阅读说明：本技术 一种挥发油类物质微纳米药物递送系统及其制备方法与应用 (Volatile oil substance micro-nano drug delivery system and preparation method and application thereof ) 是由 贾竞夫 周雪 葛发欢 于 2020-05-27 设计创作，主要内容包括：本发明属于天然产物药剂学和工程技术技术领域,具体公开了一种挥发油类物质微纳米药物递送系统及其制备方法与应用。所述方法具体为：在多孔/介孔微纳米载体与挥发油类物质混合均匀,然后通入CO<Sub>2</Sub>并升温,开始超临界态下的挥发油类物质渗透载入过程；待超临界态下的挥发油类物质渗透载入过程达到平衡后,通过降温、泄压使系统脱离超临界状态,将挥发油类物质负载于多孔/介孔微纳米载体中；重复此过程,然后收集得到载有挥发油类物质的微纳米颗粒。本发明利用超临界CO<Sub>2</Sub>环境友好、渗透性超强等独特优势,制备所得高载药量的挥发油类物质微纳米药物粉体为固体粉体,载药量>30％(wt％)。(The invention belongs to the technical field of natural product pharmacy and engineering, and particularly discloses a volatile oil substance micro-nano drug delivery system, and a preparation method and application thereof. The method specifically comprises the following steps: in porous/mesoporous micro-nanoMixing carrier and volatile oil, and introducing CO 2 Heating and starting the permeation loading process of the volatile oil substances in the supercritical state; after the permeation loading process of the volatile oil substances in the supercritical state reaches balance, the system is separated from the supercritical state through temperature reduction and pressure relief, and the volatile oil substances are loaded in the porous/mesoporous micro-nano carrier; repeating the process, and collecting the micro-nano particles loaded with the volatile oil substances. The invention utilizes supercritical CO 2 The prepared volatile oil substance micro-nano medicine powder with high drug-loading rate is solid powder with unique advantages of environmental friendliness, super-strong permeability and the like>30％(wt％)。)

1. A preparation method of a volatile oil substance micro-nano drug delivery system is characterized by comprising the following steps:

(1) permeation stage in supercritical state

In a plurality of poresUniformly mixing mesoporous micro-nano carrier and volatile oil substances, and then introducing CO₂Heating and starting the permeation loading process of the volatile oil substances in the supercritical state;

(2) loading phase of volatile oil

After the permeation loading process of the volatile oil substances in the supercritical state in the step (1) reaches balance, cooling and relieving pressure to enable the reaction system to be separated from the supercritical state, and loading the volatile oil substances in the porous/mesoporous micro-nano carrier;

(3) cyclic loading phase

And (3) repeating the steps of the steps (1) and (2), and then collecting the micro-nano particles loaded with the volatile oil substances.

2. The method of claim 1, wherein:

CO described in step (1)₂The introduction amount of the (C) is 8-30 MPa when the pressure of the supercritical state permeation stage is satisfied, and the temperature after temperature rise is 35-50 ℃.

3. The method of claim 1, wherein:

the mass-volume ratio of the porous/mesoporous micro-nano carrier to the volatile oil substances in the step (1) is 160-250 mg: 2 mL.

4. The method of claim 1, wherein:

the porous/mesoporous micro-nano carrier in the step (1) is particles with a porous or mesoporous structure, and the size of the particles is less than 100 micrometers;

the volatile oil in the step (1) is a volatile substance extracted from flowers, leaves, stems, roots or fruits of plants.

5. The method of claim 1, wherein: the porous/mesoporous micro/nano carrier in the step (1) is mesoporous silicon, mesoporous silicon modified by chitosan or fibroin nano aerosol particles; the volatile oil is at least one of oleum herba Pogostemonis, oleum Cinnamomi and oleum Curcumae.

6. The method of claim 1, wherein: the temperature after the temperature reduction in the step (2) is below 25 ℃.

7. A volatile oil substance micro-nano drug delivery system prepared by the method of any one of claims 1 to 6.

8. The application of the volatile oil substance micro-nano drug delivery system in the preparation of volatile oil functionalized nano drugs according to claim 7.

Technical Field

The invention belongs to the technical field of natural product pharmacy and engineering, and particularly relates to a volatile oil substance micro-nano drug delivery system, and a preparation method and application thereof.

