CN114831947A - Preparation method and application of nano preparation for improving drug-loading rate and oral bioavailability of 2-methoxyestradiol - Google Patents
Preparation method and application of nano preparation for improving drug-loading rate and oral bioavailability of 2-methoxyestradiol Download PDFInfo
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- CQOQDQWUFQDJMK-SSTWWWIQSA-N 2-methoxy-17beta-estradiol Chemical compound C([C@@H]12)C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CCC1=C2C=C(OC)C(O)=C1 CQOQDQWUFQDJMK-SSTWWWIQSA-N 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title claims abstract description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 94
- 239000002105 nanoparticle Substances 0.000 claims abstract description 57
- 238000003760 magnetic stirring Methods 0.000 claims abstract description 42
- 239000000725 suspension Substances 0.000 claims abstract description 37
- 239000000243 solution Substances 0.000 claims abstract description 30
- 238000004108 freeze drying Methods 0.000 claims abstract description 28
- 239000011259 mixed solution Substances 0.000 claims abstract description 22
- 239000004475 Arginine Substances 0.000 claims abstract description 21
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 21
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 claims abstract description 17
- 229910021642 ultra pure water Inorganic materials 0.000 claims abstract description 17
- 239000012498 ultrapure water Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229920002494 Zein Polymers 0.000 claims description 38
- 239000005019 zein Substances 0.000 claims description 38
- 229940093612 zein Drugs 0.000 claims description 38
- 239000003814 drug Substances 0.000 claims description 31
- 229940079593 drug Drugs 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 23
- 239000000843 powder Substances 0.000 claims description 19
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 239000003381 stabilizer Substances 0.000 claims description 11
- 239000003223 protective agent Substances 0.000 claims description 10
- 239000008347 soybean phospholipid Substances 0.000 claims description 10
- 238000009210 therapy by ultrasound Methods 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 8
- 230000002708 enhancing effect Effects 0.000 claims 6
- 238000003756 stirring Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 description 7
- 238000003304 gavage Methods 0.000 description 5
- 230000031891 intestinal absorption Effects 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 239000002539 nanocarrier Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010064851 Plant Proteins Proteins 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000021118 plant-derived protein Nutrition 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- -1 steroid compounds Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention relates to a preparation method and application of a nano preparation for improving the drug-loading rate and the oral bioavailability of 2-methoxyestradiol, which can effectively solve the problems of low drug-loading rate, poor stability and low oral bioavailability of the existing 2-methoxyestradiol nano preparation; dropwise adding the ethanol phase into the sodium cholate ultrapure water solution under magnetic stirring to form a mixed solution, placing the mixed solution into a water bath kettle, and performing magnetic stirring to obtain a 2-ME nanoparticle suspension; adding arginine into the 2-ME nanoparticle suspension, and freeze-drying to obtain the 2-methoxyestradiol nanometer preparation. The invention has the advantages of rich raw materials, scientific and reasonable components, simple preparation method and good product quality, can effectively improve the drug-loading rate and the oral bioavailability of the 2-methoxyestradiol, improves the curative effect, and is a great innovation on the antitumor drugs.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method and application of a nano preparation for improving the drug-loading rate and the oral bioavailability of 2-methoxyestradiol (2-ME).
Background
2-ME is a physiological metabolite of natural steroid compounds in vivo, and is a broad-spectrum antitumor drug. 2-ME can obviously inhibit tumor cells with faster proliferation, but can not damage normal cells, so that 2-ME becomes a medicine with good application prospect in the field of antitumor medicines. However, the results of the foreign clinical phase I and II tests show that: after the common preparation (such as tablets and capsules) is orally taken, the effective blood concentration is difficult to maintain, and the clinical test result is not ideal. Further research shows that after 2-ME is orally taken, obvious liver first pass effect and intestinal absorption saturation phenomenon exist, and the medicine has short half-life period and fast elimination. The nanometer preparation has wide research range, and has the features of raised medicine solubility, raised gastrointestinal tract stability, raised intestinal absorption, raised oral bioavailability, raised curative effect and less toxic side effect. According to the characteristics and in vivo process of 2-ME, the adoption of nanoparticles is tried to improve the oral bioavailability of the nanoparticles. Our experimental results demonstrate that this is an effective strategy to improve the oral bioavailability of 2-ME.
