KR102365597B1 - Emulsion composition, drug composition having the emulsion composition, and cosmetic composition having the emulsion composition - Google Patents

Abstract

An emulsion composition is disclosed. The emulsion composition comprises an emulsion aggregate and an amphiphilic second block copolymer compound and a first block copolymer compound and the first lecithin compound to form spherical micelles that support the active ingredient-containing oil therein. 2 The lecithin compound is provided with a micellar linker that forms a micelle form that does not carry oil therein.

Description

Emulsion composition, and pharmaceutical composition and cosmetic composition comprising the same

The present invention relates to an emulsion composition capable of delivering an active active ingredient into the human body, and a pharmaceutical composition and cosmetic composition comprising the same.

Recently, due to the growth of the bio industry, interest in functional drug delivery systems is increasing. In particular, in the field of transdermal drug delivery, many studies are being conducted to increase drug delivery efficiency by giving functionality to drug delivery platforms ranging from tens to hundreds of nanoscales, such as micelles and liposomes. Although this is the most efficient method for overcoming the skin barrier effect, which is the core of transdermal absorption, it presents problems with the physical stability of the drug delivery system or drug collection efficiency. Therefore, in order to overcome this effectively, it is required to develop a drug delivery system that is structurally stable and capable of imparting functionality using a polymer.

Recently, the development of a technology for improving the structural stability and biocompatibility of a drug delivery system using a nano-emulsion using a biodegradable polymer is in progress. However, even if a biodegradable polymer is used, it is additionally required to develop a technology that can efficiently utilize physical stability, drug trapping ability, and interaction between particles in order to enhance transdermal absorption.

One object of the present invention is to provide an emulsion composition that is physically stable and can improve the transdermal absorption capacity of a functional drug carrier by controlling the rheological properties of the nanoemulsion fluid.

Another object of the present invention is to provide a drug composition comprising the emulsion composition.

Another object of the present invention is to provide a cosmetic composition comprising the emulsion composition.

An emulsion composition according to an embodiment of the present invention, the first block copolymer compound and the first lecithin compound are emulsion aggregates forming spherical micelles supporting the active ingredient-containing oil (oil) therein; and a micelle-type linker in which the amphiphilic second block copolymer compound and the second lecithin compound form a micellar form that does not contain an oil therein, wherein each of the first and second block copolymer compounds is each other Independently, it may be a triblock copolymer in which polyethylene glycol (A), which is a hydrophilic polymer, and polycaprolactone (B), which is a hydrophobic polymer, are connected to each other via a urethane linkage derived from a diisocyanate compound.

In one embodiment, each of the first and second lecithin compounds is a compound having zwitterionic properties independently of each other, and at least one selected from the group consisting of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides and phospholipids may include

In one embodiment, each of the first and second lecithin compounds may include phosphatidylcholine, phosphatidylethanolamine or phosphatidylinositol independently of each other.

In one embodiment, the emulsion aggregate may include the first lecithin compound in a ratio of 15 to 50 parts by weight based on 100 parts by weight of the first block copolymer compound.

In one embodiment, the micellar linker may include the second lecithin compound in a ratio of 15 to 50 parts by weight based on 100 parts by weight of the second block copolymer compound.

In one embodiment, the first lecithin compound may self-associate with the first block copolymer compound, and the second lecithin compound may self-associate with the second block copolymer compound.

In one embodiment, the first block copolymer compound may have a molecular weight of 10,000 to 30,000 Da, and the second block copolymer compound may have a molecular weight of 3,000 to 12,000 Da.

In one embodiment, the molecular weight of the hydrophilic block of the second block copolymer compound is smaller than the molecular weight of the hydrophilic block of the first block copolymer compound, so the hydrophilic chain length of the second block copolymer compound is the first block It may be less than the hydrophilic chain length of the copolymer compound. For example, the molecular weight of the second block copolymer compound may be about 3000 to 9000 Da.

In one embodiment, the emulsion aggregate and the micellar linker may be included in a weight ratio of 100: 1 to 100: 10.

