KR102048710B1 - Biodegradable fructose 1,6-bisphosphate stabilizing capsule, the method for preparing the same, and the cosmetic composition containing the same - Google Patents

Abstract

The present invention relates to a fructose 1,6-bisphosphate stabilizing capsule, and more specifically, the electrostatic between the phosphate group of the fructose 1,6-bisphosphate and oligopeptides having a molecular weight of about 1,000 Biodegradable capsules capable of stabilizing fructose 1,6-bisphosphate by generating nuclei by miracle bonds and encapsulating them with amphiphilic block polymers composed of biodegradable polymers, methods for preparing the same, and cosmetic compositions comprising the capsules It is about.

Description

Biodegradable fructose 1,6-bisphosphate stabilizing capsule, the method for preparing the same, and the cosmetic composition containing the same}

The present invention relates to a fructose 1,6-bisphosphate stabilized capsule, and more specifically, the electrostatic between the phosphate group of the fructose 1,6-bisphosphate and oligopeptides of molecular weight 1,000 or more Biodegradable capsules capable of stabilizing fructose 1,6-bisphosphate by generating nuclei by miracle bonding and encapsulating them with amphiphilic block polymers composed of biodegradable polymers, methods for preparing the same, and cosmetic compositions comprising the capsules It is about.

Various stabilization methods have been proposed for utilizing chemically labile substances as cosmetic compositions. Representative stabilization methods include the derivatization of the compound, which can be seen in the Republic of Korea Patent Registration No. 10-0437102 (June 23, 2004), high reactivity material through a chemical reaction with other substances Chemical groups that cause denaturation of the chemicals are protected by a protection reaction, and then introduced into the body. However, these methods do not have a large degree of stabilization, and the compounds produced through the protective reaction are very low in returning to their original state of activity, and thus contain two to three times as much as pure substances. It can cause other problems. Another method is to encapsulate the active substance using a hydrophobic polymer and redisperse it again in the cosmetic composition. However, these methods can be used only for oil soluble active materials, as the hydrophobic polymer and solubility parameter should be similar. On the other hand, when the encapsulation is attempted with a hydrophilic polymer, it is easily dissolved in water due to the nature of the water-soluble polymer, and thus, the stabilizing effect by the barrier layer cannot be expected because the active substance is eluted into the water phase. In addition, many techniques have been introduced for capturing and encapsulating electrostatically soluble substances using cationic molecules such as chitosan and applying them to cosmetics. However, chitosan is a raw material derived from animals and used as an allergic reaction. It is known and has limitations in use. In addition, due to the cationic surface properties, there is a property to inhibit the long-term stability of the cosmetic formulation by electrostatically coupled with a polyacrylic acid-based surfactant mainly used in cosmetics.

As such, there are not many methods that can be utilized for stabilizing a hydrophilic active substance such as fructose 1,6-bisphosphate, and even if used, there is a problem that skin side effects and extremely limited formulation should be used.

Republic of Korea Patent No. 10-0437102

The present invention is to solve the problems appearing in the prior art, to stabilize the fructose 1,6-bisphosphate, to provide a technique that can be easily prepared capsules containing the same and utilized in various cosmetic formulations The purpose.

In order to achieve the above object, the present invention is a capsule core comprising a phosphate group of fructose 1,6-bisphosphate and oligopeptide having a molecular weight of 600 ~ 1,500; And it provides a biodegradable fructose 1,6-bisphosphate stabilized capsule consisting of a capsule film containing a biodegradable polymer.

In addition, the present invention 1) preparing a capsule core by forming a conjugate of the phosphate group of fructose 1,6-bisphosphate and oligopeptide having a molecular weight of 600 ~ 1,500; 2) dissolving the biodegradable polymer in a mixture of the binder dispersed in an organic solvent; And 3) preparing a capsule coating by mixing the mixture in which the biodegradable polymer is dissolved with water to form a self-aggregate. The manufacturing method of the biodegradable fructose 1,6-bisphosphate stabilized capsule comprising the to provide.

The present invention also provides a cosmetic composition comprising the biodegradable fructose 1,6-bisphosphate stabilized capsule.

The biodegradable polymer nanocapsules according to the present invention can be more simply prepared polymer nanocapsules for active substance delivery by a differentiated process, the nanocapsules prepared as described above captures the active substance at the level of nanometer particles It is possible to maximize the efficacy of the active substance, while maintaining the initial activity of the active substance. Thereby, the activity of the active substance is stably maintained by the capsule in the formulation, but when applied to the skin, the capsule is easily broken so that the active substance can act effectively on the skin.