However, some of the currently reported 2-ME nano-carriers cannot be completely prepared from pharmaceutic adjuvants, and have low drug loading and poor stability, so that clinical development and application of the 2-ME nano-carriers are limited, and therefore, how to prepare relatively stable nano-particles by adopting pharmaceutic adjuvants and improve the drug loading and the oral bioavailability is one of the focuses of domestic and foreign researches at present and is also an important technical obstacle of clinical development and application, so that how to develop a nano-preparation for improving the drug loading and the oral bioavailability and actively promote the development of 2-ME oral preparations is how to develop the 2-ME nano-carriers and relevant public reports are not found at home and abroad at present.
Disclosure of Invention
In view of the above situation, in order to solve the defects of the prior art, the present invention aims to provide a preparation method and an application of a nano preparation for improving the drug-loading rate and the oral bioavailability of 2-methoxyestradiol, which can effectively solve the problems of low drug-loading rate, poor stability and low oral bioavailability of the existing 2-methoxyestradiol nano-particle preparation.
The technical scheme of the invention is that the preparation method of the nano preparation for improving the drug loading rate and the oral bioavailability of the 2-methoxyestradiol comprises the following steps:
1) adding 40-100mg of a mixture of soybean phospholipid (PC-80) and Zein (Zein) with a weight ratio of 1: 0.5-6 into 5mL of ethanol with a volume concentration of 60% -90%, performing ultrasonic treatment for 10-30min, performing magnetic stirring for 1h, adding 1mL of 2-ME ethanol solution with a weight ratio of 2-ME to Zein (Zein) of 1: 2-20, and performing magnetic stirring for 1h to obtain an ethanol phase;
2) slowly dripping an ethanol phase into a sodium cholate ultrapure water solution with the volume concentration of 0.1-0.8% at the speed of 1-5mL/min under magnetic stirring to form a mixed solution, putting the mixed solution into a water bath kettle at the temperature of 40-70 ℃, and performing magnetic stirring for 2 hours to obtain a 2-ME nanoparticle suspension;
3) adding 1-5% of arginine in the volume of the 2-ME nanoparticle suspension into the 2-ME nanoparticle suspension, wherein the arginine is used as a freeze-drying protective agent and a stabilizing agent, and then placing the mixture into a freeze dryer for freeze drying to obtain the 2-methoxyestradiol nano preparation (freeze-dried powder).
The 2-methoxyestradiol nano preparation (freeze-dried powder) prepared by the method has the advantages of improving the drug loading capacity and the oral bioavailability, and realizing the application of the 2-methoxyestradiol nano preparation (freeze-dried powder) in the preparation of nano preparation drugs for improving the drug loading capacity and the bioavailability of the 2-methoxyestradiol.
The invention has the advantages of rich raw materials, scientific and reasonable components, simple preparation method and good product quality, can effectively improve the drug-loading rate and the oral bioavailability of the 2-methoxyestradiol, improves the curative effect, is a great innovation on the antitumor drugs, and has remarkable economic and social benefits.
Detailed Description
The following describes the embodiments of the present invention in further detail with reference to specific cases and examples.
The invention may be embodied in the form of the following examples.
Example 1
The invention relates to a preparation method of a nano preparation for improving the drug-loading rate and the oral bioavailability of 2-methoxyestradiol, which comprises the following steps:
1) adding 60mg of a mixture of soybean phospholipid (PC-80) and Zein (Zein) in a weight ratio of 1: 1 into 5mL of ethanol with a volume concentration of 70%, performing ultrasonic treatment for 15min, performing magnetic stirring for 1h, adding 1mL of 2-ME ethanol solution in which the weight ratio of 2-ME to Zein (Zein) is 1: 2, and performing magnetic stirring for 1h to obtain an ethanol phase;
2) slowly dripping an ethanol phase into a sodium cholate ultrapure water solution with the volume concentration of 0.1% at the speed of 2mL/min under magnetic stirring to form a mixed solution, wherein the volume ratio of the ethanol phase to the sodium cholate ultrapure water solution is 1: 1, placing the mixed solution into a water bath kettle at the temperature of 60 ℃, and performing magnetic stirring for 2 hours to obtain a 2-ME nanoparticle suspension;
3) adding 1 volume percent of arginine of the 2-ME nanoparticle suspension into the 2-ME nanoparticle suspension, taking the arginine as a freeze-drying protective agent and a stabilizing agent, and freeze-drying the mixture in a freeze-drying machine to obtain the 2-methoxyestradiol nano-preparation freeze-dried powder.
