KR102102098B1 - A composition of emulsion preconcentrate comprising protopaxadiol - Google Patents

Abstract

Disclosed is an emulsion preconcentrate containing 20(S)-protopanaxadiol. When using the emulsion preconcentrate or an emulsion manufactured from the same, it is possible to improve a dissolution rate and bioavailability of PPD during oral administration.

Description

A composition of emulsion preconcentrate comprising protopaxadiol}

The present invention relates to an emulsion pre-concentrate composition containing 20 (S) -protopanaxadiol as an active ingredient and a method for manufacturing the same.

20 (S) -Protopanaxadiol (sometimes abbreviated as 'PPD') is a ginsenoside derived from ginseng Rb1, Rb2, Rb3, Rh2, Rg3, Rg2, and Compound K. It is an active metabolite that is produced through complete deglycosylation metabolism from the side. The structural formula of 20 (S) -PPD is as follows:

[20 (S) -PPD structural formula]

PPD is known to exert various systemic pharmacological activities and treatment effects ranging from anti-cancer, anti-diabetic, anti-inflammatory, cardioprotective, and antidepressant in many previous studies. In addition, it has the effect of improving and preventing skin aging such as wrinkles caused by photoaging, which is caused by the inhibition of collagen or elastin of the skin through the inhibition of matrix metalloproteinases. It is said that it is because it suppresses denaturation.

However, PPD is a poorly water-soluble substance with very low solubility in water (solubility of 36.8 ng / mL or less), and it is difficult to formulate it into medicines or cosmetics for systemic or external purposes without sufficient solubilization technology, and sufficient bioavailability, skin Permeability, skin tissue distribution cannot be achieved.

Korean Patent Publication No. 10-2010-0050192

Thus, the present inventors studied a method for solubilizing poorly water-soluble PPD at a sufficiently high concentration, and when using oil and surfactant, an emulsion pre-concentrate composition capable of solubilizing PPD can be prepared, and this pre-concentrate is used. It was found that adding the aqueous phase to the composition spontaneously forms a nanoemulsion with no precipitation of the drug, is physically and chemically stable, and has an average particle size of 300 nm or less in the dispersed phase.

The pre-concentrate composition according to the present invention or the emulsion composition prepared therefrom can increase the absorption of the active ingredient upon oral administration, and preparations applied directly to the skin (for example, transdermal absorbers or cosmetics such as external preparations, patching agents, etc.) When formulated with), it is easy to apply the skin, increase skin permeability, and achieve a sufficient distribution in skin tissue.

Accordingly, the present invention is to provide an emulsion pre-concentrate composition containing PPD and an emulsion composition prepared by dispersing it in an aqueous phase.

The present invention is 20 (S)-protopanaxadiol (protopanaxadiol); oil; And it provides an emulsion pre-concentrate composition containing a surfactant.

In the present invention, as the oil, one or more selected from the group consisting of glyceryl monocaprylate and propylene glycol monocaprylate may be used. Further, in the present invention, one or more selected from the group consisting of polyoxyl 15 hydroxy stearate, polyoxyl castor oil, and polyoxyl 40 hydrogenated castor oil may be used.

In the present invention, the content of the 20 (S) -protopanaxadiol may be 0.01 to 20% by weight, preferably 2 to 12% by weight, based on the total weight of the composition. In the present invention, the content of the oil may be 10% to 85% by weight based on the total weight of the composition, and the content of the surfactant may also be 10% to 85% by weight based on the total weight of the composition.

The emulsion pre-concentrate composition according to the present invention can be easily dispersed in an aqueous phase and prepared as an emulsion composition. The average particle size of the dispersed phase in the emulsion composition thus prepared may be about 10 to 300 nm.

The emulsion pre-concentrate composition according to the present invention or the emulsion in which it is dispersed in an aqueous phase may be used as a formulation for oral preparations, external preparations, patch, etc., or may be used as a cosmetic.