1 shows a TEM image of the fructose 1,6-bisphosphate stabilized capsule of the present invention.
2 shows the particle size of fructose 1,6-bisphosphate stabilized capsules.
3 shows that fructose 1,6-bisphosphate stabilized capsules are degraded by lipase enzymes to release fructose 1,6-bisphosphate (red: Example 1, blue: Comparative Example 2).

Hereinafter, embodiments of the present invention will be described. In the following description, the description of the technical configuration and the like already well known in the art will be omitted. Even if this description is omitted, those skilled in the art can easily understand the features of the present invention through the following description.

In general, a method of using polymer particles as a method for stabilizing unstable potency materials has been widely studied. However, simply encapsulating the oil-soluble active substance in the polymer particles does not completely stabilize the active substance, especially when the particles are used in a formulation such as cosmetics, the polymer swells with water, surfactants, oils, etc. in the formulation. Due to this, the unstable active material may have a problem such as slowly flowing out to the outside for a long time.

Accordingly, in the present invention, there is provided a fructose 1,6-bisphosphate stabilized capsule, wherein the capsule is composed of a capsule core portion that is the inside of the capsule, and a capsule coating portion surrounding the outside of the capsule core, the capsule core Is a part containing a combination of fructose 1,6-bisphosphate and oligopeptide, and the capsule coating is a part containing a biodegradable polymer.

Specifically, in the present invention, by adsorbing and trapping the active material fructose 1,6-bisphosphate to the cationic functional group of the oligopeptide in the molecular weight range 600 ~ 1,500 having a high diffusion rate by the molecular weight effect, cationic groups and fructose Induces electrostatic bonding between 1,6-bisphosphate molecules to form a fructose 1,6-bisphosphate-oligopeptide conjugate to prepare a capsule core, thereby immobilizing fructose 1,6-bisphosphate in a capsule This makes it possible to stabilize fructose 1,6-bisphosphate. Thus, the formation of a combination of fructose 1,6-bisphosphate prevents the outflow of fructose 1,6-bisphosphate in the capsule, and also stabilizes it once again in the capsule by the outer barrier formed by the polymer, thereby double stabilization. To provide a system.

Oligopeptides that can be used in the present invention are components containing an amino acid having a (+) group such as lysine, histidine, arginine, alone or in a mixed form.

Fructose 1,6-bisphosphate stabilized capsules may contain up to 50% by weight of fructose 1,6-bisphosphate relative to the total weight of the capsule, if exceeded may result in crystal precipitation during manufacture.

Hereinafter, the manufacturing method of the present invention will be described in detail for each step.

The method for preparing nanocapsules used in the present invention is not particularly limited, but preferably, a general nano precipitation method may be used, and specifically includes the following steps:

i) inducing an electrostatic attraction between phosphate groups of fructose 1,6-bisphosphate and oligopeptides having a molecular weight of 600-1,500 in organic solvents such as ethanol to form a fructose 1,6-bisphosphate-oligopeptide conjugate step

ii) separating the fructose 1,6-bisphosphate-oligopeptide conjugate;

iii) dispersing the isolated fructose 1,6-bisphosphate-oligopeptide conjugate in an organic solvent to prepare a mixture;

iv) dissolving the biodegradable polymer in the mixture;

v) mixing the mixture in which the biodegradable polymer is dissolved with water to form a magnetic assembly;

vi) removing the solvent under reduced pressure.

The oligopeptides used in the present invention are those having a molecular weight of about 600 to 1,500, preferably about 1,000, the complex is not formed effectively when the molecular weight is less than 600, when absorbing the skin when using more than 1,500 It is not easy and the efficacy is halved.

A capsule core is prepared by dispersing fructose 1,6-bisphosphate and oligopeptides in a suitable organic solvent to form an organic phase and then forming a fructose 1,6-bisphosphate-oligopeptide conjugate in the organic phase. The organic solvent that can be used at this time is not particularly limited, but may be preferably mixed with water, and a non-toxic solvent having a lower vapor pressure than water may be used, and more preferably, water solubility such as methanol, ethanol, isopropanol, etc. It is possible to use alcohols which are very excellent and can be easily removed by evaporation under reduced pressure.

The formed binder is then separated and the separated binder is redispersed in a suitable organic solvent to prepare a mixture. The organic solvent used here is the same as the organic solvent used in the formation of the fructose 1,6-bisphosphate-oligopeptide conjugate, and can be mixed with water and use a non-toxic volatile solvent having a lower vapor pressure than water.

