CN112791072B - Asarin nanocrystallization method - Google Patents

Asarin nanocrystallization method Download PDF

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CN112791072B
CN112791072B CN202110124172.XA CN202110124172A CN112791072B CN 112791072 B CN112791072 B CN 112791072B CN 202110124172 A CN202110124172 A CN 202110124172A CN 112791072 B CN112791072 B CN 112791072B
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asarone
stabilizer
nanocrystallization
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organic phase
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CN112791072A (en
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蒋曙光
尹赛楠
赵新宇
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Guilin Pharmaceutical Co ltd
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China Pharmaceutical University
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Abstract

The invention discloses an asarone nanocrystallization method, and belongs to the technical field of pharmaceutical preparations. The nano-crystallization method adopts an anti-solvent precipitation method, and the asarone is dissolved in an organic solvent and then mixed with an aqueous solution of a stabilizer, so that the asarone is supersaturated and separated out to form a stable nano-scale colloidal dispersion. The invention improves the solubility and dissolution rate of asarone by a nanocrystallization technology, and solves the problems of difficult dissolution and low bioavailability of an asarone oral preparation.

Description

Asarin nanocrystallization method
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to an asarone nanocrystallization method.
Background
Asarone (ARE) is one of the main effective components of Chinese medicinal rhizoma Acori Graminei and other plant rhizome, also called alpha-Asarone and Asarone, and has chemical name of 2,4, 5-trimethoxy-1-propenyl benzene, and molecular formula C12H16O, relative molecular mass 208.26. Asarone is soluble in ethanol, ethyl acetate, chloroform and diethyl ether, and is insoluble in water. A large number of researches prove that asarone has the effect of removingPhlegm, smooth muscle of bronchus, tranquilizing center, convulsion relieving, antibacterial, antiinflammatory, anticancer, and blood lipid reducing effects.
The existing asarone preparation formulations in clinic at present are tablets, capsules and injections, and are commonly used for treating pneumonia, bronchial asthma and epileptic seizure in clinic. Due to the strong hydrophobicity of the asarone, the bioavailability of the traditional clinical asarone oral preparation is low, and the curative effect of the traditional clinical asarone oral preparation is seriously influenced; the asarin injection has serious adverse reaction due to the use of cosolvents such as polysorbate 80 and propylene glycol. In order to solve the problems of effectiveness and safety of clinical asarin medication, the invention aims to develop an asarin nanocrystallization method and provide basic technical support for development of an asarin high-efficiency oral preparation.
The nano-drug is a nano-drug (the particle size is within a range of 1-1000 nm) obtained by mechanical crushing or controlled crystallization, and is stably suspended in a dispersion medium under the action of an auxiliary material to form a stable colloid dispersion system, wherein the auxiliary material plays a role of a stabilizer. The nano-drug has the characteristics of simple preparation process, small particle size, high drug content and the like. Compared with the common preparation, the specific surface area of the nano-drug is greatly increased, so that the dissolution rate and the saturation solubility are increased, and the oral bioavailability of the drug is improved. The preparation method of the nano-drug mainly comprises the technologies of a medium grinding method, a high-pressure homogenization method, an anti-solvent precipitation method, an emulsification method and the like. Due to the fact that the asarone melting point is low (57-61 ℃), the drug melting influence nanocrystallization is easily caused by the medium grinding method, and the feasibility is low. The anti-solvent precipitation method is that the insoluble drug is dissolved in a good solvent to form a saturated solution, and then the saturated solution is added into a poor solvent to ensure that the drug is supersaturated in the solvent and separated out. In this process, the formation of the nano-drug has two stages: the formation and growth of crystal nuclei, and the addition of stabilizers help to avoid ostwald ripening and overgrowth of crystals. The diffusion of the drug in the two phases can be accelerated by stirring or ultrasound during the mixing of the two solutions, increasing the rate of supersaturation of the drug in the solution. The method is simple to operate, and has low cost and low requirements on equipment compared with other methods.
