KR20130036997A - Microemulsion type hydrogel comprising processed ginseng - Google Patents

Abstract

PURPOSE: A micro emulsion hydro gel which contains processed ginseng as an active ingredient is provided to be used as external preparation of skin for skin improvement by penetrating and localizing processed ginseng within skin. CONSTITUTION: A micro emulsion hydro gel comprises 0.02-3.0 wt% of processed ginseng, 5.0-15.0 wt% of Isopropyl myristate, 15.0-60.0 wt% of surfactant, 0.5-5.0 wt% of gelling agent, and residual water. Processed ginseng is steamed and is dried at 110 to 130>= for two to four hours.

Description

Microemulsion type hydrogel comprising processed ginseng containing processed ginseng as an active ingredient

The present invention relates to a microemulsion-based hydrogel that can be applied to topical skin, although it is expected to improve skin, such as skin whitening, regeneration and anti-wrinkle effect, but hardly soluble and difficult to absorb skin with a molecular weight of 500 Da or more.

In addition to protecting the body from the outside, the skin has functions necessary for maintaining homeostasis such as temperature control, sebum secretion and hair growth. If the function of the skin is imbalanced due to external chemical, physical stimulation, stress, and nutrition, the activity of the cells present in the skin is reduced, and the components of the skin do not maintain their original stable structure, resulting in wrinkles.

The components constituting the dermal dermis include cells such as fibroblasts and endothelial cells, and substances constituting extracellular matrix (ECM) such as collagen, elastin and fibronectin. These ECM constituents form and stabilize the structure of the dermis, which when abnormally produced or degraded, affects the structure of the entire skin, causing wrinkles on the skin and reduced skin elasticity.

Many studies have been conducted to restore skin's intrinsic function from skin aging and to inhibit skin wrinkles by activating skin cells. Wrinkle prevention and improvement cosmetics currently used are representative products containing vitamin A (retinol) or retinyl palmitate. However, products containing these raw materials are not only sensitive to changes over time, but also involve significant skin irritation if they penetrate or degrade the skin beyond its effective concentration.

Therefore, substances obtained from various natural products are used in cosmetics to suppress aging. Among them, the interest in ginseng extract (ginseng extract) is very high, and steady research is being conducted. Looking at the research direction of the ginseng extract in the meantime, the root or leaf extract of ginseng, ginseng saponin (ginseng saponin), ginseng aglycon (glycon) and ginseng polysaccharides have been used.

Ginseng saponins are glucose, rhamnose, xylose, and arabinose in the alcoholic OH groups at the R1, R2, and R3 positions of the non-sugar moiety, a triterpene of the dammaran type. Sugars such as) has an ether-bonded structure, a total of 29 species have been identified in ginseng to date. Each component of the ginseng saponin was named ginsenoside as a glycoside contained in Shibata ginseng in 1964, and it was an oleine-based saponin in order of the distance separated from thin layer chromatography (TLC). Ginsenoside-Ro and ginsenoside-Ra, -Rb1, -Rb2, -Rc, -Rd, -Re, -Rf, -Rg1, -Rg2, -Rg3 and -Rh were named.

 This ginseng saponin was found to be different in chemical structure and pharmacological efficacy from the saponins of other plants contained in about 750 kinds of plants. In particular, ginseng saponin was found to be very mild, not toxic by overdose, and hardly hemolytic.

In addition, in order to apply ginseng saponin as a raw material of anti-aging products, the efficacy of ginseng saponin in the skin has been confirmed and promotes the production of TGF-β1, which is expected to have the greatest effect on the formation of ECM to maintain skin structure. In addition, the anti-wrinkle effect is known by promoting the biosynthesis of type 1 procollagen (type I procollagen) and fibronectin (fibronectin).

However, the cosmetics containing such ginseng extract, extract, polysaccharide and ginseng saponin contain a very small amount of the active substance showing the wrinkle improvement effect has a disadvantage that the effect is not significantly superior to other raw materials used for wrinkle improvement.