The biodegradable amphiphilic polymer, which can then form a self-assembly, is dissolved in the mixture. The amphiphilic polymer that can be used at this time is not particularly limited, but preferably, the molecular weight of the amphiphilic polymer is in the range of 1,000 to 100,000, and the hydrophobic group of the amphiphilic block polymer is polyglycolide, polylactide, polycaprolactone And one or a mixture of polyethylene adipates.

Thereafter, water is added to the mixture in which the biodegradable polymer is dissolved, and the mixture is stirred at an appropriate speed, preferably 300 rpm, to form a self-association by mixing the aqueous phase and the organic phase so as to form a capsule film, which is prepared in the form of an emulsion. do.

The organic phase is then evaporated under reduced pressure using a reduced pressure evaporator, whereby only nanocapsules present in the aqueous phase can be separated.

The nanocapsules thus prepared are biodegradable capsules that stabilize fructose 1,6-bisphosphate and have a size of 1 to 1,000 nm.

The present invention also provides a cosmetic composition comprising the biodegradable fructose 1,6-bisphosphate stabilized capsule.

The fructose 1,6-bisphosphate stabilized capsule is contained in an amount of 1 to 50% by weight based on the total weight of the composition. If contained at a higher concentration than this, sub-micron sized particles are not formed.

The cosmetic composition is not particularly limited in the formulation, but soft cosmetics, nourishing cosmetics, massage cream, nutrition cream, pack, gel, essence, lipstick, makeup base, foundation, lotion, ointment, gel, cream, patch, spray It can be formulated as.

Hereinafter, the method of the present invention will be described in more detail with reference to Examples and Comparative Examples, but the scope of the present invention is not limited to the following Examples.

Example 1

To prepare capsules carrying fructose 1,6-bisphosphate, 1 g of fructose 1,6-bisphosphate and oligopeptides derived from peach leaves (silab, France) (cellvitol, molecular weight 1,000 g / mol, lysine and 2 g of arginine) was dispersed in 50 ml of ethanol. Thereafter, the mixture is left to stand for about 30 minutes after sufficiently stirring using a stirrer. The precipitated mixture was centrifuged at about 1000 G for 5 minutes. The resulting mixture was then dispersed in 100 ml of ethanol again and 2 g of the amphiphilic block polymer, polylactide-b-polyethylene glycol polymer (molecular weight 10,000 g / mol), was dissolved together. In addition, 200 ml of distilled water was introduced into a round-bottomed flask, followed by stirring. After obtaining, using a rotary evaporator (Eylela, N1200B) was treated for 1 hour at 45 ℃ under reduced pressure of 10mmhg, ethanol and a small amount of water was evaporated to give a 50ml aqueous solution.

Example 2

Polycaprolactone-b-polyethylene glycol polymer molecular weight 10,000 g / mol) was prepared in the same manner as in Example 1 when preparing the capsule.

Example 3

Polyethylene adipate-b-polyethylene glycol polymer molecular weight 10,000 g / mol) was used in the preparation of the capsule, and prepared in the same manner as in Example 1.

Comparative Example 1

When preparing the capsule was prepared in the same manner as in Example 1 without introducing an oligopeptide.

Comparative Example 2

In preparing capsules, PMMA (Poly (methyl methacrylate)) polymer was used instead of the amphiphilic block polymer to prepare the same method as in Example 1.

Comparative Example 3

When preparing a capsule, using a tripeptide having a molecular weight of 300g / mol, it was prepared in the same manner as in Example 1.

Test Example 1 Confirmation of Polymer Nanocapsule

Morphology of the fructose 1,6-bisphosphate / peach leaf-derived oligopeptide / polylactide-b-polyethylene glycol capsules prepared in Example 1 was observed using a transmission electron microscope (TEM, JEOL, JEM-1400). The results are shown in FIG. 1.

From this, it can be seen that the particles produced in Example 1 are spherical polymer particles.

Test Example 2 Confirmation of Particle Size of Capsule

The particle size of the fructose 1,6-bisphosphate / peach leaf-derived oligopeptide / polylactide-b-polyethylene glycol capsule prepared in Example 1 was observed using DLS (Malvern, Zeta Sizer 3000 HAS), The results are shown in FIG.

It can be seen from this that polymer particles of uniform size are produced.

Table 1 also shows the capsules using the polycaprolactone-b-polyethylene glycol of Example 2 together with the particle size and PDI for Example 1, and the capsules using the polycaprolactone-b-polyethylene glycol of Example 3 The particle size was measured using DLS.

sample Particle size (nm) PDI Example 1 110 nm 0.12 Example 2 100 m 0.13 Example 3 98 nm 0.15

Referring to Table 1, it can be seen that the particle size of Example 3 and Example 2 is about 100 nm and PDI is about 0.2, which is almost the same size as the sample of Example 1.

