CN113425689B - A nanometer preparation of Pithecellobium clypearia extract and its preparation method - Google Patents
A nanometer preparation of Pithecellobium clypearia extract and its preparation method Download PDFInfo
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Abstract
The invention relates to a pithecellobium clypearia extract nanometer preparation and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. A pithecellobium clypearia extract nanometer preparation is prepared from the following raw materials in parts by weight: 10-20 parts of pithecellobium clypearia extract, 10-20 parts of soybean lecithin, 5-10 parts of dipalmitoyl phosphatidylethanolamine, 2-5 parts of phosphatidylethanolamine-polyethylene glycol 2000-maleimide, 4-7 parts of cholesterol, 5-8 parts of mannitol and 0.5-1.2 parts of citric acid. The pithecellobium clypearia nano preparation provided by the invention takes soybean lecithin and cholesterol as main wall materials, dipalmitoyl phosphatidylethanolamine with hydrophilic groups and phosphatidylethanolamine-polyethylene glycol 2000-maleimide with high molecular weight and hydrophilicity are added, citric acid is added in the preparation step of liposome dispersion liquid, mannitol is taken as a freeze-drying protective agent, the pithecellobium clypearia extract nano preparation is prepared by adopting a physical dispersion method, organic solvents are not contained, and the particle size and the encapsulation rate of the nano preparation can be satisfied.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to a pithecellobium clypearia extract nanometer preparation and a preparation method thereof.
Background
The Pithecellobium clypearia is prepared from the branch with leaves of Pithecellobium clypearia (Jack) Nielsen of Pithecellobium clypearia of Leguminosae by air drying or sun drying. The pithecellobium clypearia contains flavonoid glycoside, phenols, amino acid, saccharides and the like, is mainly used for treating upper respiratory tract infection, gastroenteritis and tonsillitis in modern clinic and has antiviral effect. The commercially available pithecellobium clypearia preparation is prepared by mixing pithecellobium clypearia extract with auxiliary materials and granulating. The nano preparation is medicine carrying particle of medicine and supplementary material and in the size of 1-1000 nm, and compared with traditional preparation, the nano preparation has high bioavailability, slow releasing effect, capacity of prolonging the blood circulation time, raising the stability, raising the solubility, reducing the irritation to stomach and other advantages. The nano-particles of the pithecellobium clypearia nano-preparation provided by the original patent application CN201911409117.4 have the advantages of small particle size, uniform dispersion, good chemical and physical stability, and very high application value for improving the bioavailability and the targeted delivery efficiency of pithecellobium clypearia. However, the method adopts a two-phase dispersion method to prepare the nano preparation, and the obtained nano preparation of the pithecellobium clypearia extract can generate organic solvent residues. In the preparation process of the physical dispersion method nano preparation, the organic solvent can be almost completely volatilized in the preparation process of the film, and then the film is dispersed in water to prepare the nano preparation, so that the prepared nano preparation almost does not contain the organic solvent. Under the new preparation method system, the intensive research on the prescription of the pithecellobium clypearia nano preparation and the preparation method thereof is very necessary.
Disclosure of Invention
Based on the above, aiming at the defects of the prior art, one of the purposes of the invention is to provide a pithecellobium clypearia extract nanometer preparation and a preparation method thereof. The pithecellobium clypearia nano preparation obtained by the preparation method hardly contains organic solvents, has high encapsulation efficiency and is low in obtained particle size.
In order to solve the technical problems provided by the invention, on one hand, the invention provides a pithecellobium clypearia extract nanometer preparation which is prepared from the following raw materials in parts by weight: 10-20 parts of pithecellobium clypearia extract, 10-20 parts of soybean lecithin, 5-10 parts of dipalmitoyl phosphatidyl ethanolamine, 2-5 parts of phosphatidyl ethanolamine-polyethylene glycol 2000-maleimide, 4-7 parts of cholesterol, 5-8 parts of mannitol and 0.5-1.2 parts of citric acid.