Disclosure of Invention
The invention aims to provide an asarone nanocrystallization method, which improves the solubility and dissolution rate of asarone by a nanocrystallization technology and solves the problems of difficult dissolution and low bioavailability of an asarone oral preparation.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for preparing asarone nanometer product comprises dissolving asarone in organic solvent, mixing with water solution of stabilizer, and supersaturating to precipitate asarone to form stable asarone nanometer colloidal dispersion.
In the present invention, the stabilizer comprises one or more of the following compounds: hydroxypropyl cellulose, sodium lauryl sulfate, polyvinylpyrrolidone, polyvinyl alcohol, poloxamer, hydroxypropyl methylcellulose, 15-hydroxystearic acid polyethylene glycol ester, preferably polyvinyl alcohol, 15-hydroxystearic acid polyethylene glycol ester, and polyvinylpyrrolidone.
In the present invention, the organic solvent includes one of the following compounds: ethanol, polyethylene glycol 400, propylene glycol, preferably polyethylene glycol 400.
Further, the asarin nanocrystallization method comprises the following steps:
(1) dissolving a stabilizer in water to obtain a water phase;
(2) adding asarone into organic solvent, stirring, vortex oscillating or ultrasonic treating to dissolve completely, and collecting the solution as organic phase;
(3) slowly dripping the organic phase into the water phase under proper mixing conditions, and fully mixing to obtain the nano-scale colloidal dispersion of the asarone.
Preferably, the mass ratio of the stabilizer in the water phase in the step (1) is 0.1-10%; the mass ratio of the asarone in the organic phase in the step (2) is 1-20%; the proper mixing condition in the step (3) is probe ultrasonic or magnetic stirring, the frequency of the probe ultrasonic is 60W-180W, and the ultrasonic time is 5-15 min; the rotation speed of the magnetic stirring is 500-1000 rpm, and the time is 5-15 min.
In the invention, the average particle size of the asarone nano-scale colloidal dispersion is 50 nm-500 nm.
The asarone nanocrystallization method provided by the invention can be used for preparing asarone oral suspension, or can be solidified by adopting a proper method to prepare tablets and capsules.
The invention has the advantages that:
(1) the nano-method has the advantages of simple preparation process, safe material, safe and effective preparation, low cost and easy enlargement to industrialization.
(2) The asarone nanometer level colloidal dispersion has small grain size and narrow distribution, can obviously increase the solubility and dissolution rate of the medicine, and obviously improves the bioavailability in vivo.
(3) The asarone oral suspension can be prepared by the nano-preparation method, or can be prepared into capsules, tablets and the like after being solidified by a proper method, so that the stability of the medicine can be improved, and the storage and the transportation are convenient.
Drawings
FIG. 1 is a graph showing the distribution of the particle size of asarone in example 1 after nanocrystallization.
FIG. 2 is a graph showing the distribution of the particle size of asarone obtained in example 2 (first measurement result of F1-1).
FIG. 3 is a graph showing the distribution of the particle size of asarone obtained in example 2 (first measurement result of F2-1).
Detailed Description
The invention is described in further detail below with reference to the figures and the specific examples, which should not be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.
Example 1
Nanometer preparation method of asarone
