KR102554845B1 - Process for preparing eco-friendly and stabilized complex coacervate particles - Google Patents

Abstract

The present invention relates to a method for producing eco-friendly and stabilized complex coacervate particles, and more specifically, in producing complex coacervate particles in which a core material is encapsulated in a coacervate shell, a natural extract is used as an acid/base regulator, a crosslinking agent and a stabilizing agent are used. It relates to an eco-friendly and stabilized composite coacervate particle (HA-Ball) manufacturing method using hyaluronic acid (HA), silica, block polymer, etc. as a topic
According to the present invention, it is possible to provide an eco-friendly and stable method for preparing new coacervate particles by replacing chemical acids, base regulators and crosslinking agents conventionally used to prepare complex coacervate particles with natural materials. In addition, by using hyaluronic acid (HA) as a new stabilizer, it is possible to provide a method for preparing complex coacervate particles that stabilizes coacervate or increases strength through matrix formation or linker connection.

Description

Method for preparing eco-friendly and stabilized complex coacervate particles {Process for preparing eco-friendly and stabilized complex coacervate particles}

The present invention relates to a method for producing eco-friendly and stabilized complex coacervate particles, and more specifically, in producing complex coacervate particles in which a core material is encapsulated in a coacervate shell, a natural extract is used as an acid/base regulator, a crosslinking agent and a stabilizing agent are used. It relates to an eco-friendly and stabilized composite coacervate particle (HA-Ball) manufacturing method using hyaluronic acid (HA), silica, block polymer, etc. as a topic

Coacervation is the precipitation of polymers dissolved in an aqueous solution through intermolecular forces, specifically electrostatic attraction, electrostatic bonding, hydrogen bonding, cation-π interaction, hydrophobic interaction, and attractive van der Waals forces in the aqueous solution. refers to the droplet that occurs This reaction occurs spontaneously with low interfacial energy. Conditions that affect coacervation include solution pH and ionic strength, temperature, type of polyelectrolyte, polymer concentration, molecular weight and conformational structure of the polymer, and mixing ratio of two oppositely charged polymers. When the prepared coacervation solution is allowed to stand for a long time, droplets may be obtained by phase separation. The low interfacial energy of complex coacervates allows them to encapsulate a variety of materials, including dyes, particles, fragrances, and cells.

Microencapsulation is the process of encasing a core material in small droplets in a protective coating. This process is performed to aid storage and to treat or control the release of the encapsulated material. There are many techniques for forming microcapsules. As one of the techniques, complex coacervation is known. Coacervation is the process of separating an aqueous colloid into two liquid phases, one of which is relatively colloidally condensed and the other relatively colloidally diluted. When only a single type of colloidal material is present, the process is referred to as simple coacervation. However, when a mixture of two colloids (oppositely charged) is present, the process is referred to as complex coacervation. For complex coacervation to occur, the colloid must be ionized or capable of ionization, and the conditions for coacervation require that the colloid be oppositely charged. Conditions for coacervation can be brought about by the selection of appropriately charged colloids. Alternatively, when an amphoteric colloid (such as a protein, such as gelatin) is used, the pH of the colloidal mixture can be adjusted above or below the isoelectric point to impart a suitable charge to the amphoteric colloid.

The complex coacervate can also be produced by electrostatic bonding of cationic and anionic polymers, and by adsorbing on the surface of the core material to form a coacervate shell coating it, complex coacervate particles encapsulating the core material in the coacervate shell can be made. there is.

Coacervate technology is a reaction that occurs spontaneously, so it is easy to manufacture without any additional equipment or energy, but it requires the use of acid and base regulators and crosslinking agents to produce stable particles. However, since the acid, base regulator or crosslinking agent is a chemical, there is a problem that is not environmentally friendly.

Accordingly, as a result of intensive research efforts to overcome the problems of the prior art, the present inventors have completed an eco-friendly and stabilized novel coacervate particle manufacturing method by replacing the acid, base regulator or crosslinking agent with a natural material-based raw material.

KR 10-2020-0116870 A KR 10-1810540 B

Accordingly, the main object of the present invention is to provide a method for producing complex coacervate particles that is more environmentally friendly and more stable than conventional methods.