Further, the pithecellobium clypearia extract nanometer preparation is prepared from the following raw materials in parts by weight: 13 parts of pithecellobium clypearia extract, 18 parts of soybean lecithin, 7 parts of dipalmitoyl phosphatidylethanolamine, 3 parts of phosphatidylethanolamine-polyethylene glycol 2000-maleimide, 5 parts of cholesterol, 6.5 parts of mannitol and 0.8 part of citric acid.
The pithecellobium clypearia extract adopted by the invention is pithecellobium clypearia ethyl acetate extract, and has higher anti-inflammatory activity compared with pithecellobium clypearia aqueous extract, the pithecellobium clypearia ethyl acetate extract has lower oral bioavailability due to poor water solubility, and the water solubility of the pithecellobium clypearia ethyl acetate extract can be improved by preparing the pithecellobium clypearia ethyl acetate extract into a nano preparation by adopting a preparation process, so that the oral bioavailability is improved. The encapsulation rate and the particle size in the preparation process of the nano preparation are important indexes for controlling the quality of the nano preparation. The encapsulation efficiency reflects the degree to which the drug is encapsulated by the carrier. The smaller the particle size, the larger the specific surface area of the drug, and the more favorable the release. Therefore, the invention develops intensive research on the prescription and the preparation method of the pithecellobium clypearia nano preparation based on the two indexes.
In the formula, soybean lecithin and cholesterol are used as main wall materials, dipalmitoyl phosphatidylethanolamine with hydrophilic groups and phosphatidylethanolamine-polyethylene glycol 2000-maleimide with high molecular weight and hydrophilicity are added, the water solubility of the pithecellobium clypearia extract can be well improved, dipalmitoyl phosphatidylethanolamine and phosphatidylethanolamine-polyethylene glycol 2000-maleimide are utilized to improve the dispersity of a lipid film in water, and the pithecellobium clypearia nano preparation with smaller particle size can be prepared. Repeated experimental exploration shows that the wall material components are adopted, citric acid is added in the preparation step of the liposome dispersion liquid, mannitol is used as a freeze-drying protective agent, the preparation of the pithecellobium clypearia extract nanometer preparation is carried out by adopting a physical dispersion method, the particle size of the pithecellobium clypearia extract nanometer preparation prepared by the method is less than 200nm, and the encapsulation rate can reach more than 80%.
Specifically, the preparation method of the pithecellobium clypearia extract nanometer preparation provided by the invention specifically comprises the following steps:
1) Subcritical extracting Pithecellobium clypearia with ethyl acetate as solvent at 35-40 deg.C for 60-80min under 18-22MPa and solvent flow of 2-4kg/h, and concentrating under reduced pressure to remove ethyl acetate to obtain Pithecellobium clypearia extract;
2) Adding soybean lecithin, dipalmitoyl phosphatidylethanolamine, phosphatidylethanolamine-polyethylene glycol 2000-maleimide and cholesterol into a composite solvent of absolute ethyl alcohol and ethyl acetate, heating in a water bath, stirring and dissolving, and adding a pithecellobium clypearia extract for ultrasonic treatment to obtain a lipid solution;
3) Carrying out vacuum evaporation on the lipid solution in the step 2) to remove the organic solvent to obtain a lipid film;
4) Dissolving citric acid in water at 60-65 deg.C, adding lipid film, stirring at 60-65 deg.C in water bath at 200-400r/min for 30-60min, ultrasonic treating with ultrasonic cell pulverizer probe for 20-40min, filtering, and hydrating the filtrate for 1.5-2.5 hr to obtain liposome dispersion;
5) Adding mannitol into the liposome dispersion liquid in the step 4), and freeze-drying to obtain the monkey ear ring extract nanometer preparation.
Further, in the technical scheme of the invention, the feeding mass ratio of the pithecellobium clypearia and the ethyl acetate in the step 1) is 1:2-5.