Example 2
The invention relates to a preparation method of a nano preparation for improving the drug-loading rate and the oral bioavailability of 2-methoxyestradiol, which comprises the following steps:
1) adding 80mg of a mixture of soybean phospholipid (PC-80) and Zein (Zein) in a weight ratio of 1: 3 into 5mL of 65% ethanol, performing ultrasonic treatment for 20min, performing magnetic stirring for 1h, adding 1mL of 2-ME ethanol solution in which the weight ratio of 2-ME to Zein (Zein) is 1: 5, and performing magnetic stirring for 1h to obtain an ethanol phase;
2) slowly dropwise adding the ethanol phase into a sodium cholate ultrapure water solution with a volume concentration of 0.3% at a speed of 1mL/min under magnetic stirring to form a mixed solution, placing the mixed solution into a water bath kettle with a temperature of 65 ℃, and performing magnetic stirring for 2 hours to obtain a 2-ME nanoparticle suspension;
3) adding 2% arginine by volume of the 2-ME nanoparticle suspension into the 2-ME nanoparticle suspension, taking the arginine as a freeze-drying protective agent and a stabilizing agent, and freeze-drying in a freeze-drying machine to obtain the 2-methoxyestradiol nano preparation (freeze-dried powder).
Example 3
The invention relates to a preparation method of a nano preparation for improving the drug-loading rate and the oral bioavailability of 2-methoxyestradiol, which comprises the following steps:
1) adding 100mg of a mixture of soybean phospholipid (PC-80) and Zein (Zein) at a weight ratio of 1: 6 into 5mL of 80% ethanol, performing ultrasonic treatment for 30min, performing magnetic stirring for 1h, adding 1mL of 2-ME ethanol solution at a weight ratio of 2-ME to Zein (Zein) of 1: 10, and performing magnetic stirring for 1h to obtain an ethanol phase;
2) slowly dripping an ethanol phase into a sodium cholate ultrapure water solution with the volume concentration of 0.5% at the speed of 3mL/min under magnetic stirring to form a mixed solution, wherein the volume ratio of the ethanol phase to the sodium cholate ultrapure water solution is 1: 10, placing the mixed solution into a 50 ℃ water bath kettle, and carrying out magnetic stirring for 2 hours to obtain a 2-ME nanoparticle suspension;
3) adding 3 percent of arginine in volume of the 2-ME nanoparticle suspension into the 2-ME nanoparticle suspension, taking the arginine as a freeze-drying protective agent and a stabilizing agent, and freeze-drying in a freeze dryer to obtain the 2-methoxyestradiol nano preparation (freeze-dried powder).
Example 4
The invention relates to a preparation method of a nano preparation for improving the drug-loading rate and the oral bioavailability of 2-methoxyestradiol, which comprises the following steps:
1) adding 100mg of a mixture of soybean phospholipid (PC-80) and Zein (Zein) at a weight ratio of 1: 0.5 into 5mL of 90% ethanol, performing ultrasonic treatment for 30min, performing magnetic stirring for 1h, adding 1mL of 2-ME ethanol solution at a weight ratio of 2-ME to Zein (Zein) of 1: 20, and performing magnetic stirring for 1h to obtain an ethanol phase;
2) slowly dripping an ethanol phase into a sodium cholate ultrapure water solution with the volume concentration of 0.8% at the speed of 5mL/min under magnetic stirring to form a mixed solution, wherein the volume ratio of the ethanol phase to the sodium cholate ultrapure water solution is 1: 20, placing the mixed solution into a water bath kettle at the temperature of 70 ℃, and performing magnetic stirring for 2 hours to obtain a 2-ME nanoparticle suspension;
3) adding arginine with the volume of 5% of that of the 2-ME nanoparticle suspension into the 2-ME nanoparticle suspension, taking the arginine as a freeze-drying protective agent and a stabilizing agent, and freeze-drying the mixture in a freeze-drying machine to obtain the 2-methoxyestradiol nano preparation (freeze-dried powder).