Another object of the present invention is to provide environmentally friendly and stabilized composite coacervate particles prepared by the above production method.

According to one aspect of the present invention, the present invention provides a method for producing environmentally friendly and stabilized composite coacervate particles comprising the following steps:

(a) preparing a core material to be encapsulated in coacervate particles;

(b) preparing a coacervate emulsion by homogenizing a cationic polymer and an anionic polymer in an aqueous phase;

(c) adding the core material of step (a) to the coacervate emulsion of step (b);

(d) adding an acidic natural product or basic natural product to adjust the pH; and

(e) adding high-molecular-weight hyaluronic acid and low-molecular-weight hyaluronic acid as stabilizers for stabilizing the coacervate particles; and

(f) recovering coacervate particles after washing the precipitate separated from the product of step (e).

In the present invention, the core material of step (a) may include any material that can be encapsulated in the coacervate shell, and may be both a water-soluble material or a fat-soluble/poorly-soluble material. A water-soluble substance is a substance that cannot be dissolved in a simple aqueous phase, and has characteristics that are less stable due to factors such as strong odor or light, heat, pH, salt, etc. Vitamin U, vitamin C, glutathione, tannic acid, etc. You can choose. Common oils as fat-soluble substances include dimethicone, hydrogenated C6-14 olefin polymer, diphenylsiloxy phenyl trimethicone, mineral oil, caprylic/capric triglyceride, and C18-21 alkanes. It may contain more than one oil, and as vegetable oil, one or more kinds may be selected from meadowfoam seed oil, sunflower seed oil, camellia oil, olive oil, grapeseed oil, and fermented camellia oil. Substances that are insoluble in water are insoluble in water and have low stability due to factors such as light, heat, pH, and salt. One or more types can be selected from routines, etc.

In the present invention, preferably, the core material of the step (a) is a pharmaceutical or cosmetic active material. In the embodiment of the present invention, as a cosmetic active material, cholesteryl liquid crystal, which is a component of skin intercellular lipids, has excellent skin moisturizing effect and has excellent visual aesthetic effects due to its optical specificity, was used as a core material.

In the present invention, the cationic polymer in step (b) may be any cationic polymer capable of being cationicly charged and electrostatically bonded with anionic polymer to form a complex coacervate, but preferably, a cationic polymer Characterized in that the sexual polymer is at least one selected from the group consisting of agar, xanthan, gelatin, tylcellulose, polyacrylate, carboxyvinyl polymer, polyamide, polyvinyl alcohol, polyvinylpyrrolidone, albumin, chitosan, or polylysine. It provides a method for producing composite coacervate particles.

In the present invention, the anionic polymer in step (b) may be any anionic polymer capable of forming a complex coacervate by being anionically charged and electrostatically bonded to the cationic polymer, but preferably, Arabic At least one selected from the group consisting of gum, carboxymethylcellulose, gelatin, gellan, carboxyvinyl polymer, low methoxyl pectin, xanthan gum, sodium carboxymethyl guar gum, sodium hyaluronate, alginate, dextran sulfate, alginic acid, or carrageenan It provides a method for producing composite coacervate particles, characterized in that.

In the present invention, the acidic natural product or basic natural product in step (d) may be any natural product capable of adjusting pH by being acidic or basic, but preferably, the acidic natural product is an amino acid complex, lemon extract, or lemon fermented vinegar. , Aloe vera extract, AHA / BHA complex, or a natural product selected from vitamin extracts, and the basic natural product is avocado extract, celery extract, broccoli extract, barberry extract, yellow white extract, resurrection plant water, snail slime extract, black pearl extract, or menthol extract. It provides a method for producing complex coacervate particles characterized in that they are selected natural products.

In the present invention, as the stabilizer in step (e), the high molecular weight hyaluronic acid has an average molecular weight of 500,000 to 3,000,000 Daltons, and the low molecular weight hyaluronic acid has an average molecular weight of 500 to 50,000 Daltons. . In the present invention, the weight ratio of high-molecular-weight hyaluronic acid and low-molecular-weight hyaluronic acid is preferably 1:1 to 5:1, most preferably 2:1. As the ratio of the high molecular weight hyaluronic acid increases, the complex coacervate particles are hardened, which may be more helpful in stabilization.

