WO2020262895A1 - Emulsion preconcentrate composition containing protopanaxadiol - Google Patents

Abstract

Disclosed is an emulsion preconcentrate composition containing 20(S)-protopanaxadiol as an active ingredient. The emulsion preconcentrate composition comprises 20(S)-protopanaxadiol, an oil, and a surfactant, wherein the oil is at least one selected from the group consisting of glyceryl monocaprylate and propylene glycol monocaprylate, and the surfactant is at least one selected from the group consisting of polyoxyl 15 hydroxystearate, polyoxyl castor oil and polyoxyl 40 hydrogenated castor oil.

Description

Emulsion pre-concentrate composition containing Protopanaxadiol

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

20(S)-protopanaxadiol (also abbreviated as'PPD') is a variety of ginsenosides Rb1, Rb2, Rb3, Rh2, Rg3, Rg2 and Compound K derived from ginseng. It is an active metabolite that is produced through complete desaccharide metabolism from 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 therapeutic effects ranging from anti-cancer, anti-diabetic, anti-inflammatory, heart protection, and anti-depressant in a number of previous studies. In addition, it has the effect of improving and preventing skin aging such as wrinkles caused by photoaging, and this is the inhibition of matrix metalloproteinases (extracellular matrix metal-containing proteolytic enzymes) to prevent collagen or elastin in the skin. It is known that this is because it suppresses degeneration.

However, PPD is a poorly water-soluble substance with very low solubility in water (solubility less than 36.8 ng/mL), and if no special solubilization technology is used, it is difficult to formulate it into pharmaceuticals or cosmetics for systemic or external use, and sufficient bioavailability, skin Permeability, skin tissue distribution cannot be achieved.

Accordingly, the present inventors have studied a method for solubilizing poorly water-soluble PPD at a sufficiently high concentration, and as a result, when oil and surfactant are used, an emulsion pre-concentrate composition capable of solubilizing PPD can be prepared, and this pre-concentrate It was found that when an aqueous phase was added to the composition, there was no precipitation of drugs, and it was physicochemically stable and spontaneously formed a nanoemulsion having an average particle size of 300 nm or less in the dispersed phase.

The preconcentrate composition according to the present invention or the emulsion composition prepared therefrom can increase the absorption of the active ingredient when administered orally, and is applied directly to the skin (e.g., transdermal absorbents such as external preparations, patches, etc. ), it is easy to apply to the skin, increase skin permeability, and achieve 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; 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. In addition, as the surfactant 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 to prepare 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 obtained by dispersing it in an aqueous phase may be used in formulations such as oral preparations, external preparations, and patches, and may also be used as cosmetics.

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

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

When using the emulsion preconcentrate according to the present invention or an emulsion prepared therefrom, the dissolution rate and bioavailability of PPD during oral administration is improved, and when used for external use, skin permeability is improved, and sufficient distribution in skin tissue is achieved. Can be achieved.

The emulsion pre-concentrate of the present invention or the emulsion obtained by dispersing it in an aqueous phase may be formulated and used in various ways as oral and external pharmaceuticals or cosmetic products for cosmetic purposes.

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

Figure 2 is a graph showing the dissolution test results for the composition of the present invention.

The present invention is 20(S)-protopanaxadiol; oil; And 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. In addition, as the surfactant 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 preconcentrate 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.

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

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 thus prepared 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 obtained by dispersing it in an aqueous phase may be used in formulations such as oral preparations, external preparations, and patches, and may also be used as cosmetics.

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

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

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

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

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

The emulsion pre-concentrate can be used as it is or in the form of an emulsion dispersed in an aqueous phase, and if necessary, by adding an appropriate solid additive, in accordance with a conventional manufacturing method, soft capsules, hard capsules, tablets, powders, granules, liquids, It is possible to formulate in various oral preparations such as emulsions.