Test Example 3 Measurement of Biodegradability of Capsule

Biodegradability of fructose 1,6-bisphosphate / peach leaf-derived oligopeptide / polylactide-b-polyethylene glycol capsule and Comparative Example 2 capsule prepared in Example 1 was measured using lipase. The measurement results are shown in FIG. 3.

From this, in the capsule of Example 1, the fructose 1,6-bisphosphate introduced after a certain time is released to the outer layer to biodegrade, whereas in the case of Comparative Example 2 without using a biodegradable amphiphilic block polymer It is stable with this lipase, and it can be seen that the release amount of fructose 1,6-bisphosphate does not increase significantly over time.

Test Example 4 Measurement of Initial Content of Capsule

Initial fructose of fructose 1,6-bisphosphate / peach leaf-derived oligopeptide / polylactide-b-polyethylene glycol capsules prepared in Example 1 and capsules prepared in Examples 2, 3 and Comparative Example 3 Toss 1,6-bisphosphate concentrations were measured using HPC. The measurement results are shown in Table 2 below.

sample Theoretical value (%) Actual content (%) Example 1 2% 1.99% Example 2 2% 1.98 Example 3 2% 2.0 Comparative Example 3 2% 0.2%

From Table 2, the capsules of Examples 1 to 3 contained almost the same fructose 1,6-bisphosphate, which were theoretically introduced at the initial stage, whereas in Comparative Example 3 using a low molecular weight oligopeptide, the fructose in the capsule It can be seen that toss 1,6-bisphosphate is not effectively introduced.

Formulation Example 1

In order to confirm the stabilizing ability of the capsule prepared, a solubilized formulation in the form of a transparent gel having a composition of Table 3 was prepared. The viscosity of the formulation was about 4,000 cps. In addition, the viscosity was measured at 30 degreeC 12 rpm using Brookfield (LVDVII +).

ingredient Content (% by weight) glycerin 5 Propylene glycol 4 Nano Capsule Dispersion
(Example 1, Comparative Example 1) 5 ethanol 10 Sodium Polyacrylate 0.5 antiseptic Appropriate Purified water to 100

Subsequently, the prepared samples were stored in an oven at room temperature and 40 ° C., respectively, and then samples were taken after 1 day, 7 days, 14 days and 28 days to measure the amount of residual active substance using HPLC (waters, separation model 2695). It was. The results are shown in Table 4. As can be seen in Table 4, the fructose 1,6-bisphosphate present in the capsule in the solubilized formulation has excellent stability.

capsule Storage temperature (℃) Initial concentration retention (%) 1 day later 7 days later 14 days later In 28 days Example 1 Room temperature 100 100 100 100 40 100 100 100 100 Comparative Example 1 Room temperature 100 94 93 90 40 100 91 81 71 Fructose 1,6-bisphosphate direct introduction formulation Room temperature 98 92 86 65 40 88 61 48 30

Formulation Example 2

In order to examine the stabilizing effect in the emulsion formulation, each of the oil phase and the water phase in the composition of Table 5 was completely dissolved at 70 ℃, and emulsified at 7,000 rpm for 5 minutes to prepare a lotion in the form of an opaque gel. The viscosity of the lotion was about 2,500 cps.

ingredient Content (% by weight) Stearic acid 2 Cetyl alcohol 2 Lanolin alcohol 2 Liquid paraffin 7 Cyclomethicone 5 Polyoxyethylene monooleic acid ester 2 Preservatives, Antioxidants Appropriate glycerin 3 Propylene glycol 5 Triethylamine One Nanocapsule Dispersion (Example, Comparative Example 1) 10 Sodium Polyacrylate 0.15 Purified water to 100

Subsequently, the prepared samples were stored in an oven at room temperature and 40 ° C., respectively, and the samples were taken after a certain period of time to measure the amount of the remaining active substance using liquid chromatography. The results are shown in Table 6. As can be seen in Table 6, even in suspension emulsion formulation, fructose 1,6-bisphosphate present in the nanocapsule has excellent stability. Through this, the oligopeptide collects fructose 1,6-bisphosphate to maintain chemical structure, prevents the outflow of fructose 1,6-bisphosphate outside the capsule, and blocks external harmful environment by polymer matrix. The superiority of the stabilization system can be confirmed.