The 2-ME nanoparticles and the freeze-dried powder thereof prepared by the method have the advantages of small particle size, uniform distribution and high drug-loading rate, and the drug-loading rate of the 2-ME nanoparticles and the freeze-dried powder thereof can reach 8% -9%, which is shown in Table 1:
TABLE 12 formulation parameters of ME nanoparticles and their lyophilized powders (mean. + -. SD, n = 6)
| preparation | particle size（nm） | PDI | Zeta potential (mV) | DL(%) | EE(%) |
| 2-ME nanoparticle suspension | 180.56±15.32 | 0.183±0.062 | -20.68±5.88 | 8.56±0.05 | 99.87±0.11 |
| 2-ME nanoparticle suspension freeze-dried powder | 164.23±5.70 | 0.208±0.046 | -52.36±0.37 | 8.38±0.11 | 99.31±0.2 |
Provides important guarantee for meeting the dosage requirement in clinical application. At present, the drug-loading rate of most 2-ME nanoparticle preparations is low, generally 1% -3%, and the requirement of clinical drug dosage is difficult to meet, which is one of the main reasons for limiting the clinical popularization of nanoparticles. The 2-ME nanoparticle suspension prepared by the method has good stability and can be stabilized for four weeks at a low temperature of 4 ℃. Lyophilization may further improve stability. 2-ME nanoparticle suspension prepared without adding stabilizer can be only stable for 1 and half days at low temperature of 4 ℃.
The 2-ME nanoparticles and the freeze-dried powder thereof prepared by the method can obviously improve the drug-loading rate and the oral bioavailability of 2-ME, are expected to improve the oral effect, and realize the application of the zein in the preparation of the insoluble drug 2-ME oral nanoparticle preparation.
The method of the invention was tested (taking example 1 as an example), and the relevant experimental data are as follows:
the test data for improving the 2-ME oral bioavailability by the 2-ME nanoparticles and the freeze-dried powder thereof provided by the invention are as follows:
1. animals: SPF grade Sprague Dawley rats, female, weighing 200 + -20 g, were provided by Huaxing laboratory animal farms, Huizu district, Zhengzhou city. The certification number is as follows: SCXK 201-. The number of animals per group was 5.
2. Pharmacokinetic experiments rats were divided into 3 groups, fasted for 12h before the experiment, and allowed free access to water. After the gavage of rats with different preparations, blood is taken from the orbit at the specified time point respectively, placed in a centrifugal tube which is processed by heparinization, and centrifuged at 5000rpm for 10min, and then blood plasma is taken. The plasma concentration was measured by high performance liquid chromatography (fluorescence detector), and the pharmacokinetic parameters corresponding to each formulation are shown in table 2.
TABLE 22-ME nanoparticles and their lyophilized powder pharmacokinetic parameters after gavage in rats (mean + -SD, n = 5)
| Group of | Mode of administration | Dosage form | C max (ng/mL) | MRT(h) | AUC(ng/mL*h) | F（%） |
| 2-ME solution group | Gavage stomach | 30mg/kg | 108.43±1.36 | 2.14±0.45 | 63.844±43.43 | 100 |
| 2-ME-NaRice grain suspension | Gavage stomach | 30mg/kg | 281.6±10.87 | 5.06±0.45 | 903.4±43.43 | 1415 |
| 2-ME-nanometer freeze-dried powder | Gavage stomach | 30mg/kg | 298.4±12.65 | 5.87±0.52 | 932.3±56.87 | 1460 |
As shown in Table 2, after the 2-ME nanoparticle suspension and the freeze-dried powder thereof are perfused into the stomach of rats, compared with the 2-ME solution oral administration group, the in vivo retention time (MRT) is remarkably prolonged, and the peak concentration (C) is remarkably increased max ) And oral bioavailability.
Repeated tests all obtain the same and similar results, meanwhile, the same tests are carried out on other embodiments, the same and similar test results are also obtained, the results are not repeated, and the tests show that the product quality is stable and reliable, and the product has practical application value and popularization value.
The zein nanoparticles and the freeze-dried powder thereof are particularly suitable for 2-ME which is ineffective in oral administration by adopting a conventional preparation originally, and the zein nanoparticles and the freeze-dried powder thereof are prepared from 2-ME, so that the drug loading rate and the oral bioavailability can be obviously improved, the drug loading rate can reach 8-9 percent and is improved by 2-3 times, and the oral bioavailability and the curative effect are obviously improved; the zein is a common pharmaceutic adjuvant, is used as natural plant protein, is cheap and easy to obtain, is safe, nontoxic and non-irritant, and has good popularization and application prospects, and other adjuvants are common pharmaceutic adjuvants. The zein nanoparticles are mainly suitable for water-insoluble drugs such as 2-ME and the like, the zein nanoparticles and freeze-dried powder thereof can remarkably improve the solubility and drug-loading rate of the drugs, and are solidified after freeze-drying, so that the storage stability of the zein nanoparticles can be improved, the effective period is prolonged, direct oral administration can be realized, patients can take the drug by themselves, the drug taking is convenient, the compliance of the patients is greatly improved, the efficiency of intestinal absorption of the drugs can be improved by the nanoparticles and the freeze-dried powder thereof, the obstacles existing in the intestinal absorption process of the 2-ME in the conventional preparation, such as intestinal absorption saturation and liver first pass effect, and the oral bioavailability of the nanoparticles is improved, the current situation that the conventional preparation prepared by using the raw material drugs is ineffective in oral administration is changed, and the zein nanoparticles are a great innovation on the drugs for treating cancers and have great economic and social benefits.
