HIGH-CONTENT AND SUSTAINED-RELEASE RETINOID CAPSULE, AND COMPOSITION FOR REDUCING WRINKLES, CONTAINING SAME

Abstract

Provided is a composition for improving wrinkles including a high-content/sustained-release retinoid capsule. The high-content/sustained-release retinoid capsule according to the presently claimed subject matter can minimize skin side effects and maximize wrinkle improvement effects by significantly increasing the retinoid content in the capsule and stability and controlling the release rate.

Claims

1. A retinoid capsule particle comprising a solid lipid shell; and a liquid lipid core, wherein the liquid lipid core comprises a retinoid and an amine compound.

2. The retinoid capsule particle according to claim 1, wherein the retinoid is one or more selected from the group consisting of retinol, retinal, retinoic acid and a retinoid derivative.

3. The retinoid capsule particle according to claim 1, wherein the amine compound is one or more selected from the group consisting of stearylamine, benethamine, hexylamine, heptylamine, octylamine, chlorohexylamine, chloroheptylamine, chlorooxylamine and benzylamine.

4. The retinoid capsule particle according to claim 1 wherein the content of the retinoid is 1 to 20% by weight based on the dry weight of the retinoid capsule particle.

5. The retinoid capsule particle according to claim 1, wherein the retinoid is released from the retinoid capsule particle in a sustained manner.

6. The retinoid capsule particle according to claim 1, wherein the retinoid capsule particle is synthesized by an emulsification process under the condition of low pressure of 0.001 to 0.5 atm and high temperature of 50 to 90° C.

7. The retinoid capsule particle according to claim 1 wherein the retinoid capsule particle has a Polydispersity Index (PDI) value of 0.3 or less, measured by using a dynamic light scattering (DLS) device.

8. (canceled)

9. A composition for improving wrinkles comprising the retinoid capsule particle according to claim 1.

10. The composition for improving wrinkles according to claim 9, wherein the composition is a cosmetic composition.

11. A method for improving skin wrinkles, comprising applying the cosmetic composition according to claim 10 to a subject.

12. (canceled)

13. The retinoid capsule particle according to claim 1, wherein the retinoid is ion-bonded with the amine compound.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] FIG. 1 is a schematic diagram of the high-content/sustained-release retinoid.

[0034] FIG. 2 is the result of the solubility in oil according to the binding of an amine compound and retinoid.

[0035] FIG. 3 is the result of the release amount over time of Comparative example 1 and Example 1.

[0036] FIG. 4 is the result of confirming changes in the epidermis and dermis by cutting the cross section 3 days after applying Example 1, Comparative example 5 and Comparative example 6.

MODE FOR INVENTION

[0037] Hereinafter, the present disclosure will be described in more detail by examples. These examples are intended to illustrate the present disclosure more specifically, and it will be obvious for those skilled in the art that the scope of the present disclosure is not limited by these examples.

[0038] Example 1 is the high-content/sustained-release retinoid capsule.

[0039] Examples 2, 3 and 4 are the retinoid capsules synthesized by the emulsification process at low pressure and high temperature.

[0040] Comparative examples 1, 2 and 3 are the retinoid capsules not containing the amine compound.

[0041] Comparative example 4 is the untreated group (control group).

[0042] Comparative examples 5 and 6 are Stieve A which is a retinoic acid prescription medicine of 0.01% and 0.05%.

[0043] Comparative examples 7 and 8 are the retinoid capsules synthesized by the emulsification process at high pressure and high temperature.

EXAMPLES

I. Production of High-Content/Sustained-Release Retinoid Capsules

[0044] The composition of the retinoid capsules during synthesis included a solid lipid containing glycerol dibehenate and an amine compound (stearylamine); a liquid lipid containing caprylic/capryl triglyceride and an amine compound (stearylamine); and an aqueous solution containing a surfactant (Tween 60) and water (See Table 2; unit is % by weight). The retinoid was comprised in the liquid lipid and the solid lipid was heated to 70° C. and the liquid lipid was heated to 50° C., and a high temperature aqueous solution of the surfactant was mixed using a rotor-stator (Ultra-Turrax, Janke & Kunkel, Germany) at 8000 revolutions per minute for 2 minutes. The obtained capsules were homogenized with an ultrasonic generator and then the remaining surfactant was washed through centrifugation and then they were freeze-dried to complete. In Table 2 below, Example 1 is the high-content/sustained-release retinoid capsule and Comparative examples 1, 2 and 3 are the retinoid capsules not containing the amine compound.

TABLE-US-00002 TABLE 2 Comparative Comparative Comparative Example Composition Substance example 1 example 2 example 3 1 Solid lipid Glycerol dibehenate 4 4 4 3.7 Stearylamine 0 0 0 2 Liquid Caprylic/capryl 2 2 2 3 lipid triglyceride Stearylamine 0 0 0 0.33 Retinoic acid 0.002 0.02 0.2 0.3 Aqueous Surfactant 8 8 8 8 phase Distilled water up to 100 up to 100 up to 100 up to 100 Synthesis or not ◯ X X ⊚ Dry weight of retinoid in the final 0.03 — — 3 capsule after washing (%) ◯: synthesized (PDI > 0.6) X: not synthesized ⊚: Uniformly synthesized (PDI < 0.6)

[0045] As shown in the Table 2, the maximum concentration of the retinoic acid soluble in the liquid lipid was 0.1% of the weight of the liquid lipid, and when added more the above, the retinoic acid was not dissolved, making it impossible to synthesize capsules (Comparative examples 1, 2, 3). On the other hand, it was determined that the solubility of retinoic acid was increased over 10% of the weight of the liquid lipid, when the amine compound at the same mole concentration as retinoic acid was added during dissolving retinoic acid in the liquid lipid (See Table 2). Through this, the dry weight of the retinoid in the final capsule after washing could be increased 100 times from conventional 0.03% to 3%.

