescence.
In the present invention, the pH of the microemulsion for paclitaxel injection is preferably 4 to 6. The pH value is preferably achieved by controlling the types and the use amounts of the raw materials, and a pH regulator is not required to be added for adjustment.
The invention also provides a preparation method of the microemulsion for paclitaxel injection, which comprises the following steps:
firstly mixing paclitaxel, partial surfactant and cosurfactant to obtain a mixed solution;
and carrying out second mixing on the mixed solution, the oil phase, the rest part of the surfactant and the injection solvent, and filtering to obtain the paclitaxel micro emulsion for injection.
The invention firstly mixes paclitaxel, partial surfactant and cosurfactant to obtain mixed solution.
In the present invention, the first mixing mode is preferably vortex ultrasound, and the time of the first mixing is preferably 5 to 15min, and more preferably 10min.
After the mixed solution is obtained, the mixed solution, the oil phase, the rest part of the surfactant and the injection solvent are subjected to second mixing and then are filtered to obtain the taxol microemulsion for injection.
In the present invention, the oil phase, the remaining part of the surfactant and the solvent for injection are preferably added to the mixed solution in this order.
In the embodiment of the present invention, the oil phase is preferably added to the mixed solution first, and the mode of adding the oil phase to the mixed solution is preferably accompanied by stirring.
In the present invention, the temperature accompanied by stirring is preferably 33 to 40 ℃, more preferably 37 ℃.
After the oil phase is added, the invention preferably dissolves the rest part of the surfactant in the solvent for injection to obtain the solution for injection, and then adds the solution for injection into the obtained solution, wherein the adding mode of the solution for injection preferably adopts a dropping mode, namely a water dropping method.
And (3) sequentially adding the oil phase and the injection solution into the mixed solution to preferably obtain a clear and transparent paclitaxel microemulsion.
In the present invention, the filtration is preferably performed by sterilization through a 0.22 μm microfiltration membrane.
The invention also provides a microemulsion freeze-dried powder for paclitaxel injection, which is obtained by drying the microemulsion for paclitaxel injection.
In the present invention, the drying preferably comprises freeze-drying or spray-drying, and the conditions of the freeze-drying or spray-drying are not particularly required in the present invention, and may be performed in a manner well known to those skilled in the art.
In the present invention, the microemulsion for paclitaxel injection is preferably further prepared for infusion solution.
In order to further illustrate the present invention, the microemulsion and lyophilized powder for paclitaxel injection and the preparation method thereof provided by the present invention are described in detail below with reference to the drawings and examples, but they should not be construed as limiting the scope of the present invention.
Example 1
The paclitaxel microemulsion for injection is prepared according to the prescription composition of table 1, and 30 bags of 100mL infusion are prepared:
TABLE 1 formulation composition of microemulsion for paclitaxel injection of example 1
| Paclitaxel | 5.0g | / |
| Oleic acid ethyl ester | 175g | Oil phase |
| Vitamin E acetate | 110g | Oil phase |
| Polyethylene glycol stearate (SolutolHS 15) | 150g | Surface active agent |
| Soybean lecithin | 70g | Surface active agent |
| Diethylene glycol monoethyl ether (Trancutol HP) | 88g | Cosurfactant |
| Poloxamer 188 (P188) | 47g | Surface active agent |
| Water for injection | 2400mL | / |
The preparation process comprises the following steps:
weighing the soybean lecithin, the Trancutol HP and the Solutol HS15 according to the prescription amount, adding the taxol according to the prescription amount, and performing vortex ultrasonic mixing to obtain a mixed solution; adding the oil phase according to the prescription amount, and stirring at the constant temperature of 37 ℃ to completely dissolve the soybean lecithin and the paclitaxel; dissolving P188 in water for injection at 37 deg.C under stirring to obtain water solution, dripping into the above solution to obtain microemulsion with clear and transparent blue light, filtering with 0.22 μm microporous membrane, sterilizing, removing heat source, and packaging.
The drug loading of the microemulsion for paclitaxel injection (PTX-ME) obtained in example 1 was 1.6mg/g.
Example 2
The difference between the embodiment and the embodiment 1 is that the mass of the paclitaxel is 8.0g, the other components and the preparation process are the same as the embodiment 1, and the drug loading rate of the obtained microemulsion for paclitaxel injection is 2.6mg/g.
