CN111110587A

CN111110587A - Preparation method of nanocapsule for carrying fat-soluble active substances

Info

Publication number: CN111110587A
Application number: CN201911270435.7A
Authority: CN
Inventors: 梁蓉; 杨成; 谢桂杰
Original assignee: Jiangnan University
Current assignee: Jiangnan University
Priority date: 2019-12-12
Filing date: 2019-12-12
Publication date: 2020-05-08

Abstract

The invention discloses a preparation method of a nanocapsule for carrying fat-soluble active substances, wherein the nanocapsule comprises liquid lipid, solid lipid, the fat-soluble active substances, phospholipid, a non-ionic emulsifier, polyhydric alcohol and water; the lipid-soluble phospholipid liposome is prepared from 0.1-20% of liquid lipid, 0-20% of solid lipid, 0.1-15% of fat-soluble active matter, 0.1-10% of phospholipid, 0.1-5% of nonionic emulsifier, 40-90% of polyalcohol and the balance of water by mass percentage through high-pressure dispersion and homogenization. The solid lipid in the nanocapsule has high crystallinity, and forms a compact film on the skin surface, so that the nanocapsule has a better closure effect, reduces the evaporation of water on the skin surface, improves the hydration degree of the skin surface, and loosens the stratum corneum structure, thereby being beneficial to the transdermal absorption of active substances.

Description

Preparation method of nanocapsule for carrying fat-soluble active substances

Technical Field

The invention belongs to the technical field of micro-nano carriers, and particularly relates to a preparation method of a nanocapsule for carrying fat-soluble active substances.

Background

The micro-nano carrier technology is a technology for protecting and conveying active ingredients with low solubility, poor stability, low utilization degree and the like. The micro-nano carrier is prepared from a material with good biocompatibility, and active substances are embedded in the micro-nano carrier or adsorbed on the surface of the micro-nano carrier in the ways of adsorption, dissolution and the like, so that the micro-nano carrier is a technology for effectively protecting and conveying active ingredients. Compared with the chemical modification technology, the micro-nano carrier technology basically does not influence the functional characteristics of the active ingredients, and the operation method is relatively simple.

The commonly used micro-nano carriers mainly comprise nano emulsion, nano-structured lipid carriers, lipid nanocapsules, liposome, cyclodextrin inclusion compound, microcapsule and the like. The micro-nano carrier has the advantages of good biocompatibility, slow release, targeting property and the like, and is widely applied to the fields of cosmetics, foods, medicines and the like.

The lipid nanocapsule is a micro-nano carrier carrying lipophilic active substances, which is prepared by mixing water, phospholipid, polyalcohol or carbohydrate (glycerol, sorbitol, fructose and the like) and homogenizing under high pressure. Compared with other carriers, the lipid nanocapsule contains high-concentration polyol, can solubilize a large amount of lipid and has high drug loading; is a self-protection system with low moisture content and does not contain preservatives; the particle size is less than 100nm, and the transdermal absorption of the active substances is promoted. At present, lipid nanocapsules are used for embedding various fat-soluble active substances, such as CoQ10, vitamins, carotenoids and the like, but the problem that the nanocapsules are unstable to ions exists, and the using effect is influenced.

Disclosure of Invention

This section is for the purpose of summarizing some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. In this section, as well as in the abstract and the title of the invention of this application, simplifications or omissions may be made to avoid obscuring the purpose of the section, the abstract and the title, and such simplifications or omissions are not intended to limit the scope of the invention.

The present invention has been made in view of the above-mentioned technical drawbacks.

Accordingly, in one aspect of the present invention, the present invention overcomes the deficiencies of the prior art by providing a method for preparing nanocapsules that carry lipid soluble actives.

In order to solve the technical problems, the invention provides the following technical scheme: a nanocapsule for carrying a fat-soluble active comprising a liquid lipid, a solid lipid, a fat-soluble active, a phospholipid, a non-ionic emulsifier, a polyol and water; the lipid-soluble active substance comprises, by mass, 0.1-20% of liquid lipid, 0-20% of solid lipid, 0.1-15% of fat-soluble active substance, 0.1-10% of phospholipid, 0.1-5% of nonionic emulsifier, 40-90% of polyol and the balance of water.

As a preferred embodiment of the nanocapsule carrying a fat-soluble active according to the present invention, wherein: the solid lipid is one or more of palmitic acid triglyceride, cetyl palmitate, glyceryl monostearate, glyceryl monolaurate, stearic acid and glyceryl distearate; the liquid lipid is one or more of isopropyl myristate, caprylic/capric triglyceride, n-butyl stearate, triolein, soybean oil and olive oil.