According to the present invention, the poorly water-soluble 20 (S) -protopanaxadiol can be solubilized at a high concentration. The emulsion pre-concentrate composition according to the present invention is stable without precipitation of the drug and can be easily dispersed in the aqueous phase. By adding the aqueous phase to the emulsion pre-concentrate according to the present invention can be prepared as a nano-emulsion composition having an average particle size of 300 nm or less in the dispersed phase.

Thus, the poorly water-soluble PPD can be solubilized to a concentration of 5% by weight or more, preferably 10% by weight or more, in the emulsion pre-concentrate composition according to the present invention. In addition, emulsion compositions prepared from emulsion pre-concentrates are also stable without precipitation of the drug.

When the emulsion pre-concentrate according to the present invention or the emulsion prepared therefrom is used, it improves the dissolution rate and bioavailability upon oral administration of PPD, improves skin permeability when used for external use, and improves the distribution in skin tissue. Can be achieved.

The emulsion pre-concentrate of the present invention or the emulsion in which it is dispersed in a water phase may be variously formulated and used as oral and external medicines or cosmetic products for cosmetic purposes.

1 is a photograph of a part of the composition of the comparative example in which precipitation occurred and the composition of the example in which precipitation did not occur.
2 is a graph showing the dissolution test results for the composition of the present invention.

The present invention is 20 (S)-protopanaxadiol (protopanaxadiol); oil; And it relates to an emulsion pre-concentrate composition containing a surfactant.

In the present invention, as the oil, one or more selected from the group consisting of glyceryl monocaprylate and propylene glycol monocaprylate may be used. Further, in the present invention, one or more selected from the group consisting of polyoxyl 15 hydroxy stearate, polyoxyl castor oil, and polyoxyl 40 hydrogenated castor oil may be used.

In the pre-concentrate composition of the present invention, the content of the 20 (S) -protopanaxadiol may be 0.01 to 20% by weight, preferably 2 to 12% by weight, based on the total weight of the composition. In the present invention, the content of the oil may be 10% to 85% by weight based on the total weight of the composition, and the content of the surfactant may also be 10% to 85% by weight based on the total weight of the composition.

There is no particular limitation on the weight ratio of oil and surfactant in the present invention, and for example, it may be used in a weight ratio of 1:10 to 10: 1.

The emulsion pre-concentrate composition according to the present invention is easily dispersed in an aqueous phase to form an emulsion (eg, nanoemulsion) composition. The average particle size of the dispersed phase in the nanoemulsion composition prepared as described above may be about 10 to 400 nm, preferably about 10 to 300 nm.

The emulsion pre-concentrate composition according to the present invention or the emulsion in which it is dispersed in an aqueous phase may be used as a formulation for oral preparations, external preparations, patch, etc., or may be used as a cosmetic.

Since PPD is an active metabolite of ginsenoside used for pharmaceutical or cosmetic purposes, when PPD is administered orally or absorbed into the skin, much greater clinical usefulness can be expected compared to the use of the precursor ginsenoside. You can. Since the solubility of PPD in water is very poor, it is difficult to formulate PPD for oral administration or skin application without solubilization technology, and thus it is difficult to ensure that PPD can be sufficiently absorbed.

In the present invention, by using an oil and a surfactant excellent in the ability to solubilize PPD, it was possible to develop a nanoemulsion pre-concentrate that can be easily dispersed in the aqueous phase. The emulsion prepared by dispersing the emulsion pre-concentrate according to the present invention by adding at least 2 times the water phase may contain PPD at a concentration of, for example, at least 3% or more, that is, 30 mg / mL or more, which is known for water of PPD. It has a high concentration of 800,000 times higher than the solubility of 36.8 ng / mL, is stable without precipitation of the drug, and the particles are small and uniform.

The emulsion pre-concentrate composition according to the present invention does not need to additionally use a co-surfactant or a viscosity modifier to solubilize the active ingredient.