Background

The volatile oil (Essential oil) is one of the important component classes in the traditional Chinese medicine, is an oily liquid which has strong volatility and lipid solubility, is insoluble in water, has fragrance or pungent smell, and plays an important role in the treatment of the traditional Chinese medicine. Modern pharmaceutical research proves that the Chinese medicinal volatile oil has multiple functions of resisting bacteria, inflammation, allergy, tumor, parasite and the like.

However, volatile oil is very unstable and volatile, and is easily oxidized and decomposed to lose or reduce pharmacological effects, which brings great difficulty to the medicinal use of the traditional Chinese medicine volatile oil. With the wide application of modern preparation technology, particularly, solid preparations such as tablets, capsules, granules and the like become mainstream Chinese medicine dosage forms, and the weakness of poor stability of volatile oil is increasingly prominent. In order to improve the stability of the volatile oil, beta-cyclodextrin is adopted to firstly include the volatile oil and then the volatile oil is prepared into a preparation singly or together with other medicinal parts, but the working procedures are complicated, the temperature is high, the inclusion rate and the volatile oil utilization rate are low, the volatile oil effectiveness is not fully exerted due to the introduction of a large amount of cyclodextrin, and the problem of organic solvent residue is difficult to overcome. The key problem that the traditional Chinese medicine preparation needs to solve urgently is how to efficiently and reasonably solve the stability of the traditional Chinese medicine volatile oil and give full play to the effectiveness of the volatile oil.

Secondly, the components of the traditional Chinese medicine volatile oil have extremely poor water solubility and low bioavailability of the conventional preparation, so that the volatile oil does not show effective treatment effect or cannot fully play the efficacy in vivo. Although the dosage can be relieved to a certain extent by increasing the dosage, the problems of overlarge dosage, irritation to the mucous membrane of the organism, strong side effect and the like are brought. Therefore, how to improve the bioavailability of the traditional Chinese medicine volatile oil, improve the treatment effect and reduce the toxic and side effects is also a key problem to be solved in the clinical application of the traditional Chinese medicine volatile oil preparation.

The preparation of the traditional Chinese medicine volatile oil into the micro-nano medicine carrying system is a research hotspot in recent years and receives more and more attention so as to improve the stability and bioavailability of the volatile oil. The nano-drug can effectively improve the dissolution rate and bioavailability of the volatile oil of the traditional Chinese medicine by virtue of the size advantages of the nano-drug, reduce toxic and side effects, enhance the original curative effect, realize slow release control, enrich the dosage form and the like. From the published patent content, the micro-nano preparation forms of the traditional Chinese medicine volatile oil mainly comprise:

(1) liquid preparation

The liquid preparation form of the traditional Chinese medicine volatile oil comprises microemulsion and liposome, the two preparations are mainly prepared by a high-pressure homogenization method at present, but the volatile oil is very easy to lose in the process, so that the property and the particle size of the product are difficult to control; meanwhile, due to the nature of the liquid dispersion, the storage stability of the microemulsion and the liposome is poor, and the phospholipid in the liposome is very easy to oxidize and degrade to cause the leakage of volatile oil components. In addition, the microemulsion preparation needs to use a high-concentration surfactant, which can generate great side effects on gastrointestinal tracts, and although the dosage of the surfactant can be reduced by adopting means such as multiple high-pressure homogenization and the like, the reduction amount is limited; other methods for preparing volatile oil liposomes, such as ethanol injection and thin film dispersion, use large amounts of organic solvents and are difficult to remove.

(2) Solid nanoparticles

At present, solid nanoparticles reported for traditional Chinese medicine volatile oil comprise polymer nanoparticles, solid lipid nanoparticles, microcapsules and the like. The polymer nanoparticles and the solid lipid nanoparticles are particles formed by uniformly mixing the volatile oil and a polymer material or a lipid material to form a nanometer scale, and the microcapsule is formed by coating the volatile oil by using a certain high molecular material as a capsule wall material to form a nanometer microcell. The solid nano-particles greatly increase the stability of medicine storage and have the advantages of the liquid nano-preparation, so the nano-preparation is a medicine carrying form with great prospect. However, the conventional method for preparing volatile oil solid nanoparticles is mainly a high-pressure homogenization-spray drying method, and due to repeated operation, high temperature and the like, the volatile oil components are very easy to change, the medicinal value is lost or reduced, and the problem of easy volatilization loss of the volatile oil in the process cannot be avoided.