As a preferred embodiment of the nanocapsule carrying a fat-soluble active according to the present invention, wherein: the phospholipid is one or more of PC60, PC70, PC80 and hydrogenated lecithin; the nonionic emulsifier is one or more of Tween80, Tween20, Span60, Span20, decaglycerol monolaurate, decaglycerol monomyristate, decaglycerol monostearate, hexaglycerol monolaurate, hexaglycerol monomyristate and hexaglycerol monostearate.

As a preferred embodiment of the nanocapsule carrying a fat-soluble active according to the present invention, wherein: the polyol is one or more of glycerol, sorbitol, pentaerythritol, dipropylene glycol and xylitol; the fat-soluble active matter is one or more of vitamin E, coenzyme Q10, curcumin and ceramide.

As a preferred embodiment of the nanocapsule carrying a fat-soluble active according to the present invention, wherein: the solid lipid is one or more of palmitic acid triglyceride and cetyl palmitate; the phospholipid is one or more of PC60 and PC 80; the non-ionic emulsifier is one or more of decaglycerol monolaurate, decaglycerol monomyristate, hexaglycerol monolaurate and hexaglycerol monomyristate; the liquid lipid is one or more of isopropyl myristate and caprylic/capric triglyceride; the polyol is one or more of glycerol, sorbitol and xylitol; the fat-soluble active matter is one or more of vitamin E, coenzyme Q10, curcumin and ceramide.

In one aspect of the present invention, the present invention overcomes the deficiencies of the prior art by providing a method for preparing nanocapsules for carrying fat soluble actives, wherein: mixing and dissolving polyalcohol, phospholipid, a nonionic emulsifier and water to obtain a water phase; mixing and dissolving solid lipid, liquid lipid and fat-soluble active substance to obtain oil phase; and adding the water phase into the oil phase, and dispersing and homogenizing to obtain the nanocapsule carrying the fat-soluble active substance.

As a preferred embodiment of the preparation method of the nanocapsule carrying fat-soluble active substance of the present invention, wherein: the lipid-soluble active substance comprises, by mass, 0.1-20% of liquid lipid, 0-20% of solid lipid, 0.1-15% of fat-soluble active substance, 0.1-10% of phospholipid, 0.1-5% of nonionic emulsifier, 40-90% of polyol and the balance of water. The lipid-soluble lipid-containing food additive comprises, by mass, 0.1-20% of liquid lipid, 0-20% of solid lipid, 0.1-15% of fat-soluble active substances, 0.1-10% of phospholipid, 0.1-5% of nonionic emulsifier, 40-90% of polyhydric alcohol and the balance of water.

As a preferred embodiment of the preparation method of the nanocapsule carrying fat-soluble active substance of the present invention, wherein: the rotating speed of the dispersion is 10000-20000 rpm, and the dispersion time is 1-5 min; the pressure of the homogenization is 50-100 MPa, and the homogenization times are 3-8 times.

As a preferred embodiment of the preparation method of the nanocapsule carrying fat-soluble active substance of the present invention, wherein: the obtained nanocapsule is transparent liquid, the particle size is 50-80 nm, and the appearance and the particle size are not obviously changed after the nanocapsule is placed at room temperature for 90 days.

The invention has the beneficial effects that:

the invention applies the nanocapsule which contains different solid lipids and carries fat-soluble active substances to transdermal absorption. The addition of the polyalcohol can dissolve a large amount of lipid, so that the loading capacity and the encapsulation rate of the fat-soluble active substance are obviously improved; the ion stability of the nanocapsule is obviously improved, and the nanocapsule has good storage stability and thermal stability; the addition of the solid lipid enables the skin surface to have better closure effect, improves the skin hydration degree, loosens the structure of the stratum corneum and is more beneficial to the transdermal absorption of the active substances.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and 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 to obtain other drawings based on these drawings without inventive exercise. Wherein:

figure 1 is a graph of the particle size distribution of the nanocapsules of example 4 carrying a fat-soluble active;

FIG. 2 is a transmission electron micrograph at 61nm of nanocapsules of example 5 carrying a fat-soluble active;

FIG. 3 shows the results of examples 2, 3, 4 and 5 applied to transdermal absorption.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with examples are described in detail below.

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.

Furthermore, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.