In addition, most ginseng saponins are poorly soluble in water and have a molecular weight of 500 g / mol or more, penetrating the stratum corneum and reaching the dermal layer, which is a functioning point. The quantitative and qualitative evaluation of how much ginsenoside reaches the dermal layer, which is the point of action in the skin, has not been performed.

Therefore, when ginseng saponin is administered to the skin for the purpose of skin improvement, first, it overcomes the problem of overcoming the low solubility of ginsenoside, an active ingredient, and reaching the dermal layer through the stratum corneum, the skin barrier. And it is necessary to develop a topical skin application formulation that can effectively deliver the active ingredient to the desired site.

On the other hand, various formulations are being studied to apply the drug to the topical skin, but among them, it is applicable to both hydrophilic and hydrophobic drugs, and there are many studies on microemulsions that are thermodynamically stable, have high solubility, and are easy to manufacture. It is becoming. In addition, microemulsions are known to reduce skin barrier properties of the stratum corneum, which is a permeation barrier for skin absorption, and act as a skin absorption enhancer, thereby showing excellent skin permeability.

Thus, the present inventors conducted a study of a microemulsion hydrogel for the development of a topical application of processed ginseng, and the o / w microemulsion containing the processed ginseng was easily applied to the skin by the water phase of the outer layer, and processed ginseng Labrasol and propylene glycol, which are used as surfactants to maintain the oil phase, not only improve skin permeation but also are non-toxic and suitable for bioavailability. Phospholipids are one of the skin constituents. Due to its binding power, it can enhance the skin retention effect of processed ginseng, and the gelling agent can improve the viscosity and overcome the disadvantage that the active ingredient can not be absorbed sufficiently due to the long lasting on the skin when the microemulsion is administered. The present invention was completed.

Therefore, an object of the present invention is a microemulsion-based hydrogel that can be applied to topical skin processed ginseng components that are expected to improve skin, such as skin whitening, regeneration and anti-wrinkle effect, but poorly soluble and difficult to absorb skin with a molecular weight of 500 Da or more. To provide.

In order to achieve the above object, the present invention comprises 0.02 to 3.0% by weight of processed ginseng, 5.0 to 15.0% by weight of isopropyl myristate, 15.0 to 60.0% by weight of surfactant, 0.5 to 5.0% by weight of the gelling agent and the balance of water It provides a microemulsion hydrogel.

The processed ginseng plays the role of an active ingredient that exhibits a pharmacological effect, and when present in excess of the content range, excessive precipitation of the processed ginseng may occur, whereas when present in a small amount, the processed ginseng may have less transition to the skin, thereby achieving the desired pharmacological effect. Can not get

As the processed ginseng, steamed ginseng dried at 110 to 130 ° C. for 2 to 4 hours, preferably 3 hours, extracted with an alcohol of C1 to C4, preferably methanol, and then removed under reduced pressure. In one embodiment, the processed ginseng is stored in a plant herbarium of Seoul National University College of Pharmacy ginseng cultivated in Geumsan, Chungnam, and steamed for 3 hours using an autoclave at 110 to 130 ℃ The mixture can be extracted with methanol, and then depressurized to remove methanol.

The processed ginseng includes ginsenoside Rg3, in particular ginsenoside Rg1 (0.22-0.27, w / w), Rg2 (0.30-0.32, w / w), Rg3 (0.62-0.32, w / w), Rg5 (0.35-0.64%, w / w) etc. are preferable.

In particular, ginseng saponins are increased in the components of red ginseng processed by heating ginseng than in white ginseng dried as it is, and moreover at 110-130 ° C., which is higher than ordinary red ginseng usually prepared at 98-100 ° C. The ginseng saponin component is further increased in steamed and dried processed ginseng over time.

The isopropyl myristate serves as a solvent for preparing the active ginseng as an active ingredient in an oil phase, and when present in excess of the content range, excessive skin irritation may occur, and microemulsions are broken and microemulsion formation occurs. In order to change the content of each component is required. On the other hand, the presence of a small amount is not enough to dissolve the processed ginseng, and as in the case of an excessive amount, it is impossible to form a microemulsion and may cause a problem requiring control of each component content to form.