Further, in the technical scheme of the invention, the volume ratio of the absolute ethyl alcohol to the ethyl acetate in the composite solvent in the step 2) is 1: (1.2-1.8).
Further, in the technical scheme of the invention, the mass ratio of the lipid in the step 2) to the composite solvent is 1: (10-20);
the heating temperature of the water bath in the step 2) is 50-65 ℃.
Further, in the technical scheme of the invention, the ultrasonic frequency in the step 2) is 40-60kHz, the temperature is 50-65 ℃, and the ultrasonic time is 20-30min.
Further, in the technical scheme of the invention, the adding amount of the water in the step 4) is 1.5-5 times of that of the soybean lecithin.
Further, in the technical scheme of the present invention, the specific conditions of the lyophilization in the step 5) are as follows: freezing at-20 deg.C for 8-10 hr, and vacuum freeze-drying at-40 deg.C under vacuum degree of 20-40Pa for 8-12 hr.
Compared with the prior art, the technical scheme of the invention has the advantages that:
the preparation method of the pithecellobium clypearia nano preparation adopts a physical dispersion method, so that the residue of an organic solvent in the nano preparation can be greatly reduced. The formula of the pithecellobium clypearia nano preparation provided by the invention takes soybean lecithin and cholesterol as main wall materials, dipalmitoyl phosphatidylethanolamine with hydrophilic groups and phosphatidylethanolamine-polyethylene glycol 2000-maleimide with high molecular weight and hydrophilicity are added, citric acid is added in the step of preparing liposome dispersion liquid, mannitol is taken as a freeze-drying protective agent, the pithecellobium clypearia extract nano preparation is prepared by adopting a physical dispersion method, the particle size of the obtained nano preparation is less than 200nm, and the encapsulation rate is more than 80%.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
A pithecellobium clypearia extract nanometer preparation is prepared from the following raw materials in parts by weight:
13 parts of pithecellobium clypearia extract, 18 parts of soybean lecithin, 7 parts of dipalmitoyl phosphatidylethanolamine, 3 parts of phosphatidylethanolamine-polyethylene glycol 2000-maleimide, 5 parts of cholesterol, 6.5 parts of mannitol and 0.8 part of citric acid.
The preparation method of the nano preparation comprises the following steps:
1) Crushing the pithecellobium clypearia, sieving with a 150-mesh sieve, performing subcritical extraction with ethyl acetate as a solvent, wherein the mass ratio of the pithecellobium clypearia to the ethyl acetate is 1:4, the subcritical extraction temperature is 40 ℃, the extraction time is 70min, the extraction pressure is 20MPa, the solvent flow is 3kg/h, and removing the ethyl acetate by reduced pressure concentration to obtain the pithecellobium clypearia extract;
2) Adding 18 parts by weight of soybean lecithin, 7 parts by weight of dipalmitoyl phosphatidylethanolamine, 3 parts by weight of phosphatidylethanolamine-polyethylene glycol 2000-maleimide and 5 parts by weight of cholesterol into 400 parts by weight of a mixed solvent of absolute ethyl alcohol and ethyl acetate (the volume ratio of the absolute ethyl alcohol to the ethyl acetate is 1: 1.5), heating in a water bath to about 60 ℃, stirring to dissolve lipids, adding 13 parts by weight of pithecellobium clypearia extract into the mixture, and performing ultrasonic treatment at the ultrasonic frequency of 50kHz and the temperature of 60 ℃ for 30min to obtain a lipid solution;
3) Vacuum evaporating the lipid solution to remove the organic solvent to obtain lipid film;
4) Dissolving 0.8 part of citric acid in 54 parts of water at 63 ℃, adding the lipid film, stirring for 30min at 350r/min under the water bath condition of 63 ℃, performing ultrasonic treatment for 30min by using an ultrasonic cell disruptor probe, filtering, and hydrating the filtrate for 2h to obtain a lipid dispersion liquid;
5) Adding 6.5 parts mannitol into the liposome dispersion, freezing at-25 deg.C or below for 10 hr, and vacuum freeze drying at-42 deg.C under vacuum degree of 25Pa for 10 hr to obtain Pithecellobium clypearia extract nanometer preparation.