Example 1

Isopropyl myristate: 3g

Cetyl palmitate: 7g of

Coenzyme Q10: 2.5g

PC60：3g

Glycerol: 20g of

Water: the balance, total 100g

Mixing PC60, hexa-polyglycerol monolaurate, glycerol and water, and magnetically stirring in a water bath kettle at 80 deg.C until the water phase is clear and transparent; mixing caprylic/capric triglyceride, cetyl palmitate and fat-soluble active substance, heating and dissolving in 80 deg.C water bath until oil phase is clear and transparent; adding the water phase into the oil phase, dispersing at 10000rpm for 3min, circulating for 6 times by using a high-pressure homogenizer at 60MPa, and cooling at room temperature to obtain the nanocapsule carrying curcumin.

The obtained nanocapsule is opaque, the loading capacity of coenzyme Q10 is 2.5%, the encapsulation rate is about 99.6%, the particle size is 150nm measured by adopting a Zeta potential and nano particle size analyzer, the particle size is obviously increased after the nanocapsule is placed at room temperature for 90 days, white substances are separated out from the upper bottle wall, and the system is unstable.

Example 2

Caprylic capric triglyceride: 5g

Coenzyme Q10: 5g

PC60：2g

Decaglycerol monolaurate: 3g

Glycerol: 70g

Water: the balance, total 100g

Mixing PC80, myristyl myristoleate, glycerol and water, and magnetically stirring in a water bath kettle at 60 deg.C until the water phase is clear and transparent; mixing caprylic capric triglyceride and coenzyme Q10, heating and dissolving in water bath at 60 deg.C until oil phase is clear and transparent; adding the water phase into the oil phase, dispersing at 15000rpm for 2min, circulating for 3 times at 80MPa by using a high-pressure homogenizer, and cooling at room temperature to obtain the nanocapsule carrying coenzyme Q10.

The obtained nanocapsule is transparent liquid, the loading amount of the coenzyme Q10 is 5%, and the encapsulation rate is about 99.2%; measuring the particle diameter to 59nm by Zeta potential and nanometer particle size analyzer, standing at room temperatureAfter 90 days, the appearance and the particle size of the product are not obviously changed, the retention rate is more than 95%, and the product has good storage stability; with 0.05mol/L of CaCl₂After the materials are mixed according to the ratio of 1:1 and placed for 24 hours, the particle size is slightly increased to about 62nm, and the system has good ionic stability.

Example 3

Caprylic capric triglyceride: 2.5g

Cetyl palmitate glyceride: 2.5g

Coenzyme Q10: 5g

PC60：2g

Decaglycerol monolaurate: 3g

Glycerol: 70g

Water: the balance, total 100g

The obtained nanocapsule is transparent liquid, the loading capacity of coenzyme Q10 is 5%, the encapsulation rate is about 99.5%, and Differential Scanning Calorimetry (DSC) results show that the solid lipid is in a supercooled molten state and a melting peak of the solid lipid does not appear; the particle size is measured to be 57nm by adopting a Zeta potential and nano-particle size analyzer, after the particle size is placed for 90 days at room temperature, the appearance and the particle size of the particle size have no obvious change, the retention rate is more than 95 percent, and the particle size has good storage stability; with 0.05mol/L of CaCl₂After the materials are mixed according to the ratio of 1:1 and placed for 24 hours, the particle size is slightly increased to about 65nm, and the system has good ionic stability. .

Example 4

Caprylic capric triglyceride: 1.5g

Cetyl palmitate glyceride: 3.5g

Coenzyme Q10: 5g

PC60：2g

Decaglycerol monolaurate: 3g

Glycerol: 70g

Water: the balance, total 100g

The obtained nanocapsule is transparent liquid, the loading amount of coenzyme Q10 is 5%, the encapsulation rate is about 99.2%, and the DSC result shows that the crystallinity of the solid lipid is 16.23%; the particle size is measured to be 60nm by adopting a Zeta potential and nano-particle size analyzer, after the nano-particle size analyzer is placed for 90 days at room temperature, the appearance and the particle size of the nano-particle size analyzer have no obvious change, the retention rate is more than 95 percent, and the nano-particle size analyzer has good storage stability; with 0.05mol/L of CaCl₂After the materials are mixed according to the ratio of 1:1 and placed for 24 hours, the particle size is slightly increased to about 72nm, and the system has good ionic stability.

Example 5

Caprylic capric triglyceride: 0.5g

Cetyl palmitate glyceride: 4.95g

Coenzyme Q10: 5g

PC60：2g

Decaglycerol monolaurate: 3g

Glycerol: 70g

Water: the balance, total 100g

The obtained nanocapsule is transparent liquid, the loading amount of the coenzyme Q10 is 5 percent, and the encapsulation rate is about 99.9 percentRight, DSC results indicate that the crystallinity of the solid lipid is 20.68%; the particle size is measured to be 61nm by adopting a Zeta potential and nano-particle size analyzer, after the nano-particle size analyzer is placed for 90 days at room temperature, the appearance and the particle size of the nano-particle size analyzer have no obvious change, the retention rate is more than 95 percent, and the nano-particle size analyzer has good storage stability; with 0.05mol/L of CaCl₂After the materials are mixed according to the ratio of 1:1 and placed for 24 hours, the particle size is slightly increased to about 75nm, and the system has good ionic stability.