In addition, in order to use it in a form applicable to the skin, it is used as an emulsion pre-concentrate, or in the form of an emulsion in a form dispersed in an aqueous phase, or if necessary, add appropriate additives to make emulsions, ointments, and creams according to conventional manufacturing methods. , It is possible to formulate in liquid or semi-solid preparations such as lotions, sprays, patches, and patches.

In addition, in order to use it as a cosmetic material applied to the skin, it can be used as an emulsion pre-concentrate, or in the form of an emulsion in a form dispersed in an aqueous phase, or if necessary, add an appropriate type of additive to make a lotion, cream, essence, It is possible to formulate eye cream, cleansing cream, cleansing foam, cleansing water, pack, powder, body lotion, body oil, makeup base, shampoo, rinse, toothpaste, mouthwash toner, lotion, essence, spray.

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

[Example]

Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited by the following examples. Embodiments of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.

1. Test Example 1: Measurement of solubility of PPD

In order to prepare a nanoemulsion, an oil and a surfactant that can solubilize the main component must first be selected. The solubility of PPD was measured by the following method, targeting 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 a 5 mL vial, heated to 50° C. with a water bath, and 5 mg of the active ingredient 20(S)-PPD was added at a time and stirred for 30 minutes. It melts, and this process is repeated until no more 20(S)-PPD is dissolved. In each vial, calculate the total amount of 20(S)-PPD added to the moment when the 20(S)-PPD is no longer dissolved, and calculate the solubility (%, w/w) using the following calculation:

[formula]

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

The solubility obtained as described above is shown in Table 1 below:

division	product name	Ingredient name	Of drugs on the mechanism 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	Polyglyceryl3 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		Polyoxyl 40 Hydrogenated Castor Oil	4.5±1.5%

In order to select the base (oil and surfactant) to be used for solubilization of the drug, individual solubility tests were conducted for 7 types of oil and 4 types of surfactant according to the above solubility test method. It was confirmed that the solubility of caprylate and propylene glycol monocaprylate showed a high value of 20% (w/w%) or more. All four types of surfactants showed similar levels. Based on these results, two types of glyceryl monocaprylate and propylene glycol monocaprylate were selected among oils, and the four types of surfactants were selected. All surfactants were selected, but the dispersibility, stability, and solubilization ability according to the combination of the seven oils and the four surfactants were evaluated below.

2. Preparation of Comparative Example Composition

The components and contents shown in Table 2 below were weighed so that the total weight (ie, the total weight of the main component, oil, and surfactant) was 200 mg, and put into a 5 mL vial. The mixture was dissolved by stirring for 5 hours while bathing in water to a temperature of 50°C, and then cooled at room temperature to prepare an emulsion preconcentrate.

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	Polyoxyl15hydroxystearate
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 Caster 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	Polyoxyl15hydroxystearate
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. Preparation of Example Composition The components and contents shown in Table 3 below were weighed so that the total weight (ie, the total weight of the main component, oil, and surfactant) was 200 mg, and put into a 5 mL vial. The mixture was dissolved by stirring for 5 hours while bathing in water to a temperature of 50°C, and then cooled at room temperature to prepare an emulsion preconcentrate.

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		Polyoxyl 40 Hydrogenated Castor Oil
Example 7	10	54	36	6: 4

4. Test Example 2: Evaluation of properties of preconcentrate (1) Solubilization

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, when the active ingredient 20(S)-PPD was completely dissolved and there was no residue, it was evaluated as melted, and when a residue was observed, it was evaluated as not dissolved.

(2) Evaluation of physical stability during dispersion

A preferred nanoemulsion preconcentrate should form a stable dispersed phase without causing phase separation or precipitation of active ingredients when it encounters an aqueous phase. Among the compositions of Comparative Examples and Examples, the active ingredient 20(S)-PPD was completely dissolved in the composition, and 3 mL of water was added to each of these compositions, followed by lightly stirring to disperse.

After dispersion, it was evaluated whether or not phase separation was observed within 5 hours.In addition, 1 mL of the dispersed phase was taken and placed in a microtube and centrifuged for 5 minutes at 15000 RPM using a centrifuge (Labogene 1730R), and the presence or absence of precipitation was observed by observing the presence or absence of sediment at the bottom Was evaluated.