II. Confirmation of Release Rate of High-Content/Sustained-Release Retinoid Capsules

[0046] In order to compare the effect of the release rate of the retinoid capsules ion-bonded to the amine compound, Comparative example 1 and Example 1 were diluted to the same concentration, and then the supernatant was collected over time to confirm the release amount of retinoid. As a result, it was confirmed that the release rate was significantly reduced, compared to Comparative example 1 (See FIG. 3).

TABLE-US-00003 TABLE 3 D50 D70 D80 D90 Comparative example 1 13.9 31.8 46.3 78.8 Example 1 75.8 134.2 160 186 (Calc.) (Calc.) (Calc.) D**: Time taken to release up to **%

III. Confirmation of Effects of High-Content/Sustained-Release Retinoid Capsules

[0047] In order to compare the effects of the high-content/sustained-release retinoid capsules, the degree of the effects and side effects were confirmed by applying 0.01% Example and the prescription medicine, Stieva A 0.01% and 0.05% (Comparative examples 5 and 6) using 3D skin (Tegoscience, Korea) consisting of epidermis and dermis, and then culturing it for 3 days and fractionizing skin. The thickness and area of the epidermis, and the collagen amount and density and collagenase yield as the effects, and the amount of Interleukin-1α that is an inflammatory marker as the side effects were confirmed.

[0048] As shown in Table 4 and FIG. 4, it was confirmed that all the indexes of the effects were significantly increased in case of Example 1, compared to Comparative example 4, and the inflammatory index was reduced. Moreover, it could be confirmed that the effects were increased more than Comparative examples 5 and 6 that are the prescription medicine at a high concentration.

TABLE-US-00004 TABLE 4 Effect index Dermis Collagen Epidermis amount and Collagenase Inflammatory index Treatment method Thickness Area density (MMP-1) Interleukin-1α Comparative 100 100 100 100 100 example4 Example1 295 370 251 52 111 Comparative 240 215 166 109 238 example5 Comparative 129 145 147 93 139 example6

IV. Confirmation of Effects According to Reduction of Surfactant of High-Content/Sustained-Release Retinoid Capsules

[0049] In Examples 2, 3 and 4, retinoid capsules were synthesized through the emulsification process at low pressure (0.05 atm) and high temperature (70˜80° C.), and in Comparative examples 7 and 8, retinoid capsules were synthesized through the emulsification process at high pressure (1 atm) and high temperature (70˜80° C.).

[0050] During synthesis of retinoid capsules, when the emulsification process was progressed at high pressure and high temperature, capsules were synthesized in case that the emulsifier content was 25% or higher of the total content excluding water (Table 5, Comparative example 7), and in case that the emulsifier content was reduced, when the temperature was lowered after emulsification, aggregation of lipid occurred and therefore capsules were not synthesized (Table 5, Comparative example 8). In addition, also in case that the emulsifier content was 25% or higher of the total content excluding water, a micrometer size of particles were included besides a nanometer size of particles and therefore polydisperse index (PDI) was not uniform. It was confirmed that during the emulsification process progressed in the present disclosure, when the emulsification was proceeded with the reduced pressure in the reactor, the synthesis of capsules was possible even when the emulsifier content was 10% or less of the total content excluding water, and uniform particles in the minodisperse form with the PDI value of 0.3 or less were formed.

[0051] The emulsifier is an element which can irritate the skin, and therefore, retinol capsules having reduced emulsifier content may reduce skin irritation. Through determining interleukin 1-a as an inflammatory index using cellular experiment, it was confirmed that in case of retinol capsules having reduced emulsifier content, the inflammatory index was reduced by more than 40% compared to the retinol capsules having the conventional emulsifier content.

TABLE-US-00005 TABLE 5 Comparative Comparative Example Example Example Composition Substance example 7 example 8 2 3 4 Solid lipid Glycerol 6 6 6 6 6 dibehenate Stearylamine 3 3 3 3 3 Liquid lipid Caprylic/capryl 5 5 5 5 5 triglyceride Stearylamine 1 1 1 1 1 Retinol 2.5 2.5 2.5 2.5 2.5 Aqueous Surfactant 6.5 3 6.5 3 1.5 phase Distilled water up to 100 up to 100 up to 100 up to 100 up to 100 Synthesis or not X ⊚ ⊚ ⊚ Dry weight of retinoid in the — 10.4 12.1 13.1 final capsule after washing (%) Polydispersity index (PDI) 0.6 X 0.08 0.18 0.21

[0052] In the above, the applicant has described preferable examples of the present disclosure, but these examples are only one example which implements the technical spirit of the present disclosure, and any modification or alteration should be interpreted as belonging to the scope of the present disclosure as long as it implements the technical spirit of the present disclosure.