In the invention, preferably, when 0.5% of liquid lipid, 4.95% of solid lipid, 5% of fat-soluble active substance, 1.5% of phospholipid, 3.5% of nonionic emulsifier, 80% of polyalcohol and the balance of water are selected, after a water phase and an oil phase are respectively prepared, high-speed dispersion and homogenization are carried out, and the high-stability nanocapsule carrying the fat-soluble active substance can be obtained.

Example 6

Examples 2, 3, 4 and 5 were applied to transdermal absorption.

The pigskin was placed between the supply cell and the receiving cell of the Franzs diffusion cell, 0.5ml of sample was added to the supply cell and placed in the transdermal diffusion tester for 12h reaction. After the reaction is finished, the content of CoQ10 in the epidermis is measured by a tape striping method: sticking the horny layer of the pigskin by using a 3M adhesive tape, abandoning the first layer, and continuously sticking 20 layers; collecting in a centrifuge tube, adding an extracting agent for extraction, and measuring the content of CoQ10 by HPLC (high performance liquid chromatography), namely the content of CoQ10 in the epidermis.

Cutting the skin left after removing the stratum corneum by sticking the 21 layers of 3M adhesive tapes, collecting the cut skin in a centrifuge tube, adding an extracting agent for extraction, and measuring the content of CoQ10 by adopting HPLC (high performance liquid chromatography), namely the content of CoQ10 in dermis.

The results show that the transdermal content of coenzyme Q10 increases significantly with the increase of solid lipid content, indicating that the addition of solid lipid can promote the transdermal absorption of fat-soluble active substances. The addition of the solid lipid obviously improves the transdermal delivery of the nanocapsule to the fat-soluble active substance, and the transdermal performance of the fat-soluble active substance is obviously improved along with the increase of the content of the solid lipid.

Example 7

Caprylic capric triglyceride: 5g

Coenzyme Q10: 5g

PC60：2g

Decaglycerol monolaurate: 3g

Glycerol: 70g

Water: balance of

The obtained nanocapsule is transparent liquid, the particle size is measured to be 69nm by adopting a Zeta potential and nanometer particle size analyzer, and the nanocapsule is placed for 1d, 7d, 15d and 30d at the temperature of 50 ℃, has no obvious change in appearance and particle size and has good thermal stability.

Therefore, the nanocapsule carrying the fat-soluble active substance, which is prepared by selecting proper phospholipid and nonionic emulsifier in a compounding manner, can obviously improve the ionic stability, the thermal stability and the storage stability of the nanocapsule. Meanwhile, appropriate solid lipid is added into the nanocapsule, so that the transdermal absorption of the fat-soluble active substance can be further promoted.

Example 8

Caprylic capric triglyceride: 5g

Coenzyme Q10: 5g

PC60：2g

Glycerol: 70g

Water: balance of

Mixing PC60, myristyl myristoleate, glycerol and water, and magnetically stirring in a water bath kettle at 60 deg.C until the water phase is clear and transparent; mixing caprylic capric triglyceride and coenzyme Q10, heating and dissolving in water bath at 60 deg.C until oil phase is clear and transparent; adding the water phase into the oil phase, dispersing at 15000rpm for 2min, circulating for 3 times at 80MPa by using a high-pressure homogenizer, and cooling at room temperature to obtain the nanocapsule carrying coenzyme Q10.

The obtained nanocapsule is transparent liquid, the loading amount of the coenzyme Q10 is 5%, and the encapsulation rate is about 99.5%; the particle size is measured to be 63nm by adopting a Zeta potential and nano particle size analyzer, after the sample is placed at room temperature for 90 days, the appearance and the particle size of the sample have no obvious change, the retention rate is more than 95 percent, and the sample has good storage stability; with 0.05mol/L of CaCl₂After the materials are mixed according to the ratio of 1:1 and placed for 24 hours, the particle size is obviously increased to about 216nm, the demulsification phenomenon occurs, and the system is unstable.

It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.