The average particle diameter of the pithecellobium clypearia nano preparation is 124nm and the encapsulation efficiency is 88.9 percent.
Example 2
A pithecellobium clypearia extract nanometer preparation is prepared from the following raw materials in parts by weight:
13 parts of pithecellobium clypearia extract, 18 parts of soybean lecithin, 5 parts of dipalmitoyl phosphatidylethanolamine, 3 parts of phosphatidylethanolamine-polyethylene glycol 2000-maleimide, 5 parts of cholesterol, 6.5 parts of mannitol and 0.8 part of citric acid. The above-described amounts of the recipe in the production method of example 1 were replaced by the recipe, and the remainder was the same as in example 1.
The monkey ear ring nano preparation has the average particle diameter of 121nm and the encapsulation efficiency of 87.6 percent through measurement.
Example 3
A pithecellobium clypearia extract nanometer preparation is prepared from the following raw materials in parts by weight:
13 parts of pithecellobium clypearia extract, 18 parts of soybean lecithin, 6 parts of dipalmitoyl phosphatidyl ethanolamine, 3 parts of phosphatidyl ethanolamine-polyethylene glycol 2000-maleimide, 5 parts of cholesterol, 6.5 parts of mannitol and 1.2 parts of citric acid. The above-described prescription amounts in the preparation method of example 1 were replaced according to the prescription, and the remainder was the same as in example 1.
The average particle diameter of the pithecellobium clypearia nano preparation is 136nm and the encapsulation efficiency is 86.3 percent through measurement.
Example 4
A pithecellobium clypearia extract nanometer preparation is prepared from the following raw materials in parts by weight:
13 parts of pithecellobium clypearia extract, 18 parts of soybean lecithin, 8 parts of dipalmitoyl phosphatidyl ethanolamine, 3 parts of phosphatidyl ethanolamine-polyethylene glycol 2000-maleimide, 5 parts of cholesterol, 6.5 parts of mannitol and 0.5 part of citric acid. The above-described amounts of the recipe in the production method of example 1 were replaced by the recipe, and the remainder was the same as in example 1.
The average particle diameter of the pithecellobium clypearia nano preparation is 141nm and the encapsulation efficiency is 84.5 percent.
Example 5
A pithecellobium clypearia extract nanometer preparation is prepared from the following raw materials in parts by weight:
13 parts of pithecellobium clypearia extract, 18 parts of soybean lecithin, 7 parts of dipalmitoyl phosphatidylethanolamine, 2 parts of phosphatidylethanolamine-polyethylene glycol 2000-maleimide, 5 parts of cholesterol, 6.5 parts of mannitol and 0.8 part of citric acid. The above-described prescription amounts in the preparation method of example 1 were replaced according to the prescription, and the remainder was the same as in example 1.
The average particle diameter of the pithecellobium clypearia nano preparation is 141nm and the encapsulation efficiency is 88.6 percent.
Example 6
A pithecellobium clypearia extract nanometer preparation is prepared from the following raw materials in parts by weight:
13 parts of pithecellobium clypearia extract, 18 parts of soybean lecithin, 6 parts of dipalmitoyl phosphatidyl ethanolamine, 4 parts of phosphatidyl ethanolamine-polyethylene glycol 2000-maleimide, 5 parts of cholesterol, 6.5 parts of mannitol and 0.8 part of citric acid. The above-described prescription amounts in the preparation method of example 1 were replaced according to the prescription, and the remainder was the same as in example 1.
The pithecellobium clypearia nakai nanometer preparation has the average particle diameter of 123nm and the encapsulation efficiency of 83.7 percent through measurement.