The surfactant may include any one or two or more selected from the group consisting of Labrasol, propylene glycol, and phospholipids, and more preferably include all of Labrasol, propylene glycol, and phospholipids. can do.

Therefore, the microemulsion hydrogel according to the present invention is processed ginseng 0.02 to 3.0% by weight, isopropyl myristate 5.0 to 15.0% by weight, Labrasol 5.0 to 20.0% by weight, propylene glycol 5.0 to 20.0% by weight, Phospholipid 5.0 to 20.0% by weight, gelling agent 0.5 to 5.0% by weight and the balance of water.

Labrasol (Labrasol) is a main surfactant used in the present invention not only improves skin permeation but is also non-toxic suitable for bioavailability, and in particular does not cause any irritation even after prolonged contact with the skin, out of the content range If present in an excessive or small amount, it is impossible to form microemulsions and may affect the degree of skin migration of processed ginseng, which may cause problems in the expression of pharmacological effects.

In addition, the propylene glycol is one of the auxiliary surfactants used in the present invention, not only improves skin permeation but also is non-toxic and suitable for bioavailability, and in particular, does not cause any irritation even after prolonged contact with the skin, and is outside the above content range. If present in an excessive or small amount, it is impossible to form microemulsions and may affect the degree of skin migration of processed ginseng, which may cause problems in the expression of pharmacological effects.

In addition, the phospholipid is one of the sub-surfactant used in the present invention to enhance the skin retention effect of the processed ginseng as one of the skin constituents, and if present in an excessive or small amount outside the content range of the micro It is impossible to form mullion and may affect the degree of skin transition of processed ginseng, causing problems in the expression of pharmacological effects.

The diameter of the microemulsion formed in the present invention is preferably 20 to 200 nm, and larger or smaller diameter outside the above range may affect the degree of skin migration of processed ginseng, which may cause problems in the expression of pharmacological effects.

The gelling agent is a component added to overcome the disadvantage that the active ingredient is not sufficiently absorbed due to the flow of the microemulsion does not remain on the skin during the administration of the microemulsion, can be used any one selected from carbopol or xanthan gum. have. When the gelling agent is present in an excessive or small amount out of the content range, the degree of gel formation is too weak or too viscous in forming the microemulsion agent, so that application of the skin is not easy and may cause a problem in the skin transition of the processed ginseng.

In addition, the present invention is a ginsenoside Rg3 0.02 to 3.0% by weight, 5.0 to 15.0% by weight of isopropyl myristate, 15.0 to 60.0% by weight of surfactant, 0.5 to 5.0% by weight of the gelling agent and the balance of water It provides a microemulsion hydrogel comprising a.

In addition, the present invention comprises the steps of dissolving processed ginseng in isopropyl myristate; Preparing an oil phase by adding a surfactant to the dissolved solution; And it provides a method of producing a microemulsion hydrogel comprising the step of adding an aqueous phase to which the gelling agent is added to the prepared oil.

The oil phase comprises 10-70 parts by weight based on 100 parts by weight of the total microemulsion hydrogel, wherein the oil phase is 0.02-3.0% by weight of processed ginseng, 5.0-15.0% by weight of isopropyl myristate and 82.0-92.0% by weight of surfactant. It is preferable to contain.

At this time, if the oil phase is contained in an excess or a small amount out of the above range may affect the stability of the processed ginseng and the possibility of forming the o / w microemulsion system and may cause problems due to the phase separation when mixed with the water phase The oil phase is prepared by dissolving processed ginseng in isopropyl myristate at room temperature and then adding a surfactant under stirring.

In addition, the aqueous phase is composed of 30 to 90 parts by weight based on 100 parts by weight of the total microemulsion hydrogel, wherein the aqueous phase preferably contains 0.5-5.0% by weight of carbopol or xanthan gum and 95.0-99.5% by weight of water. .

At this time, if the aqueous phase is contained in an excessive or small amount out of the above range may affect the stability of the fully dissolved ginseng and the possibility of forming the o / w microemulsion system, and there is a possibility of phase separation in mixing with the oil phase It can be caused, and the preparation of the aqueous phase is made so that it is sufficiently dissolved and uniform with stirring Carbopol or xanthan gum in water.