Example 3
The difference between the present example and example 1 is that the weight of paclitaxel is 4.0g, the other components and preparation process are the same as example 1, and the drug loading rate of the microemulsion for paclitaxel injection is 1.3mg/g.
Comparative example 1
This comparative example differs from example 1 above only in that no paclitaxel was added, resulting in a Blank microemulsion (Blank-ME).
Test example 1
The Blank microemulsion (Blank-ME) of comparative example 1 and the microemulsion (PTX-ME) for paclitaxel injection of example 1 were each taken at 200. Mu.L and added to a 10mL volumetric flask, diluted to the scale with distilled water, shaken gently, and the particle diameter, the polydispersity index (PDI) and the Zeta potential were measured using a ZS90 particle size and potential measuring instrument. The particle size distribution is shown in FIG. 1, and the average particle size, PDI and Zate potential (25 ℃, n = 10) are shown in Table 2.
Table 2 particle size, PDI and Zate potential (25 ℃, n = 10) of blank microemulsion and paclitaxel microemulsion for injection
| Composition | Blank-ME | PTX-ME |
| Size(nm) | 49.4±0.93 | 50.1±1.21 |
| PDI | 0.145±0.006 | 0.153±0.005 |
| Zetapotential(mv) | -0.537±0.12 | -0.832±0.28 |
The results show that the grain sizes of the two microemulsions are uniform and are both about 50 nm. The Zate potential results show that both microemulsions are electrically neutral.
And (3) observing by using a transmission electron microscope:
1mL of the microemulsion for paclitaxel injection prepared in example 1 was added to a 10mL volumetric flask, diluted to the mark with distilled water, and shaken up. Taking one drop on a copper mesh, counterstaining, observing by an electron microscope, and measuring the particle diameter of the medicine to be about 50nm and the shape to be spherical or similar to spherical by a scanning image of a transmission electron microscope as shown in figure 2.
Examination of plasma stability:
in vivo blood environment was simulated by diluting Fetal Bovine Serum (FBS) with PBS (pH 7.4) to 10% by mass, 0.5mL of PTX-ME obtained in example 1 and example 2, respectively, was added to 1mL of 10% by mass FBS solution, the mixture was placed on a 37 ℃ constant temperature water bath shaker, shaken at 100rpm for 0h, 4h, 8h, 12h, 24h, and 48h, 0.2mL of the mixture was used for particle size measurement, and the results of the measurement were performed in triplicate for each group and are shown in Table 3.
Table 3 plasma stability test results (n = 3)
Experimental results show that the PTX-ME with drug loading of 1.6mg/g and 2.6mg/g respectively has no obvious difference in particle size within 0h and 48h, which indicates that the prepared microemulsion for paclitaxel injection is stable in blood plasma within 48 h.
Preparation of diluted PTX-ME with different solvents storage stability at 4 ℃ investigation:
the PTX-ME obtained in example 1 was diluted with water for injection, physiological saline and glucose for injection, respectively, and left at 4 ℃ for 0, 1, 2, 3, 4 and 5 days, respectively, and the precipitation of the drug was observed every day, and the particle size was measured by sampling, and the results are shown in Table 4.
TABLE 4 preparation of particle size (nm) of diluted PTX-ME stored at 4 ℃ for 5 days in different solvents
The experimental result shows that the particle size of the three solvents is not changed greatly after being placed for 5 days, no obvious difference is seen, the three solvents are clear and transparent by naked eye observation, no medicine is separated out, and the fact that the medicine is kept stable in the three solvents and the medicine is not separated out is shown.
Test example 2
1. In vitro release experiments:
the microemulsion for paclitaxel injection (PTX-ME) prepared in example 1 and paclitaxel injection (PTX-ME) which is a commercially available preparation are mixed by dialysis method
And Free paclitaxel (Free-PTX) were prepared into solutions containing 8mg/5mL of paclitaxel, 1mL of each was dropped into a dialysis bag (12000 Da), the dialysis bag was sealed, placed in 150mL of PBS containing 1.0% Tween80 (pH 7.4), placed in a constant temperature shaker at 100rpm and 37 ℃, 1mL was sampled at predetermined time points of 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, 72 hours, and supplemented with an equal volume of fresh release medium, the sampling time was adjusted according to the results, samples at different time points were passed through a 0.22 μm filter, and the drug concentration was measured by HPLC and the cumulative release amount was calculated. Microemulsion for paclitaxel injection (PTX-ME) and paclitaxel injection
And Free paclitaxel (Free-PTX) as shown in figure 3.