0.250g of polyethylene glycol 15-hydroxystearate and 0.250g of polyvinyl alcohol were weighed and placed in a beaker, and about 50g of water was added to completely dissolve them, to prepare an aqueous solution of the stabilizer. Weighing 0.500g of asarone raw material medicine, placing the asarone raw material medicine into a 10mL sample bottle, adding 5g of polyethylene glycol 400, and oscillating to dissolve the medicine to prepare an organic phase. Under the condition of probe ultrasound (2s on, 3s off), the ultrasound parameters are power 60W and time 5min, the organic phase is sucked up by a dropper and slowly added into the stabilizer aqueous solution at uniform speed, thus obtaining the asarone nanometer colloidal dispersion, the particle size is 119.37nm by adopting a laser particle sizer, the PDI is 0.261, and the figure is 1.
Example 2
Influence of probe ultrasonic power and time on nano particle size of asarone
0.050g of 15-hydroxystearic acid polyethylene glycol ester and 0.050g of polyvinyl alcohol were weighed and placed in a beaker, and about 50g of water was added to completely dissolve the polyethylene glycol ester and polyvinyl alcohol, thereby preparing a stabilizer aqueous solution. Weighing 0.050g asarone raw material medicine, placing into a 10mL sample bottle, adding 5g polyethylene glycol 400, shaking to dissolve the medicine, and making into organic phase.
(1) Ultrasonic power
Preparing the stabilizer aqueous solution and the organic phase, sucking the organic phase by a dropper under the condition of probe ultrasound (2s on, 3s off), slowly adding into the stabilizer aqueous solution at a constant speed, setting the ultrasonic power at 60W, 120W and 180W respectively, and fixing the ultrasonic time for 10min to obtain the asarone nanoscale colloidal dispersions respectively marked as F1-1, F1-2 and F1-3. The particle size and PDI of asarone obtained by the nano-crystallization process are detected by a laser particle size analyzer, and each sample is measured three times, and the result is shown in Table 1, wherein the first measurement result of F1-1 is shown in FIG. 2.
Table 1: influence of ultrasonic power on particle size of asarone nanoscale colloidal dispersion
Figure BDA0002923350900000031
(2) Time of ultrasound
Preparing the stabilizer aqueous solution and the organic phase, sucking the organic phase by a dropper under the condition of probe ultrasound (2s on, 3s off), slowly adding into the stabilizer aqueous solution at a constant speed, setting the ultrasound time to be 5min, 10min and 15min respectively, and setting the fixed ultrasound power to be 60W, so as to obtain the asarone nanoscale colloidal dispersions respectively marked as F2-1, F2-2 and F2-3. The particle size and PDI of asarone obtained by the nano-crystallization process were measured by a laser particle sizer three times for each sample, and the results are shown in Table 2, wherein the first measurement result of F2-1 is shown in FIG. 3.
Table 2: influence of ultrasound time on particle size of asarone nanoscale colloidal dispersion
Figure BDA0002923350900000041
As can be seen from tables 1 and 2, as the ultrasonic power of the probe increases, the difference between the particle size and PDI is not great; as the probe sonication time increases, particle size and PDI tend to increase. Finally, considering the protection of the instrument, the ultrasonic power is preferably 60W and the ultrasonic time is preferably 5 min.

Claims (1)

1. A asarin nanocrystallization method is characterized by comprising the following steps: the method comprises the following steps:
(1) dissolving a stabilizer in water to obtain a water phase;
(2) adding asarone into organic solvent to completely dissolve the medicine, and taking the obtained solution as organic phase;
(3) dripping the organic phase into the water phase, and mixing to obtain nanometer colloidal dispersion of asarone;
the stabilizer is selected from one or a mixture of more of polyvinyl alcohol, 15-hydroxystearic acid polyethylene glycol ester or polyvinylpyrrolidone;
the organic solvent is polyethylene glycol 400;
the mass ratio of the stabilizer in the water phase in the step (1) is 0.1-10%; the mass ratio of the asarone in the organic phase in the step (2) is 1-20%;
and (3) dissolving the medicine by adopting probe ultrasonic or magnetic stirring, wherein the probe ultrasonic frequency is 60-180W, the ultrasonic time is 5-15 min, and the magnetic stirring rotating speed is 500-1000 rpm and the magnetic stirring time is 5-15 min.
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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
星点设计-效应面法优化α-细辛脑纳米粒原位凝胶的处方及其体外释放性能考察;臧巧真等;《中国实验方剂学杂志》;20160731;第22卷(第13期);第7-10页 *

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