Comparative example 1
A pithecellobium clypearia extract nanometer preparation is prepared from the following raw materials in parts by weight:
13 parts of pithecellobium clypearia extract, 18 parts of soybean lecithin, 7 parts of dipalmitoyl phosphatidylethanolamine, 0 part of phosphatidylethanolamine-polyethylene glycol 2000-maleimide, 5 parts of cholesterol, 6.5 parts of mannitol and 0.8 part of citric acid.
The preparation method comprises the following steps of 2): adding 18 parts of soybean lecithin, 7 parts of dipalmitoyl phosphatidyl ethanolamine and 5 parts of cholesterol into a mixed solvent of 400 parts of absolute ethyl alcohol and ethyl acetate (the volume ratio of the absolute ethyl alcohol to the ethyl acetate is 1.5), heating in a water bath to about 60 ℃, stirring to dissolve lipids, adding 13 parts of pithecellobium clypearia extract into the mixture, and performing ultrasonic treatment at an ultrasonic frequency of 50kHz and at a temperature of 60 ℃ for 30min to obtain a lipid solution.
Otherwise, as in example 1, the prepared nano-formulation was measured to have an average particle size of 168nm and an encapsulation efficiency of 76.4%. As a result, it was found that the particle size was affected by not adding phosphatidylethanolamine-polyethylene glycol 2000-maleimide to the formulation, and the encapsulation efficiency was also decreased.
Comparative example 2
A pithecellobium clypearia extract nanometer preparation is prepared from the following raw materials in parts by weight:
13 parts of pithecellobium clypearia extract, 18 parts of soybean lecithin, 7 parts of dipalmitoyl phosphatidylethanolamine, 3 parts of phosphatidylethanolamine-polyethylene glycol 2000-maleimide, 5 parts of cholesterol, 6.5 parts of mannitol and 0 part of citric acid.
The preparation method comprises the following steps of 4): adding the lipid film into 54 parts of water at 63 deg.C, stirring at 63 deg.C in water bath at 350r/min for 30min, performing ultrasonic treatment with ultrasonic cell pulverizer probe for 30min, filtering, and hydrating the filtrate at 63 deg.C under low-speed stirring at 20r/min for 2h to obtain liposome dispersion; the rest of the procedures are the same as example 1, and the prepared nano preparation has the average particle size of 143nm and the encapsulation efficiency of 73.2 percent. The results show that the addition of citric acid in the formula has no obvious influence on the particle size, and the encapsulation efficiency is reduced more, which indicates that the addition of citric acid in the method can well improve the encapsulation efficiency.
Finally, it is also noted that the above-mentioned lists merely illustrate a few specific embodiments of the invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested by the person skilled in the art from the present disclosure are to be considered within the scope of the present invention.
Claims (9)
1. The pithecellobium clypearia extract nanometer preparation is characterized by being prepared from the following raw materials in parts by weight: 10-20 parts of pithecellobium clypearia extract, 10-20 parts of soybean lecithin, 5-10 parts of dipalmitoyl phosphatidylethanolamine, 2-5 parts of phosphatidylethanolamine-polyethylene glycol 2000-maleimide, 4-7 parts of cholesterol, 5-8 parts of mannitol and 0.5-1.2 parts of citric acid;
the preparation method comprises the following steps:
1) Performing subcritical extraction of Pithecellobium clypearia with ethyl acetate as solvent at 35-40 deg.C for 60-80min under 18-22MPa and solvent flow of 2-4kg/h, and concentrating under reduced pressure to remove ethyl acetate to obtain Pithecellobium clypearia extract;
2) Adding soybean lecithin, dipalmitoyl phosphatidylethanolamine, phosphatidylethanolamine-polyethylene glycol 2000-maleimide and cholesterol into a composite solvent of absolute ethyl alcohol and ethyl acetate, heating in a water bath, stirring and dissolving, and adding a pithecellobium clypearia extract for ultrasonic treatment to obtain a lipid solution;
3) Carrying out vacuum evaporation on the lipid solution obtained in the step 2) to remove the organic solvent to obtain a lipid film;
4) Dissolving citric acid in water at 60-65 deg.C, adding lipid film, stirring at 60-65 deg.C in water bath at 200-400r/min for 30-60min, ultrasonic treating with ultrasonic cell pulverizer probe for 20-40min, filtering, and hydrating the filtrate for 1.5-2.5 hr to obtain liposome dispersion;
5) Adding mannitol into the liposome dispersion liquid in the step 4), and freeze-drying to obtain the monkey ear ring extract nanometer preparation.