The emulsion pre-concentrate composition according to the present invention can be prepared by adding PPD to a mixed solution of oil and surfactant and stirring at room temperature. In order to solubilize at a faster rate, it can be stirred while lowering the viscosity at a heating condition of 30 ° C or higher. However, these warming conditions are not necessarily required to prepare the pre-concentrate composition according to the present invention, and the stirring strength is not necessarily strong.

When an aqueous pre-concentrate composition such as water is added in a volume of 2 times or more to the emulsion pre-concentrate composition thus prepared, the emulsion pre-concentrate composition is easily dispersed in the aqueous solution to form an emulsion. A person skilled in the art can appropriately prepare an emulsion by dispersing a pre-concentrate so that the active ingredient in the emulsion can be a desired concentration value (for example, 10 ng / mL to 50 mg / mL).

The emulsion pre-concentrate may be used as it is or in the form of an emulsion dispersed in an aqueous phase, and if necessary, appropriate solid additives may be added to prepare soft capsules, hard capsules, tablets, powders, granules, and liquids according to conventional methods. It is possible to formulate with various oral preparations such as emulsions.

In addition, in order to be used in a form applicable to the skin, the emulsion may be used as a pre-concentrate, or in the form of an emulsion dispersed in the water phase, or by adding appropriate additives as necessary to emulsify, ointment, or cream. , It is possible to formulate a liquid or semi-solid formulation such as lotion, spray, patch, patch.

In addition, in order to be used as a cosmetic applied to the skin, the emulsion may be used as a pre-concentrate, or in the form of an emulsion dispersed in an aqueous phase, or by adding an additive in an appropriate form, if necessary, according to a conventional manufacturing method. It is possible to formulate with eye cream, cleansing cream, cleansing foam, cleansing water, pack, powder, body lotion, body oil, makeup base, shampoo, conditioner, toothpaste, mouthwash, lotion, essence, and spray.

The formulation as described above merely illustrates a formulation that the emulsion pre-concentrate of the present invention or an emulsion in which it is dispersed in an aqueous phase can have, and thus the formulation is not limited.

[Example]

Hereinafter, examples will be described in detail to help understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited by the following examples. The embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

One. Test example  One: PPD  Solubility measurement

In order to prepare nanoemulsions, oils and surfactants capable of solubilizing the main component must first be selected. The solubility of PPD was measured by the following methods for additive components that are pharmaceutically acceptable for oral and external use.

For each of the oils and surfactants (bases) listed in Table 1 below, 500 mg was taken in 5 mL vials and heated to 50 ° C. with water bath, while 5 mg of the active ingredient 20 (S) -PPD was added at a time and stirred for 30 minutes. Melt, but this process is repeated until the 20 (S) -PPD is no longer melting. In each vial, the total amount of 20 (S) -PPD added until the moment when 20 (S) -PPD is no longer soluble is calculated, and the solubility (%, w / w) is calculated using the following formula:

[formula]

Solubility (%, w / w) = Total 20 (S) -PPD (mg) * 100 (%) / [Total 20 (S) -PPD (mg) + Oil or surfactant (500mg) ]

The solubility thus obtained is shown in Table 1 below:

division product name Ingredient name Of drugs for mechanisms
Solubility (w / w% ) oil Capmul MCM C8 Glyceryl monocaprylate 24.7 ± 2.0% CAPRYOL90 Propylene glycol monocaprylate 24.13 ± 2.2% Kollisolv MCT 70 Medium chain triglycerides 2.06 ± 0.1% Plurol Oleique CC497 Polyglyceryl 3 dioleate 8.89 ± 0.1% Labrafil M 1944CS Oleoyl polyoxyl-6 glyceride 6.17 ± 0.4% Labrafil M 2125CS Linoleoyl polyoxyl-6 glycerin 6.55 ± 0.6% Surfactants Kolliphor HS15 Polyoxyl15 hydroxystearate 5.32 ± 1.1% Kolliphor EL Polyoxyl castor oil 4.65 ± 1.1% Kolliphor PS 80 Polysorbate 80 4.9 ± 1.2% Kolliphor RH40 Polyoxyl40 Hydrogenated Castor Oil 4.5 ± 1.5%

In order to select the base (oil and surfactant) to be used for solubilization of the drug, as a result of individual solubility tests according to the solubility test method for 7 types of oil and 4 types of surfactant, as shown in Table 1 above, glyceryl mono as an oil It was confirmed that the solubility of caprylate and propylene glycol monocaprylate showed a high value of 20% (w / w%) or higher. As surfactants, all four types showed similar levels.