The results show that the microemulsion for paclitaxel injection and the commercial preparation of the invention
Shows similar release trend and releases slowly.
2. In vitro anti-cell proliferation assay:
the microemulsion for paclitaxel injection of example 1 and
cytotoxic effects on MCF-7 and MDA-MB-231 cells. MCF-7 and MDA-MB-231 cells were seeded in 96-well cell culture plates at a cell density of 1X 10 4 Cells were grown adherently in wells (180. Mu.L) and incubated for 24 h. The paclitaxel (FreePtx), blank microemulsion, microemulsion for paclitaxel injection, taxol-Blan k (Cremophor EL/Ethanol), and Taxol are mixed at series concentration
mu.L of each was added to the cell culture wells to give a final concentration gradient of PTX for each experimental group in both MCF-7 and MDA-MB-231 cells: 1.5, 10, 20, 32, 50 μ g/mL, 6 duplicate wells per concentration were set, plates of both cells were placed in an incubator for incubation at two time points of 24h and 48 h. After the end of the administration, the supernatant was discarded, washed 2 times with PBS, and 20. Mu.L of MTT solution (5.0 mg/mL) and 100. Mu.L of serum-free medium were added to each well and incubation was continued for 4h. After purple formazan crystals were formed, the supernatant was discarded, and 200. Mu.L of DMSO was added to each well. Shaking horizontally at room temperature for 20min to dissolve the crystals completely. The absorbance value (OD value) of each well was measured at a wavelength of 490nm using a microplate reader, and the antiproliferative activity was expressed as cell viability, and the calculation formula was as shown in formula 1:
in formula 1, ODd is the OD value of the cells incubated with the preparation sample, ODb is the OD value of the cell culture medium, and ODr is the OD value of the cells incubated with the culture medium alone.
The results of the in vitro anti-cell proliferation assay are shown in FIG. 4. The results show that under the same concentration at the same time, the inhibition rate of each preparation on the breast cancer cells is as follows:
EL/Ethanol>Blank-ME>FreePtx, prepared PTX-ME and commercially available
Has the same tumor inhibiting effect, but compared with blank material (blank microemulsion group)
(Taxol-Blank group) has lower toxicity; when the preparation concentration is 50 mu g/mL and the preparation is incubated for 48 hours, the survival rate of both cells is less than 10 percent.
3. Tumor growth inhibition experiment:
taking 30 BALB/c nude mice, establishing tumor-bearing nude mouse models, inoculating MDA-MB-231 cells for 7 days, and growing the tumor volume to about 100mm 3 Meanwhile, tumor-bearing nude mice were randomly divided into 3 groups of 10 mice each. The following three groups of formulations were administered by tail vein injection, respectively: (1) PTX-ME dose 10mg/kg;
the dosage is 10mg/kg; and (3) physiological saline (saline). The administration time was to grow to about 100mm in tumor size 3 The calculation is started, and the medicine is taken every three days, and the dosage of each time is the same as the first time. The living state of the tumor-bearing mice was observed, the body weights thereof were weighed on the day of administration, and the tumor volumes thereof were measured with a vernier caliper, and the tumor volumes were measured with V (mm) 3 ) And (4) showing. After the experiment is finished, a tumor growth curve is drawn by taking the average value of the tumor volume of each group of tumor-bearing nude mice as the ordinate and the measurement time as the abscissa; the results of the tumor growth inhibition experiment are shown in FIG. 5. And (4) statistically analyzing the tumor volume and calculating the tumor volume inhibition rate. The calculation formula of the tumor volume inhibition rate is shown as formula 2:
the results showed that the group administered PTX-ME and
has certain inhibiting effect on tumors, wherein the PTX-ME group has the best tumor inhibiting effect, the volume inhibiting rate of the PTX-ME group on the tumors is 68.09 percent,
the inhibition rate of the tumor volume is 56.50 percent.