2. The pithecellobium clypearia extract nanometer preparation as claimed in claim 1, is characterized in that it is prepared from the following raw materials in parts by weight: 13 parts of pithecellobium clypearia extract, 18 parts of soybean lecithin, 7 parts of dipalmitoyl phosphatidylethanolamine, 3 parts of phosphatidylethanolamine-polyethylene glycol 2000-maleimide, 5 parts of cholesterol, 6.5 parts of mannitol and 0.8 part of citric acid.
3. The method for preparing the pithecellobium clypearia extract nano preparation as claimed in claim 1, comprising the steps of:
1) Subcritical extracting Pithecellobium clypearia with ethyl acetate as solvent at 35-40 deg.C for 60-80min under 18-22MPa and solvent flow of 2-4kg/h, and concentrating under reduced pressure to remove ethyl acetate to obtain Pithecellobium clypearia extract;
2) Adding soybean lecithin, dipalmitoyl phosphatidylethanolamine, phosphatidylethanolamine-polyethylene glycol 2000-maleimide and cholesterol into a composite solvent of absolute ethyl alcohol and ethyl acetate, heating in a water bath, stirring and dissolving, and adding a pithecellobium clypearia extract for ultrasonic treatment to obtain a lipid solution;
3) Carrying out vacuum evaporation on the lipid solution obtained in the step 2) to remove the organic solvent to obtain a lipid film;
4) Dissolving citric acid in water at 60-65 deg.C, adding lipid film, stirring at 60-65 deg.C in water bath at 200-400r/min for 30-60min, ultrasonic treating with ultrasonic cell pulverizer probe for 20-40min, filtering, and hydrating the filtrate for 1.5-2.5 hr to obtain liposome dispersion;
5) Adding mannitol into the liposome dispersion liquid in the step 4), and freeze-drying to obtain the pithecellobium clypearia extract nanometer preparation.
4. The method for preparing the monkey ear ring extract nanometer preparation according to the claim 3, characterized in that the mass ratio of the monkey ear ring and the ethyl acetate in the step 1) is 1:2-5.
5. The method for preparing the pithecellobium clypearia extract nanometer preparation according to claim 3, wherein the volume ratio of the absolute ethyl alcohol to the ethyl acetate in the composite solvent in the step 2) is 1: (1.2-1.8).
6. The method for preparing the pithecellobium clypearia extract nano preparation according to any one of claims 3-5, wherein the mass ratio of the lipid to the complex solvent in the step 2) is 1: (10-20);
the heating temperature of the water bath in the step 2) is 50-65 ℃.
7. The method for preparing the pithecellobium clypearia extract nanometer preparation according to any one of claims 3-5, wherein the ultrasonic frequency in the step 2) is 40-60kHz, the temperature is 50-65 ℃, and the ultrasonic time is 20-30min.
8. The method for preparing the pithecellobium clypearia extract nano-preparation according to claim 3, wherein the water in the step 4) is added in an amount of 1.5-5 times of the soybean lecithin.
9. The method for preparing the pithecellobium clypearia extract nanometer preparation according to claim 3, wherein the specific conditions of the lyophilization in the step 5) are as follows: freezing at-20 deg.C for 8-10 hr, and vacuum freeze-drying at-40 deg.C under vacuum degree of 20-40Pa for 8-12 hr.
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