Since the carbopol is gelated in a weak base, it is necessary to add a weak alkalizing agent such as triethanolamine (pH 7.3 to 8.3). It is possible to adjust the desired pH without any other alkalizing agent.

According to the present invention, a microemulsion hydrogel obtained by preparing a microemulsion of 100 nm or less containing processed ginseng, isopropyl myristate, labrasol, propylene glycol and phospholipid as an active ingredient and adding a gelling agent to the microemulsion Gel is expected to improve skin such as skin whitening, regeneration and anti-wrinkle effect, but processed ginseng is effective ingredient because it is poorly soluble and it can penetrate and localize processed ginseng which is difficult to absorb skin with molecular weight of 500Da or more. It can be usefully used as a skin external preparation for skin improvement.

Figure 1 relates to the phase equilibrium of the microemulsion that is the basis of the formation of the microemulsion hydrogel according to the present invention,
Figure 2 relates to a transmission electron micrograph showing the nature and size of the microemulsion prepared in one embodiment of the present invention,
Figure 3 relates to the result of measuring the amount of deposition in the skin after removing the keratin after applying the microemulsion prepared in one embodiment of the present invention to the mouse skin in vitro according to Experimental Example 1,
Figure 4 relates to the result of measuring the amount of deposit in the skin removed keratin after 24 hours of applying the microemulsion hydrogel prepared in one embodiment of the present invention to the mouse skin in vitro according to Experimental Example 1.
Figure 5 relates to the result of measuring the amount of deposit in the skin after removing the keratin after applying the microemulsion prepared in one embodiment of the present invention to the mouse skin in vivo according to Experimental Example 2,
Figure 6 relates to the result of measuring the amount of sedimentation in the skin removed from the dead skin 24 hours after applying the microemulsion hydrogel prepared in one embodiment of the present invention to the mouse skin in vivo according to Experimental Example 2.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

<Examples 1 to 3> Preparation of Microemulsion

Processed ginseng was dissolved in isopropyl myristate to prepare an oil phase, and then a mixture of Labrasol and phosphatidylcholine (S75 PC): propylene glycol (1: 4) was 1: 9, 2: 8, 3: 7 and 4, respectively. It added at the weight ratio of: 6, 5: 5, 6: 4, 7: 3, 8: 2, and 9: 1, and stirred at room temperature.

At this time, the used ginseng was stored in the plant herbarium of Seoul National University College of Pharmacy ginseng cultivated in Geumsan, Chungnam, and used to steam and dried for 3 hours using an autoclave at 110 to 130 ℃ After extraction, the mixture was removed under reduced pressure to use methanol. The processed ginseng is ginsenoside Rg1 (0.22 ~ 0.27, w / w), Rg2 (0.30 ~ 0.32, w / w), Rg 3 (0.62 ~ 1.32, w / w) and Rg 5 (0.35 ~ 0.64%, w / w ).

Water was added to the oil phase and the surfactant mixture to identify a region where a uniform microemulsion was formed, and a pseudo-ternary phase diagram as shown in FIG. 1 was formed.

As a result, a stable microemulsion in which no phase separation occurred according to the composition and the ratio as shown in Table 1 was prepared.

Ingredient (%, w / w) Example 1 (F1) Example 2 (F2) Example 3 (F3) Processed ginseng 23.1 23.1 23.1 Isopropyl myristate 3.8 3.8 3.8 Labrasol 19.2 25.6 28.8 Propylene glycol 15.4 10.2 7.7 Phosphatidylcholine 3.8 2.6 1.9 water 34.7 34.7 34.7

In addition, as shown in Figure 2, the appearance of the formed microemulsion (Example 1) was confirmed by transmission electron microscope (TEM) (x 25,000), wherein the diameter of the microemulsion was 100 nm or less.