Based on these results, two types of glyceryl monocaprylate and propylene glycol monocaprylate were selected from the oil, and all four types of surfactant were selected as surfactants, but the seven types of oil and Dispersibility, stability, and solubilization ability according to the combination of the four surfactants were evaluated below.

2. Comparative example  Preparation of the composition

The total weight (i.e., the total weight of the main component, oil, and surfactant) of the components and contents shown in Table 2 was weighed to be 200 mg, and placed in a 5 mL vial. The mixture was melted by stirring for 5 hours while being water-soaked to a temperature condition of 50 ° C, and then cooled at room temperature to prepare an emulsion pre-concentrate.

division Main ingredient ( % ) oil ( % ) Surfactants ( % ) Oil: surfactant
(Weight ratio) 20 (S) -PPD Glyceryl monocaprylate Polysorbate 80 Comparative Example 1 5 38 57 4: 6 Comparative Example 2 5 47.5 47.5 5: 5 Comparative Example 3 5 57 38 6: 4 Comparative Example 4 10 36 54 4: 6 Comparative Example 5 10 45 45 5: 5 20 (S) -PPD Propylene glycol monocaprylate Polysorbate 80 Comparative Example 6 5 38 57 4: 6 Comparative Example 7 5 47.5 47.5 5: 5 Comparative Example 8 5 57 38 6: 4 Comparative Example 9 10 36 54 4: 6 20 (S) -PPD Glyceryl monocaprylate Polyoxyl 15 hydroxystearate Comparative Example 10 5 38 57 4: 6 Comparative Example 11 5 47.5 47.5 5: 5 Comparative Example 12 5 57 38 6: 4 Comparative Example 13 10 36 54 4: 6 Comparative Example 14 10 45 45 5: 5 20 (S) -PPD Glyceryl monocaprylate Polyoxyl 40 Hydrogenated Castor Oil Comparative Example 15 10 36 54 4: 6 20 (S) -PPD Medium chain triglycerides Polyoxyl castor oil Comparative Example 16 2 39.2 58.8 4: 6 Comparative Example 17 2 49 49 5: 5 Comparative Example 18 2 58.8 39.2 6: 4 20 (S) -PPD Medium chain triglycerides Polysorbate 80 Comparative Example 19 2 39.2 58.8 4: 6 Comparative Example 20 2 49 49 5: 5 Comparative Example 21 2 58.8 39.2 6: 4 20 (S) -PPD Medium chain triglycerides Polyoxyl 15 hydroxystearate Comparative Example 22 2 39.2 58.8 4: 6 Comparative Example 23 2 49 49 5: 5 Comparative Example 24 2 58.8 39.2 6: 4

3. Example  Preparation of the composition

The total weight (i.e., the total weight of the main component, oil, and surfactant) of the components and contents shown in Table 3 was weighed to be 200 mg, and placed in a 5 mL vial. The mixture was melted by stirring for 5 hours while being water-soaked to a temperature condition of 50 ° C, and then cooled at room temperature to prepare an emulsion pre-concentrate.

division Main ingredient ( % ) oil ( % ) Surfactants ( % ) Oil: surfactant
(Weight ratio) 20 (S) -PPD Glyceryl monocaprylate Polyoxyl castor oil Example 1 5 38 57 4: 6 Example 2 7.5 37 55.5 4: 6 20 (S) -PPD Propylene glycol monocaprylate Polyoxyl castor oil Example 3 5 57 38 6: 4 Example 4 10 54 36 6: 4 20 (S) -PPD Propylene glycol monocaprylate Polyoxyl15 hydroxystearate Example 5 5 38 57 4: 6 Example 6 10 36 54 4: 6 20 (S) -PPD Propylene glycol
Monocaprylate Polyoxyl40 Hydrogenated Castor Oil Example 7 10 54 36 6: 4