Claims

1. A nanocapsule for carrying a fat-soluble active, wherein: comprises the steps of (a) preparing a mixture of a plurality of raw materials,

liquid lipid, solid lipid, fat-soluble active substance, phospholipid, nonionic emulsifier, polyalcohol and water;

the lipid-soluble active substance comprises, by mass, 0.1-20% of liquid lipid, 0-20% of solid lipid, 0.1-15% of fat-soluble active substance, 0.1-10% of phospholipid, 0.1-5% of nonionic emulsifier, 40-90% of polyol and the balance of water.

2. The nanocapsule carrying a fat-soluble active agent of claim 1, wherein: the solid lipid is one or more of palmitic acid triglyceride, cetyl palmitate, glyceryl monostearate, glyceryl monolaurate, stearic acid and glyceryl distearate; the liquid lipid is one or more of isopropyl myristate, caprylic/capric triglyceride, n-butyl stearate, triolein, soybean oil and olive oil.

3. The nanocapsule carrying a fat-soluble active substance of claim 1 or 2, wherein: the phospholipid is one or more of PC60, PC70, PC80 and hydrogenated lecithin; the nonionic emulsifier is one or more of Tween80, Tween20, Span60, Span20, decaglycerol monolaurate, decaglycerol monomyristate, decaglycerol monostearate, hexaglycerol monolaurate, hexaglycerol monomyristate and hexaglycerol monostearate.

4. The nanocapsule carrying a fat-soluble active agent of claim 3, wherein: the polyol is one or more of glycerol, sorbitol, pentaerythritol, dipropylene glycol and xylitol; the fat-soluble active matter is one or more of vitamin E, coenzyme Q10, curcumin and ceramide.

5. The nanocapsule carrying a fat-soluble active agent of claim 3, wherein: the solid lipid is one or more of palmitic acid triglyceride and cetyl palmitate; the phospholipid is one or more of PC60 and PC 80; the non-ionic emulsifier is one or more of decaglycerol monolaurate, decaglycerol monomyristate, hexaglycerol monolaurate and hexaglycerol monomyristate; the liquid lipid is one or more of isopropyl myristate and caprylic/capric triglyceride; the polyol is one or more of glycerol, sorbitol and xylitol; the fat-soluble active matter is one or more of vitamin E, coenzyme Q10, curcumin and ceramide.

6. A method for preparing a nanocapsule for carrying a fat-soluble active substance, the method comprising the steps of:

mixing and dissolving polyalcohol, phospholipid, a nonionic emulsifier and water to obtain a water phase;

mixing and dissolving solid lipid, liquid lipid and fat-soluble active substance to obtain oil phase;

and adding the water phase into the oil phase, and dispersing and homogenizing to obtain the nanocapsule carrying the fat-soluble active substance.

7. The method of preparing nanocapsules for carrying fat-soluble active substances according to claim 6, wherein: the lipid-soluble active substance comprises, by mass, 0.1-20% of liquid lipid, 0-20% of solid lipid, 0.1-15% of fat-soluble active substance, 0.1-10% of phospholipid, 0.1-5% of nonionic emulsifier, 40-90% of polyol and the balance of water. The lipid-soluble lipid-containing food additive comprises, by mass, 0.1-20% of liquid lipid, 0-20% of solid lipid, 0.1-15% of fat-soluble active substances, 0.1-10% of phospholipid, 0.1-5% of nonionic emulsifier, 40-90% of polyhydric alcohol and the balance of water.

8. A process for the preparation of nanocapsules carrying fat-soluble active substances as claimed in claim 6 or 7, wherein: the lipid-soluble active substance comprises, by mass, 0.1-20% of liquid lipid, 0-20% of solid lipid, 0.1-15% of fat-soluble active substance, 0.1-10% of phospholipid, 0.1-5% of nonionic emulsifier, 40-90% of polyol and the balance of water. The lipid-soluble lipid-containing food additive comprises, by mass, 0.1-20% of liquid lipid, 0-20% of solid lipid, 0.1-15% of fat-soluble active substances, 0.1-10% of phospholipid, 0.1-5% of nonionic emulsifier, 40-90% of polyhydric alcohol and the balance of water.

9. A process for the preparation of nanocapsules carrying fat-soluble active substances as claimed in claim 6 or 7, wherein: the rotating speed of the dispersion is 10000-20000 rpm, and the dispersion time is 1-5 min; the pressure of the homogenization is 50-100 MPa, and the homogenization times are 3-8 times.

10. The process for the preparation of nanocapsules carrying fat-soluble active substances according to claim 6 or 7, wherein: the obtained nanocapsule is transparent liquid, the particle size is 50-80 nm, and the appearance and the particle size are not obviously changed after the nanocapsule is placed at room temperature for 90 days.