<Example 4 to Example 5> Preparation of the external skin preparation (hydrogel) using the microemulsion

A skin external preparation which is a gelling agent using the composition of the microemulsion obtained in Example 1 was prepared according to the prescription of Table 2. That is, the processed ginseng was dissolved in isopropyl myristate to prepare an oil phase, and then a mixture of Labrasol and phosphatidylcholine (S75 PC): propylene glycol (1: 4) was mixed in the oil phase. Water was added dropwise while stirring to prepare a microemulsion, and each of xanthan gum or Carbopol 980 was added thereto to prepare a microemulsion hydrogel. Carbopol 980 formulated triethanolamine was added to the neutral pH to complete the gel.

Ingredient (%, w / w) Example 4 (F1-1) Example 5 (F1-2) Processed ginseng 23.1 23.1 Isopropyl myristate 3.8 3.8 Labrasol 19.2 19.2 Propylene glycol 15.4 15.4 Phosphatidylcholine 3.8 3.8 Xanthan gum - 0.8 Cabopol 980 0.8  - Triethanolamine 0.2  - water 33.7 33.9

Experimental Example 1 Viscosity Test

The viscosity of the microemulsion formulations prepared in the examples was measured with a viscometer (BROOKFIELD, USA) at 50 rpm using a # LV4 spindle (s64) at room temperature. F1 of Example 1 and F2 of Example 2, compared with F1-1 of Example 4 and F1-2 of Example 5, 9870 cP and 3343 at 46.3 cP and 49.1 cP, respectively, depending on the addition of the gelling agent. The viscosity increased significantly with cP. Therefore, it can be seen that the increase in viscosity of the microemulsion hydrogel facilitates the application to the skin by increasing the retention time during skin application.

<Experimental Example 2> In vitro of the preparation ( in vitro Skin Penetration Experiment

Male hairless mice (5-6 weeks old, 18-20 g) were used as experimental animals. The hairless mouse was lethal to the cervical vertebra and the skin was removed from the back area with an area of about 3cm x 3cm, and the subcutaneous fat and tissues were carefully removed so as not to damage the skin.

The permeation rate and permeation rate of processed ginseng through the skin were measured using Franz diffusion cell. The stratum corneum was anchored between the donor phase and the receptor phase to direct the donor phase. Phosphoric acid buffer (PBS), ethanol, dimethyl sulfoxide (DMSO) = 5: 4: 1 (v / v / v) mixture was used as the receptor phase, and the mixture was continuously stirred at 600 rpm while maintaining at 37 ± 0.5 ° C.

The area of skin in contact with the receptor phase was 2.0 cm ² and the dose of the receptor phase was 12 ml. 500 μl of the composition prepared in Examples 1 to 5 was administered to the skin surface on the donor phase side, and skin was removed after a certain time (3, 6, 12, and 24 hours).

Washed with methanol to remove the drug remaining on the surface, and took 2.0 cm ² of skin area in contact with the formulation. The dead skin was stripped five times using Cellophane adhesive tape (CeDerm coporation, Dallas, USA) to remove the stratum corneum.

Finely cut the skin from which the stratum corneum has been removed, add 2 ml of methanol, grind it for 2 minutes at 16,000 rpm with a homogenizer, vortex for 5 minutes, centrifuge at 10,000 rpm for 10 minutes, and take the supernatant (1.5 ml) to filter the membrane. (0.2 μm). At this time, the evaporated filtrate and reconcentration with 150 μl of methanol to measure the processed ginseng deposited in the skin by HPLC.

Intradermal deposits of processed ginseng were analyzed using ginsenoside Rg3 as a reference. The column used Kinetex C18 (4.6 X 150 mm, 2.6um, Phenomenex), the mobile phase was a mixture of acetonitrile and water at 43:57 v / v, the flow rate is 0.6ml / min, injection volume 50 The detection wavelength was measured by a UV detector at 204nm.

As mentioned above, the most important component of ginseng is ginsenoside called ginseng saponin, and ginsenoside Rg3 is the most abundant and powerful drug in ginseng. Therefore, it was judged that Rg3 was suitable as a reference material.