4. Test example  2: Reserve  Characteristic evaluation

(1) Solubilization evaluation

In order to form a nanoemulsion, the active ingredient must first be soluble in oil and surfactant. In the compositions of Comparative Examples and Examples, 20 (S) -PPD, an active ingredient, was completely dissolved and evaluated as melted when there was no residue, and when observed, it was evaluated as not melted.

(2) Evaluation of physical stability during dispersion

Preferred nano-emulsion pre-concentrate should form a stable dispersion phase without encountering phase separation or precipitation of active ingredients when encountering the aqueous phase. In the compositions of Comparative Examples and Examples, targeting compositions in which the active ingredient 20 (S) -PPD was completely dissolved, 3 mL of water was added to each of these compositions and lightly stirred to disperse.

After dispersion, it was evaluated whether phase separation was observed within 5 hours. In addition, 1 mL of the dispersed phase was collected in a microtube and centrifuged at 15000RPM Х for 5 minutes using a centrifuge (Labogene 1730R) to observe the presence or absence of sediment on the bottom. Was evaluated.

1 is a photograph of a part of the composition of the comparative example in which precipitation occurred and the composition of the example in which precipitation did not occur.

(3) Dispersion phase particle size evaluation

When the nanoemulsion pre-concentrate is dispersed in the water phase to form an emulsion, it is preferable that the average particle size is 300 nm or less. The solubilization of the active ingredient in the nanoemulsion and the stability of the dispersion system are closely related to the particle size, so the particle size in the nanoemulsion was measured.

A particle size analyzer (NanoBrook 90Plus, Brookhaven instruments Corporation) was used for solubilizing the main component 20 (S) -PPD in the item (1) and targeting the compositions of Comparative Examples and Examples in which phase separation did not appear in the item (2). The particle size of the dispersed phase was measured.

The evaluation results and measured values are shown in Table 4 below:

division Solubilization Dispersion Precipitation at dispersion Comparative Example 1 record 315.30 ± 12.76 nm none Comparative Example 2 record Phase separation none Comparative Example 3 record Phase separation none Comparative Example 4 record Phase separation has exist Comparative Example 5 record Phase separation has exist Comparative Example 6 record 338.37 ± 47.43 nm has exist Comparative Example 7 record Phase separation has exist Comparative Example 8 record Phase separation has exist Comparative Example 9 record 916.43 ± 250.18 nm has exist Comparative Example 10 record 792.80 ± 92.99 nm has exist Comparative Example 11 record Phase separation has exist Comparative Example 12 record Phase separation has exist Comparative Example 13 record Phase separation has exist Comparative Example 14 record Phase separation has exist Comparative Example 15 Insoluble - has exist Comparative Example 16 Insoluble - has exist Comparative Example 17 Insoluble - has exist Comparative Example 18 Insoluble - has exist Comparative Example 19 Insoluble - has exist Comparative Example 20 Insoluble - has exist Comparative Example 21 Insoluble - has exist Comparative Example 22 Insoluble - has exist Comparative Example 23 Insoluble - has exist Comparative Example 24 Insoluble - has exist Example 1 record 270.87 ± 23.71 nm none Example 2 record 265.50 ± 44.10 nm none Example 3 record 151.23 ± 24.36 nm none Example 4 record 125.07 ± 12.56 nm none Example 5 record 232.43 ± 19.38 nm none Example 6 record 247.67 ± 45.79 nm none Example 7 record 222.17 ± 15.00 nm none

In the compositions of Comparative Examples 15 to 24 using heavy chain triglycerides in solubilization evaluation, it was confirmed that the solubilization ability was remarkably low in the same manner as in solubility evaluation.