In the experimental example of the present invention, it was confirmed that the stabilization effect was higher when high-molecular and low-molecular-weight hyaluronic acid were used together, compared to when only high-molecular-weight hyaluronic acid or low-molecular-weight hyaluronic acid was used. Conventionally, hyaluronic acid (HA) is used as a kind of anionic polymer for making coacervates, whereas in the present invention, hyaluronic acid (HA) is used as a stabilizer for stabilizing coacervates.

In the present invention, preferably, the stabilizer in step (e) further comprises at least one stabilizer selected from silica or block copolymers in addition to high-molecular and low-molecular-weight hyaluronic acid. to provide. In the present invention, it is preferable to use a block copolymer having a hydrophilic/lipophilic group at the same time as the block copolymer, and for example, a PEG-PCL copolymer or a PS-PCL copolymer may be used. In the experimental example of the present invention, it was confirmed that the stabilization effect was higher when silica and a block copolymer were further included in addition to the high-molecular and low-molecular-weight hyaluronic acid, compared to the case containing only the high-molecular-weight and low-molecular-weight hyaluronic acid. The stabilizer in step (e) stabilizes the coacervate or increases strength through linker connection or matrix formation.

According to another aspect of the present invention, the present invention provides a composite coacervate particle in which a core material prepared by the production method of the present invention is encapsulated.

In the present invention, the primary stabilizer, which is preferably silica or block copolymer, is arranged like a linker between the coacervate shell and the core material, and the secondary stabilizer, which is high molecular weight or low molecular weight hyaluronic acid, is outside the coacervation shell. It provides a composite coacervate particle characterized in that it is oriented on the side to form a matrix shell.

According to the present invention, it is possible to provide an eco-friendly and stable method for preparing new coacervate particles by replacing chemical acids, base regulators and crosslinking agents conventionally used to prepare complex coacervate particles with natural materials. In addition, by using hyaluronic acid (HA) as a new stabilizer, it is possible to provide a method for preparing complex coacervate particles that stabilizes coacervate or increases strength through matrix formation or linker connection.

1 is a schematic view showing the structure and manufacturing method of the complex coacervate particles of the present invention.
Figure 2 is a photograph of a comparative experiment of 25 ℃ stability after 3 months of complex coacervate particles according to Examples and Comparative Examples of the present invention (Figure 2a is Example 1-3, Figure 2b is Comparative Example 1-4)

Hereinafter, the present invention will be described in more detail through examples. Since these examples are intended to illustrate the present invention only, the scope of the present invention is not to be construed as being limited by these examples.

Examples and Comparative Examples: Preparation of Complex Coacervate Particles

(a) preparing an active ingredient to be encapsulated in coacervate particles

In the ratios shown in Table 1 below, cholesteryl chloride (CC), cholesteryl stearate (CS), and cholesteryl benzoate (CB) were homogenized using AZI MIXER at high temperature (70-80 degrees) By mixing, a cholesteric liquid crystal composition exhibiting various colors was prepared.

Content (g)
raw material name liquid crystal 1 liquid crystal 2 LCD 3 LCD 4 cholesteryl chloride (CC) 3.0 2.5 2.0 3.5 Cholesteryl Stearate (CS) 6.0 4.0 3.0 5.0 cholesteryl benzoate (CB) 1.5 4.0 5.0 2.0

(b) preparing a coacervate emulsion by homogenizing a cationic polymer and an anionic polymer in an aqueous phase;

Agar as a cationic polymer was put in purified water to make a 5% solution, carrageenan as an anionic polymer was put in purified water to make a 5% solution, and then the two solutions were homogenized with AZI MIXER at 500 rpm for 30 minutes to prepare a coacervate emulsion.

(c) adding the liquid crystal raw material of step (a) to the coacervate emulsion of step (b);

Among the cholesterol liquid crystal compositions prepared in (a), the cholesteryl liquid crystal (CLC) made of liquid crystal 1 was put into the aqueous emulsion of step (b) and encapsulated in coacervate particles using AZI MIXER.

(d) adding an acidic or basic natural product to adjust the pH;

Coacervation can be induced by adjusting the pH to 7 to 9 using lemon extract as an acidic natural product and resurrection plant water as a basic natural product.