1 is a photograph of a part of a comparative example composition with precipitation and an example composition without precipitation.

(3) Evaluation of the particle size of the dispersed phase

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

A particle size analyzer (NanoBrook 90Plus, Brookhaven instruments Corporation) was used for the composition of Comparative Examples and Examples in which the main component 20(S)-PPD was solubilized in item (1) and no phase separation appeared in item (2). Was used to measure the particle size of the dispersed phase.

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

division	Solubilization	Distributed state	Presence of precipitation during 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	Does not melt	-	has exist
Comparative Example 16	Does not melt	-	has exist
Comparative Example 17	Does not melt	-	has exist
Comparative Example 18	Does not melt	-	has exist
Comparative Example 19	Does not melt	-	has exist
Comparative Example 20	Does not melt	-	has exist
Comparative Example 21	Does not melt	-	has exist
Comparative Example 22	Does not melt	-	has exist
Comparative Example 23	Does not melt	-	has exist
Comparative Example 24	Does not melt	-	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 solubilization evaluation, in the compositions of Comparative Examples 15 to 24 using medium-chain triglycerides, it was confirmed that the solubilization ability was significantly low in the same manner as in the solubility evaluation. All glyceryl monocaprylate and propylene glycol monocaprylate were used. In the composition of the example, PPD could be solubilized as a preconcentrate having a concentration of 5 to 10% by weight.

As a result of evaluating the dispersibility 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 was stable without precipitation.

5. Test Example 3: Evaluation of dissolution test of pre-concentrate

The dissolution test was carried out in the following manner for the main component 20(S)-PPD powder and the preconcentrate compositions of Comparative Examples 4, 4, and 6:

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

For the samples collected at each time point, a solution obtained by mixing acetonitrile and distilled water at a volume ratio of 95:5 was used as a diluent to prepare a sample solution. A standard solution was prepared by weighing 20(S)-PPD corresponding to a 100% dissolution rate based on the main component, and dissolving it with the diluent. The prepared sample solution and standard solution were quantitatively analyzed by measuring the absorbance of the ultraviolet visible part at 203 nm, respectively.

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

Accordingly, it can be seen that the composition of the example has a higher dissolution rate and is faster than the composition of the comparative example.

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

Claims (11)

1. 20(S)-protopanaxadiol;

   oil; And

   As an 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 preconcentrate composition, characterized in that at least one selected from the group consisting of polyoxyl 15 hydroxy stearate, polyoxyl castor oil, and polyoxyl 40 hydrogenated castor oil.
2. The pre-concentrate composition of claim 1, wherein the content of the 20(S)-protophanoxadiol is 0.01 to 20% by weight based on the total weight of the composition.
3. The preconcentrate composition of claim 1, wherein the content of the 20(S)-protopanaxadiol is 2 to 12% by weight based on the total weight of the composition.
4. The method of claim 1,

   The content of the oil is 10% to 85% by weight based on the total weight of the composition,

   The pre-concentrate composition, characterized in that the content of the surfactant is also 10% to 85% by weight based on the total weight of the composition.
5. The method of claim 1,

   (i) the oil is glyceryl monocaprylate and the surfactant is polyoxyl castor oil, or

   (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. Pre-concentrate composition.
6. The preconcentrate composition according to claim 1, which is used as an oral preparation or an external preparation.
7. The preconcentrate composition according to claim 1, which is used as a cosmetic.
8. An emulsion composition in which the preconcentrate composition according to any one of claims 1 to 5 is dispersed in an aqueous phase.
9. The emulsion composition according to claim 8, wherein the average particle size of the dispersed phase in the emulsion composition is 10 to 300 nm.
10. The emulsion composition according to claim 8, which is used as an oral preparation or an external preparation.
11. The emulsion composition according to claim 8, which is used as a cosmetic.

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