In the composition of all examples using glyceryl monocaprylate and propylene glycol monocaprylate, PPD could be solubilized as a pre-concentrate at a concentration of 5 to 10% by weight.

As a result of dispersibility evaluation when water was added, phase separation occurred in the compositions of Comparative Examples 2 to 14, or the average particle size was greater than 300 nm. The average particle size of the composition of Comparative Example 1 slightly exceeded 300 nm.

In the compositions of all examples, all of the main components were solubilized, the average particle size of the dispersed phase was 300 nm or less, and it was stable without precipitation.

5. Test example  3: Evaluation of dissolution test of preliminary concentrate

The dissolution test was conducted on the preliminary concentrate composition of Comparative Example 4, Example 4, and Example 6 and the main component 20 (S) -PPD powder as follows:

Each sample was contained in a gelatin capsule to contain 50mg as a main component, and a dissolution test was conducted for 2 hours under conditions of pH 1.2 buffer (NaCl / HCl buffer) 900ml, paddle rotation speed 50RPM, and 37 ° C.

With respect to the samples collected at each time point, a test solution was prepared using a mixture of acetonitrile and distilled water in a volume ratio of 95: 5 as a diluent. The 20 (S) -PPD corresponding to the 100% dissolution rate was weighed based on the main component, and a standard solution was prepared by dissolving with the diluent. The prepared test solution and standard solution were quantitatively analyzed at 203 nm using an ultraviolet-visible absorbance measurement method.

As a result of the dissolution test, 20 (S) -PPD powder did not show a significant dissolution rate value for 2 hours. The compositions of Examples 4 and 6 exhibited significantly higher and faster dissolution rates than the compositions of Comparative Example 4. 2 is a graph showing the dissolution test results.

Therefore, it can be seen that the composition of Examples has a higher dissolution rate and faster than the composition of Comparative Examples.

According to the present invention, the poorly water-soluble 20 (S) -protopanaxadiol can be solubilized at a high concentration. The emulsion pre-concentrate composition according to the present invention can be easily dispersed in the aqueous phase.

Claims (14)

20 (S) -protopanaxadiol;
oil; And
Emulsion pre-concentrate composition containing a surfactant,
Here, the oil is one or more selected from the group consisting of glyceryl monocaprylate and propylene glycol monocaprylate,
The surfactant is an emulsion pre-concentrate composition, characterized in that one or more selected from the group consisting of polyoxyl 15 hydroxy stearate, polyoxyl castor oil, and polyoxyl 40 hydrogenated castor oil. delete delete The pre-concentrate composition according to claim 1, wherein the content of the 20 (S) -protopanaxadiol is 0.01 to 20% by weight based on the total weight of the composition. The pre-concentrate composition according to claim 1, wherein the content of 20 (S) -protopanaxadiol is 2 to 12% by weight based on the total weight of the composition. According to claim 1,
The content of the oil is 10% to 85% by weight relative to the total weight of the composition,
Pre-concentrate composition, characterized in that the content of the surfactant is 10% to 85% by weight relative to the total weight of the composition. According to claim 1,
(i) the oil is glyceryl monocaprylate and the surfactant is polyoxyl castor oil,
(ii) The oil is propylene glycol monocaprylate, and the surfactant is at least one selected from the group consisting of polyoxyl castor oil, polyoxyl15 hydroxy stearate and polyoxyl40 hydrogenated castor oil. The pre-concentrate composition. delete The pre-concentrate composition according to claim 1, which is used as an oral preparation or an external preparation. The preconcentrate composition according to claim 1, which is used as a cosmetic. An emulsion composition in which the pre-concentrate composition according to any one of claims 1 and 4 to 7 is dispersed in an aqueous phase. The emulsion composition of claim 11, wherein an average particle size of the dispersed phase in the emulsion composition is 10 to 300 nm. The emulsion composition according to claim 11, which is used as an oral preparation or an external preparation. The emulsion composition according to claim 11, which is used as a cosmetic.

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