(e) adding a stabilizer to cure the coacervate particles;

In the present invention, high-molecular HA (Mw 1.8 ~ 0.6 Mda), low-molecular HA (Mw 0.5 ~ 10.1 Kda, silica, and PEG-PCL block copolymer were used as stabilizers. As a positive control, GA, widely known as a crosslinking agent for curing coacervate, was used. (Glutaraldehyde) was used The raw material names and contents used in Examples and Comparative Examples are shown in Table 2 below.

Content (g)
raw material name Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 cholesteric liquid crystal One One One One One One One baby 0.5 0.5 0.5 0.5 0.5 0.5 0.5 carrageenan 0.7 0.7 0.7 0.7 0.7 0.7 0.7 Lemon Extract 3 3 3 3 3 3 3 Resurrection Seconds 5 5 5 5 5 5 5 small molecule HA One One One - One - - polymer HA 2 2 5 2 - - - PEG-PCL block copolymer - 0.5 0.5 0.5 0.5 0.5 - Silica - 0.3 0.3 0.3 0.3 0.3 - GA - - - - - - 3

(f) recovering coacervate particles after washing the precipitate separated from the emulsion;

Wash with purified water to remove unreacted substances from coacervation and to obtain coacervate particles (HA-Ball) (repeated 3 times)

Figure 1 shows a schematic diagram of the structure and manufacturing method of the complex coacervate particles (HA-Ball) of the present invention prepared according to the above example.

Experimental Example 1: Stability test of complex coacervate particles

조건에서 제조 직후, 1개월 경과후, 3개월 경과후로 나누어 관찰했다. 평가는 입자 안정도에 따라 X: 입자 터짐, △: 약간 변함, ○: 입자 안정, ●: 입자 경화로 표시하였다. In order to compare the stability of the composite coacervate particles prepared according to the above examples and comparative examples, the state of the particles dispersed in purified water was

Conditions were observed immediately after manufacture, after 1 month, and after 3 months. Evaluation was expressed as X: Particle burst, △: Slight change, ○: Particle stability, ●: Particle hardening according to particle stability.

of particles
appearance Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 immediately after manufacturing ○ ○ ○ X X X ○ 1 month old ○ ○ ○ X X X ○ 3 months △ ○ ● X X X ○

As shown in the table above, in Examples 1 to 3 (HA-Ball) using high-molecular and low-molecular-weight HA as a stabilizer according to the present invention, the particles did not burst and the stability was maintained until 3 months later. However, in Comparative Examples 1 to 3, in which only high-molecular or low-molecular-weight HA was used as a stabilizer, or both were not used, the particles burst immediately after manufacture, and stability was not maintained. When only high-molecular and low-molecular-weight HA was used as a stabilizer (Example 1), the particles showed slight changes after 3 months, but it was much more stable than when only high-molecular or low-molecular-weight HA was used or neither was used (Comparative Examples 1 to 3). showed up When the content of the polymer HA was high (Example 3), the particles showed curing after 3 months, but the particles did not burst as in Comparative Examples 1 to 3. When both high and low molecular weight HA, silica, and block copolymers were included as stabilizers (Example 2), the particles were most stably maintained until after 3 months.

High-molecular and low-molecular-weight HA enhances stability by forming a matrix shell at the outermost part of the complex coacervate particle (HA-Ball). Silica and block copolymers are arranged like a linker between the CLC in the core and the coacervation shell to act as a stabilizer that lowers the interfacial energy. As in Example 2, the HA-Ball is most stable when the primary stabilizer (silica, block copolymer, etc.) and the secondary stabilizer (high/low molecular weight HA) are present together. When only the 1st or 2nd stabilizer is used, particles are well formed in the initial months, but HA-Ball particles may change or break as additional months pass.

Figure 2 is a photograph of a comparative experiment of 25 ° C stability of composite coacervate particles according to Examples and Comparative Examples of the present invention after 3 months (Example 1-3, Comparative Example 1-4 in order) Example 1-3 and In Comparative Example 4, the stability of the particles was maintained, but in Comparative Examples 1-3, the stability was not maintained because the particles burst.

Cosmetics of various formulation examples were prepared using the composite coacervate particles (HA-Ball) of Example 2.