It should be noted that the embodiments given in the present invention are only examples, and are not intended to limit the scope of the present invention, and the nano-preparations prepared by the method of the present invention for improving the drug loading and bioavailability of 2-methoxyestradiol may be any dosage forms suitable for oral administration, such as granules, lyophilized powders, capsules, pills, oral liquids, etc., and therefore, all technical solutions substantially the same as the present invention by using equivalent and equivalent substitution means belong to the scope of the present invention.
Claims (6)
1. A preparation method of a nano preparation for improving the drug loading rate and the oral bioavailability of 2-methoxyestradiol is characterized by comprising the following steps:
1) adding 40-100mg of a mixture of soybean phospholipid and zein with a weight ratio of 1: 0.5-6 into 5mL of ethanol with a volume concentration of 60% -90%, performing ultrasonic treatment for 10-30min, performing magnetic stirring for 1h, adding 1mL of 2-ME ethanol solution with a weight ratio of 2-ME to zein of 1: 2-20, and performing magnetic stirring for 1h to obtain an ethanol phase;
2) slowly dripping an ethanol phase into a sodium cholate ultrapure water solution with the volume concentration of 0.1-0.8% at the speed of 1-5mL/min under magnetic stirring to form a mixed solution, putting the mixed solution into a water bath kettle at the temperature of 40-70 ℃, and performing magnetic stirring for 2 hours to obtain a 2-ME nanoparticle suspension;
3) adding arginine with the volume of 1-5% of that of the 2-ME nanoparticle suspension into the 2-ME nanoparticle suspension, taking the arginine as a freeze-drying protective agent and a stabilizing agent, and freeze-drying in a freeze-drying machine to obtain the 2-methoxyestradiol nanometer preparation.
2. The method of preparing a nano-formulation for enhancing drug loading and oral bioavailability of 2-methoxyestradiol according to claim 1, comprising the steps of:
1) adding 60mg of a mixture of soybean phospholipid and zein in a weight ratio of 1: 1 into 5mL of 70% ethanol by volume, performing ultrasonic stirring for 15min, performing magnetic stirring for 1h, adding 1mL of 2-ME ethanol solution in which the weight ratio of 2-ME to zein is 1: 2, and performing magnetic stirring for 1h to obtain an ethanol phase;
2) slowly dripping an ethanol phase into a sodium cholate ultrapure water solution with the volume concentration of 0.1% at the speed of 2mL/min under magnetic stirring to form a mixed solution, wherein the volume ratio of the ethanol phase to the sodium cholate ultrapure water solution is 1: 1, placing the mixed solution into a water bath kettle at the temperature of 60 ℃, and performing magnetic stirring for 2 hours to obtain a 2-ME nanoparticle suspension;
3) adding 1 volume percent of arginine of the 2-ME nanoparticle suspension into the 2-ME nanoparticle suspension, taking the arginine as a freeze-drying protective agent and a stabilizing agent, and freeze-drying the mixture in a freeze-drying machine to obtain the 2-methoxyestradiol nano-preparation freeze-dried powder.
3. The method of preparing a nano-formulation for enhancing drug loading and oral bioavailability of 2-methoxyestradiol according to claim 1, comprising the steps of:
1) adding 80mg of a mixture of soybean phospholipid and zein in a weight ratio of 1: 3 into 5mL of 65% ethanol, performing ultrasonic treatment for 20min, performing magnetic stirring for 1h, adding 1mL of 2-ME ethanol solution in which the weight ratio of 2-ME to zein is 1: 5, and performing magnetic stirring for 1h to obtain an ethanol phase;
2) slowly dripping an ethanol phase into a sodium cholate ultrapure water solution with the volume concentration of 0.3% at the speed of 1mL/min under magnetic stirring to form a mixed solution, putting the mixed solution into a 65 ℃ water bath kettle, and carrying out magnetic stirring for 2 hours to obtain a 2-ME nanoparticle suspension;
3) adding 2% by volume of arginine into the 2-ME nanoparticle suspension, wherein the arginine is used as a freeze-drying protective agent and a stabilizing agent, and then placing the mixture into a freeze dryer for freeze-drying to obtain the 2-methoxyestradiol nanometer preparation.