capsule Storage temperature Initial concentration retention (%) 1 day later 7 days later 14 days later In 28 days Example 1 Room temperature 100 100 100 100 40 100 100 100 95 Comparative Example 1 Room temperature 100 97 89 84 40 99 91 83 77 Fructose 1,6-bisphosphate direct introduction formulation Room temperature 99 89 85 65 40 89 64 53 39

[Formulation Example 3]

To confirm the stability of the active material collected in the prepared polymer capsules, a cream was prepared in the composition of Table 7 below. The preparation was the same as in Formulation Example 2.

ingredient Content (% by weight) Beads wax 2 Stearyl alcohol 5 Stearic acid 8 Squalane 10 Propylene Glycol Monostearate 3 Polyoxyethylene cetyl ether One Preservatives and Antioxidants Appropriate Propylene glycol 8 glycerin 4 Triethylamine One Capsule Dispersion (Example 1, Comparative Example 1) 10 Purified water to 100

Subsequently, the prepared samples were stored in an oven at room temperature and 40 ° C., respectively, and the samples were taken after a certain period of time to measure the amount of the remaining active substance using liquid chromatography. The results are shown in Table 8. Like the lotion formulation, the cream formulation, it was confirmed that the capsules contributed to the stabilization of fructose 1,6-bisphosphate.

capsule Storage temperature Initial concentration retention (%) 1 day later 7 days later 14 days later In 28 days Example 1 Room temperature 100 100 100 100 40 100 100 100 94 Comparative Example 1 Room temperature 100 98 89 86 40 99 92 81 75 Fructose 1,6-bisphosphate direct introduction formulation Room temperature 99 89 85 65 40 88 61 55 37

From the above results, the fructose 1,6-bisphosphate in the polymer particles were in contact with the external environment due to swelling of the particles by moisture, oil, surfactant, etc. in the cosmetic formulation, and did not show excellent stability. On the other hand, the capsule using the oligopeptide prepared in 1 is effectively phase-separated by forming nuclei in the polymer particles, and stabilizes the chemical structure of fructose 1,6-bisphosphate by chain folding of the polymer main chain of the oligopeptide. Adsorption increased the capturing ability to prevent outflow to the outside of the capsule, showing better stability in the formulation than other systems. The capsules prepared in Example 1 together with the internal oligopeptide groups immobilizing fructose 1,6-bisphosphate significantly reduced the swelling of the particles due to moisture or oil in the formulation by the polymer matrix wall. It is expected to block external stimulation more effectively.

Claims (10)

A capsule core comprising a fructose 1,6-bisphosphate-oligopeptide conjugate formed by combining a phosphate group of fructose 1,6-bisphosphate and a cationic group of an oligopeptide having a molecular weight of 600 to 1,500; And
A biodegradable fructose 1,6-bisphosphate stabilized capsule consisting of a capsule coating containing a biodegradable polymer,
The monomer constituting the oligopeptide is at least one cationic amino acid selected from the group consisting of lysine, histidine and arginine,
The biodegradable polymer is an amphiphilic block polymer having a molecular weight ranging from 1,000 to 100,000 in the group consisting of polylactide-b-polyethylene glycol, polycaprolactone-b-polyethylene glycol, and polyethylene adipate-b-polyethylene glycol Biodegradable fructose 1,6-bisphosphate stabilized capsules, characterized in that at least one selected. delete delete delete As a method for producing biodegradable fructose 1,6-bisphosphate stabilized capsule,
1) preparing a capsule core by forming a fructose 1,6-bisphosphate-oligopeptide conjugate formed by combining a phosphate group of fructose 1,6-bisphosphate with a cationic group of an oligopeptide having a molecular weight of 600 to 1,500;
2) dissolving the biodegradable polymer in a mixture of the binder dispersed in an organic solvent; And
3) preparing a capsule film by mixing the mixture in which the biodegradable polymer is dissolved with water to form a magnetic assembly;
Including;
The monomer constituting the oligopeptide is at least one cationic amino acid selected from the group consisting of lysine, histidine and arginine,
The biodegradable polymer is an amphiphilic block polymer having a molecular weight ranging from 1,000 to 100,000 in the group consisting of polylactide-b-polyethylene glycol, polycaprolactone-b-polyethylene glycol, and polyethylene adipate-b-polyethylene glycol Method for producing a biodegradable fructose 1,6-bisphosphate stabilized capsule, characterized in that at least one selected. delete delete delete 6. The method of claim 5, wherein the organic solvent is a large solvent that can be mixed with water and is non-toxic and having a lower vapor pressure than water. Cosmetic composition comprising a biodegradable fructose 1,6-bisphosphate stabilized capsule according to claim 1.

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