In general, the traditional nanocrystallization technology of the traditional Chinese medicine volatile oil has more problems, the prepared volatile oil nanometer product cannot completely reflect the unique advantages of the nanometer medicine, and the traditional method is difficult to effectively construct the functional nanometer medicine with real meaning.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention mainly aims to provide a preparation method of a volatile oil substance micro-nano drug delivery system.

The invention also aims to provide the volatile oil substance micro-nano drug delivery system prepared by the method.

The invention further aims to provide application of the volatile oil substance micro-nano drug delivery system prepared by the method in preparation of volatile oil functionalized nano drugs.

The purpose of the invention is realized by the following scheme:

a preparation method of a volatile oil substance micro-nano drug delivery system comprises the following steps:

(1) permeation stage in supercritical state

Uniformly mixing the porous/mesoporous micro-nano carrier with volatile oil substances, and introducing CO₂Heating and starting the permeation loading process of the volatile oil substances in the supercritical state;

(2) loading phase of volatile oil

After the permeation loading process of the volatile oil substances in the supercritical state in the step (1) reaches balance, cooling and relieving pressure to enable the reaction system to be separated from the supercritical state, and loading the volatile oil substances in the porous/mesoporous micro-nano carrier;

(3) cyclic loading phase

And (3) repeating the steps of the steps (1) and (2), and then collecting the micro-nano particles loaded with the volatile oil substances.

The volatile oil substances in the supercritical state in the step (1) permeate and carryThe process is preferably carried out in an autoclave; wherein volatile oil substances and CO₂Injecting through two different nozzles respectively; the two different nozzle configurations are either coaxial nozzles or parallel independent nozzles.

The porous/mesoporous micro-nano carrier in the step (1) is particles with a porous or mesoporous structure with the size of less than 100 microns, and the shapes of the particles include but are not limited to spherical, spongy, irregular blocks and the like; the material classes of the carrier include, but are not limited to, organic or inorganic materials such as silica, proteins, polymers, and the like. Preferably, the surface of the porous/mesoporous micro-nano carrier is provided with a grafting functional group. More preferably, the porous/mesoporous micro/nano-carrier is mesoporous silicon, chitosan-modified mesoporous silicon or fibroin nano aerosol particles.

The volatile oil in the step (1) can be dissolved in supercritical CO₂Including but not limited to volatile materials extracted from flowers, leaves, stems, roots or fruits of plants by supercritical extraction, steam distillation, extrusion, cold soaking or other solvent extraction methods, and the like. Preferably, the volatile oil is at least one of patchouli oil, cinnamon oil and zedoary turmeric oil.

The mass-volume ratio of the porous/mesoporous micro-nano carrier to the volatile oil substances in the step (1) is 160-250 mg: 2 mL; preferably 200 mg: 2 mL.

CO described in step (1)₂The introduction amount of the (C) is 8-30 MPa in the supercritical state permeation stage, the temperature after temperature rise is 35-50 ℃, and the permeation duration is 0.5-2 h.

The temperature of the cooled product in the step (2) is below 25 ℃; preferably, the temperature is reduced through kettle body condensate water, and the temperature of the condensate water is 2-6 ℃. The pressure after pressure relief is normal pressure, and the pressure relief time is 15-40 min.

CO in step (2)₂And the volatile oil substances which are not loaded can be recycled.

And (4) repeating the step (3) for 1-5 times.

A volatile oil substance micro-nano drug delivery system is prepared by the method.

The volatile oil substance micro-nano drug delivery system is applied to the preparation of volatile oil functionalized nano drugs.

Compared with the prior art, the invention has the following advantages and beneficial effects:

the invention utilizes supercritical CO₂The preparation method has the unique advantages of environmental friendliness, super-strong permeability, solvability, no solvent residue and the like, and provides the preparation method of the volatile oil substance micro-nano particles with simple process, stable components and high drug-loading rate. The obtained volatile oil substance micro-nano medicine powder with high drug loading rate is solid powder with drug loading rate>30% (wt%). When the carrier is a porous/mesoporous carrier grafted with functional groups, the obtained volatile oil substance micro-nano medicine powder with high medicine-loading rate can keep the space structure of the carrier undamaged and the functional characteristics intact while loading the volatile oil substance.

Detailed Description

The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.