4. Tumor-bearing nude mouse tissue distribution experiment:
after the tumor growth inhibition experiment is finished, paclitaxel microemulsion and paclitaxel microemulsion are respectively injected into tail vein according to the dose of 10mg/kg
Nude mice were sacrificed at 1h and 24h after drug administration, heart, liver, spleen, lung, kidney, brain, and tumor tissues were isolated, and after sample treatment, sample analysis by LC-MS was performed, and the results of the tumor-bearing nude mice tissue distribution experiment are shown in FIG. 6.
The experimental results show that PTX-ME is reacted with
Compared with the prior art, the PTX-ME liposome is less distributed in each tissue and tumor after administration for 1h, and the PTX-ME liposome is higher in tumor tissue concentration after administration for 24h, probably because the microemulsion has targeting property. PTX-ME comparison
There is less distribution of heart, liver, spleen, lung, kidney, brain, higher tumor distribution, meaning less toxicity and better antitumor effect.
Although the present invention has been described in detail with reference to the above embodiments, it is to be understood that the present invention is not limited to the details of the embodiments, and that various modifications, additions, substitutions, and equivalents may be made without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. The microemulsion for paclitaxel injection is characterized by comprising the following components in parts by weight: 4 to 8 portions of paclitaxel, 235 to 300 portions of oil phase, 210 to 275 portions of surfactant, 70 to 90 portions of cosurfactant and 1900 to 2500 portions of solvent for injection.
2. The microemulsion of claim 1 wherein the oil phase comprises one or more of castor oil, oleic acid, ethyl oleate, medium chain fatty acid glycerides, isopropyl myristate and vitamin E acetate.
3. The microemulsion of claim 1 wherein the surfactant comprises one or more of tween80, polyethylene glycol stearate, poloxamer 188 and soy lecithin.
4. A microemulsion as claimed in claim 1, wherein the co-surfactant comprises one or more of absolute ethanol, polyethylene glycol 400 and diethylene glycol monoethyl ether.
5. The microemulsion of claim 1, wherein the injection solvent comprises one or more of water for injection, physiological saline for injection, and glucose solution for injection.
6. The microemulsion of any one of claims 1 to 5, wherein the particle size of the microemulsion is 40 to 80nm.
7. A microemulsion as claimed in any one of claims 1-5, wherein the pH value of the microemulsion is 4-6.
8. A process for preparing a microemulsion of paclitaxel for injection according to any of claims 1 to 7, characterized in that it comprises the following steps:
firstly mixing paclitaxel, partial surfactant and cosurfactant to obtain a mixed solution;
and secondly, mixing the mixed solution, the oil phase, the rest part of the surfactant and the injection solvent for the second time, and filtering to obtain the taxol microemulsion for injection.
9. The method of claim 8, wherein the first mixing is performed for a time of 5 to 15min.
10. A microemulsion freeze-dried powder for paclitaxel injection is characterized in that the microemulsion freeze-dried powder is obtained by drying the microemulsion for paclitaxel injection of any one of claims 1 to 7 or the microemulsion for paclitaxel injection obtained by the preparation method of claim 8 or 9.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101428002A (en) * | 2008-11-20 | 2009-05-13 | 沈阳万爱普利德医药科技有限公司 | Paclitaxel freeze drying microemulsion for injection and method of producing the same |
| CN101548949A (en) * | 2009-01-23 | 2009-10-07 | 海口市制药厂有限公司 | Paclitaxel nanoemulsion injection |
| US20120308616A1 (en) * | 2009-10-29 | 2012-12-06 | Institute Of Mataria Medica, Chinese Academy Of Medical Sciences | Submicro emulsion of paclitaxel using steroid complex as intermediate carrier |
| CN103110581A (en) * | 2013-02-26 | 2013-05-22 | 西南大学 | Taxol microemulsion drug composition and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101428002A (en) * | 2008-11-20 | 2009-05-13 | 沈阳万爱普利德医药科技有限公司 | Paclitaxel freeze drying microemulsion for injection and method of producing the same |
| CN101548949A (en) * | 2009-01-23 | 2009-10-07 | 海口市制药厂有限公司 | Paclitaxel nanoemulsion injection |
| US20120308616A1 (en) * | 2009-10-29 | 2012-12-06 | Institute Of Mataria Medica, Chinese Academy Of Medical Sciences | Submicro emulsion of paclitaxel using steroid complex as intermediate carrier |
| CN103110581A (en) * | 2013-02-26 | 2013-05-22 | 西南大学 | Taxol microemulsion drug composition and preparation method thereof |
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