Formulation Example 1: Preparation of lotion containing HA-Ball composition

A lotion was prepared in a conventional manner with the composition described in the table below.

ingredient content(%) HA-Ball 0.5 carbomer 0.05 tromethamine q.s Glycerin 3 BG 4 PEG-60 Hydrogenated Castor Oil 0.3 EDTA 0.02 preservatives, flavorings q.s Purified water To 100

Formulation Example 2: Preparation of Essence Containing HA-Ball Composition

Essence was prepared by a conventional method with the composition described in the table below.

ingredient content(%) HA-Ball One Hydroxyethyl Acrylate/Sodium Acryloyldimethyltaurate Copolymer 0.2 Glycerin 7 BG 5 allantoin 0.1 betaine 0.2 Polyglyceryl-10 Stearate 0.1 EDTA 0.02 preservatives, flavorings q.s Purified water To 100

Formulation Example 3: Preparation of nutritious cream containing HA-Ball composition

Nutritional cream was prepared in a conventional manner with the composition described in the table below.

ingredient content(%) HA-Ball 0.5 Ammonium Acryloyl Dimethyl Taurate/VP Copolymer 0.3 Glycerin 5 BG 7 squalane 2 Caprylic/Capric Triglyceride 3 Sorbitan Stearate One cetearyl alcohol One polysorbate 60 0.5 EDTA 0.02 preservatives, flavorings q.s Purified water To 100

Although the above embodiments have been referred to and described for the present invention, these are merely examples, and those skilled in the art will understand that various modifications and equivalent other embodiments are possible therefrom. . Therefore, the true technical protection scope of the present invention will be determined by the technical details of the appended claims.

Claims (8)

A method for producing environmentally friendly and stabilized complex coacervate particles comprising the following steps:
(a) preparing a core material to be encapsulated in coacervate particles;
(b) preparing a coacervate emulsion by homogenizing a cationic polymer and an anionic polymer in an aqueous phase;
(c) adding the core material of step (a) to the coacervate emulsion of step (b);
(d) adding an acidic natural product or basic natural product to adjust the pH; and
(e) adding a high molecular weight hyaluronic acid having an average molecular weight of 500,000 to 3,000,000 daltons and a low molecular weight hyaluronic acid having an average molecular weight of 500 to 50,000 daltons as a stabilizer for stabilizing the coacervate particles; and
(f) recovering coacervate particles after washing the precipitate separated from the product of step (e). The method of claim 1, wherein the cationic polymer of step (b) is agar, xanthan, gelatin, ethyl cellulose, polyacrylate, carboxyvinyl polymer, polyamide, polyvinyl alcohol, polyvinylpyrrolidone, albumin, chitosan, Or a method for producing composite coacervate particles, characterized in that at least one selected from the group consisting of polylysine. The method of claim 1, wherein the anionic polymer in step (b) is gum arabic, carboxymethylcellulose, gelatin, gellan, carboxyvinyl polymer, low methoxyl pectin, xanthan gum, sodium carboxymethyl guar gum, sodium hyaluronate, alginate , A method for producing complex coacervate particles, characterized in that at least one selected from the group consisting of dextran sulfate, alginic acid, and carrageenan. The method of claim 1, wherein the acidic natural product in step (d) is a natural product selected from amino acid complex, lemon extract, lemon fermented vinegar, aloe vera extract, AHA/BHA complex, or vitamin extract, and the basic natural product is avocado extract, celery extract , Broccoli extract, barberry extract, yellow white extract, resurrection plant water, snail mucus extract, black pearl extract, or menthol extract. delete The method of claim 1, wherein the stabilizer in step (e) further comprises at least one stabilizer selected from silica or block copolymers in addition to high-molecular and low-molecular-weight hyaluronic acid. A composite coacervate particle encapsulated with a core material prepared by the method of any one of claims 1 to 4 and 6. The method of claim 7, wherein the primary stabilizer, which is silica or a block copolymer, is arranged like a linker between the coacervate shell and the core material, and the secondary stabilizer, which is a high molecular weight or low molecular weight hyaluronic acid, is oriented outside the coacervation shell. A composite coacervate particle characterized in that it forms a matrix shell.

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