4. The method of preparing a nano-formulation for enhancing drug loading and oral bioavailability of 2-methoxyestradiol according to claim 1, comprising the steps of:
1) adding 100mg of a mixture of soybean phospholipid and zein in a weight ratio of 1: 6 into 5mL of 80% ethanol, performing ultrasonic treatment for 30min, performing magnetic stirring for 1h, adding 1mL of 2-ME ethanol solution in which the weight ratio of 2-ME to zein is 1: 10, and performing magnetic stirring for 1h to obtain an ethanol phase;
2) slowly dripping an ethanol phase into a sodium cholate ultrapure water solution with the volume concentration of 0.5% at the speed of 3mL/min under magnetic stirring to form a mixed solution, wherein the volume ratio of the ethanol phase to the sodium cholate ultrapure water solution is 1: 10, placing the mixed solution into a 50 ℃ water bath kettle, and carrying out magnetic stirring for 2 hours to obtain a 2-ME nanoparticle suspension;
3) adding 3 percent of arginine in volume of the 2-ME nanoparticle suspension into the 2-ME nanoparticle suspension, taking the arginine as a freeze-drying protective agent and a stabilizing agent, and freeze-drying in a freeze dryer to obtain the 2-methoxyestradiol nanometer preparation.
5. The method of preparing a nano-formulation for enhancing drug loading and oral bioavailability of 2-methoxyestradiol according to claim 1, comprising the steps of:
1) adding 100mg of a mixture of soybean phospholipid and zein with a weight ratio of 1: 0.5 into 5mL of 90% ethanol, performing ultrasonic treatment for 30min, performing magnetic stirring for 1h, adding 1mL of 2-ME ethanol solution with a weight ratio of 2-ME to zein of 1: 20, and performing magnetic stirring for 1h to obtain an ethanol phase;
2) slowly dripping an ethanol phase into a sodium cholate ultrapure water solution with the volume concentration of 0.8% at the speed of 5mL/min under magnetic stirring to form a mixed solution, wherein the volume ratio of the ethanol phase to the sodium cholate ultrapure water solution is 1: 20, placing the mixed solution into a water bath kettle at the temperature of 70 ℃, and performing magnetic stirring for 2 hours to obtain a 2-ME nanoparticle suspension;
3) adding arginine with the volume of 5 percent of that of the 2-ME nanoparticle suspension into the 2-ME nanoparticle suspension, taking the arginine as a freeze-drying protective agent and a stabilizing agent, and freeze-drying in a freeze dryer to obtain the 2-methoxyestradiol nanometer preparation.
6. Use of a 2-methoxyestradiol drug loading and oral bioavailability enhancing nano-formulation prepared by the method of any one of claims 1-5 in the preparation of a 2-methoxyestradiol drug loading and oral bioavailability enhancing nano-formulation medicament.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101612131A (en) * | 2009-07-17 | 2009-12-30 | 郑州大学 | 2-methoxyestradiol nanosuspension frozen powder and preparation method thereof |
| CN105456200A (en) * | 2015-12-08 | 2016-04-06 | 郑州大学 | Preparation method and application of nanoparticle microsphere for improving oral bioavailability of poorly soluble drugs |
| CN110251487A (en) * | 2019-08-01 | 2019-09-20 | 郑州大学 | A kind of preparation method and applications for the alcohol soluble protein nanoparticle improving docetaxel drugloading rate and oral administration biaavailability |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101612131A (en) * | 2009-07-17 | 2009-12-30 | 郑州大学 | 2-methoxyestradiol nanosuspension frozen powder and preparation method thereof |
| CN105456200A (en) * | 2015-12-08 | 2016-04-06 | 郑州大学 | Preparation method and application of nanoparticle microsphere for improving oral bioavailability of poorly soluble drugs |
| CN110251487A (en) * | 2019-08-01 | 2019-09-20 | 郑州大学 | A kind of preparation method and applications for the alcohol soluble protein nanoparticle improving docetaxel drugloading rate and oral administration biaavailability |
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