As shown in FIG. 3, F1 of Example 1, F2 of Example 2, F3 of Example 3, and F0 (propylene glycol) of Example showed a tendency to increase the amount of ginsenoside Rg3 deposition in the skin with time. . In addition, at the initial time of 3 hours, the skin deposition amounts of the control group F0 of Examples and the microemulsion preparations of Examples 1 to 3 were 0.05, 0.16, 0.17 and 0.11 μg / cm ² , respectively. As the difference gradually increased, the skin deposition amount of the control group F0 of Example and the microemulsion preparations of Examples 1 to 3 showed a significant difference of up to 10 times or more, respectively 0.29, 2.98, 2.78 and 2.74 µg / cm ² . However, there was no significant difference in each skin deposition amount in Examples 1 to 3 at each time period.

In addition, as shown in Figure 4, the amount of skin deposition during the 24 hours of the composition according to the composition of Example F1 and F1-1 of Example 4 and F1-2 of Example 5, which is a gel formulation based on the F1 composition, respectively At 2.98, 2.12 and 1.49 μg / cm ² , there was a difference in the amount of microemulsion and skin deposition of Example F1 without adding the gelling agent (Examples 1 and 5: p <0.05). There was no significant difference between Example 4 and Example 5 which differed.

Experimental Example 3 Formulation in vivo  Transdermal administration

Male hairless mice (5 to 6 weeks old, 18 to 20 g) were fixed, and the formulations of Examples 1 to 5 were applied to the dorsal area by applying 500 μl to the back area in an area of 1.776 cm ² .

After 24 hours, it was lethal to the cervical vertebra and treated in the same manner as in Experimental Example 1 to measure the amount of drug deposited in the exfoliated skin.

As shown in FIG. 5, the skin deposition amounts of the control group F0 (proylene glycol) of Examples and the microemulsion formulations of Examples 1 to 3 were 42.1, 160.2, 114.3, and 115.9 ng / cm ² , respectively, and the difference was in vitro. It was smaller than the skin permeation experiment, but all showed a significant difference (p <0.05) compared to the control group.

In addition, as shown in Figure 6, the amount of skin deposition during the 24 hours of the composition according to the composition of Example F1 and F1-1 of Example 4 and F1-2 of Example 5, which is a gel formulation based on the F1 composition, respectively At 160.2, 89.3 and 80.0 ng / cm ² , the microemulsion and the amount of skin deposition of Example F1 without the gelling agent, as in the in vitro skin permeation experiment, were different (Example 1 and Example 5: p <0.05). ), There was no significant difference between Examples 4 and 5 with different kinds of gelling agents.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (8)

Micro-emulsion hydrogel comprising 0.02 to 3.0% by weight of processed ginseng, 5.0 to 15.0% by weight of isopropyl myristate, 15.0 to 60.0% by weight of surfactant, 0.5 to 5.0% by weight of a gelling agent and a balance of water. The microemulsion hydrogel of claim 1, wherein the processed ginseng is steamed and dried for 2 to 4 hours at 110 to 130 ° C. The microemulsion hydrogel according to claim 1 or 2, wherein the processed ginseng comprises ginsenoside Rg3. The microemulsion hydrogel of claim 1, wherein the surfactant is any one or two or more selected from the group consisting of Labrasol, propylene glycol, and phospholipids. The method according to claim 1, 0.02 to 3.0% by weight of processed ginseng, 5.0 to 15.0% by weight of isopropyl myristate, 5.0 to 20.0% by weight of Labrasol, 5.0 to 20.0% by weight of propylene glycol, 5.0 to 20.0% by weight of phospholipids, Microemulsion hydrogel comprising 0.5 to 5.0% by weight of gelling agent and the balance of water. The method of claim 1, wherein the gelling agent is a microemulsion hydrogel, characterized in that any one selected from carbopol or xanthan gum. A microemulsion hydrogel comprising ginsenoside Rg3 0.02 to 3.0 wt%, isopropyl myristate 5.0 to 15.0 wt%, surfactant 15.0 to 60.0 wt%, gelling agent 0.5 to 5.0 wt% and the balance of water. Dissolving the processed ginseng in isopropyl myristate; Preparing an oil phase by adding a surfactant to the dissolved solution; And adding an aqueous phase to which a gelling agent is added to the prepared oil phase.

Images