The emulsion composition may be applied as a carrier in the body of an active ingredient in a pharmaceutical composition or a cosmetic composition.

According to the emulsion composition of the present invention, since it contains a micellar linker together with the emulsion aggregate, it is possible to control the rheological properties of a physically stable nanoemulsion fluid to improve the transdermal absorption ability of the functional drug carrier, and through this, cosmetics, pharmaceuticals, etc. Performance as a drug delivery system can be improved.

In addition, in the emulsion composition of the present invention, since the formulation can be prepared through a simple emulsification method, it is suitable for solubilization and mass production, and various active ingredients such as various drugs can be simultaneously supported according to the solubilization conditions, and furthermore, the polymer It can lead to diversification of nano-linker-based drug delivery system formulations that can control the dipole-dipole interaction between phospholipids according to polymer properties.

1A and 1B are views for explaining an emulsion composition according to an embodiment of the present invention.
2 is a particle size distribution ('A') measured using a particle size analyzer (ELS-Z2, Otsuka, Japan) using dynamic light scattering for the micellar nanolinker prepared according to Example 1; , average particle size ('■') and zeta potential ('●') ('B') measured using ELS-Z2 (Otsuka, Japan) and nanoemulsion fluid, hydrophilic micelle type with short length Electron microscopy images ('C', 'D', 'E') of the nano-linker, the micelle-type nano-linker with a long hydrophilic length are shown.
3 is a graph showing the storage modulus (closed symbol) and loss modulus (open symbol) distribution ('B') according to the vibrational strain ('A') and vibration frequency of the nanoemulsion fluid into which the micellar nanolinker is introduced.
4 is a graph showing the results of the in vitro skin absorption test method of the nanoemulsion fluid.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. Since the present invention can have various changes and can have various forms, specific embodiments are illustrated in the drawings and described in detail in the text. However, this is not intended to limit the present invention to the specific disclosed form, it should be understood to include all modifications, equivalents and substitutes included in the spirit and scope of the present invention. In describing each figure, like reference numerals have been used for like elements.

The terms used in the present application are only used to describe specific embodiments and are not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly dictates otherwise. In the present application, terms such as “comprise” or “have” are intended to designate that a feature, step, operation, component, part, or combination thereof described in the specification is present, and includes one or more other features or steps. , it should be understood that it does not preclude the possibility of the existence or addition of an operation, a component, a part, or a combination thereof.

Unless defined otherwise, all terms used herein, including technical and scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and should not be interpreted in an ideal or excessively formal meaning unless explicitly defined in the present application. does not

1A and 1B are views for explaining an emulsion composition according to an embodiment of the present invention.

1A and 1B, the emulsion composition according to an embodiment of the present invention may include an emulsion aggregate and a micellar linker.

The emulsion aggregate may include an amphiphilic first block copolymer compound, a first lecithin compound, and an active ingredient-containing oil, wherein the first block copolymer compound and the first lecithin compound are It is possible to form spherical micelles carrying an active ingredient-containing oil therein.

The first block copolymer compound may include an ABA type triple block polymer. In one embodiment, in the first block copolymer compound, polyethylene glycol (A), which is a hydrophilic polymer, and polycaprolactone (B), which is a hydrophobic polymer, are connected to each other through a urethane linkage derived from a diisocyanate (diisocanate) compound. It may be a triblock copolymer (ABA). The first block copolymer compound may include the polyethylene glycol (A) and the polycaprolactone (B) in a molecular weight ratio of about 1: 0.1 to 1: 5.

In one embodiment, the first block copolymer compound may be a triblock copolymer (A-B-A) having a molecular structure of Formula 1 below.

[Formula 1]

In Formula 1, m may be an integer of about 10 to 350, and n may be an integer of about 2 to 100.

In one embodiment, the first block copolymer compound may have a molecular weight of about 10,000 to 30,000 Da.

The first lecithin compound is a compound having zwitterionic properties, and may be a fatty substance group consisting of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids. For example, the first lecithin compound may include one or more selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and the like.

When the emulsion aggregate includes the first lecithin compound together with the first block copolymer compound, the first lecithin compound acts as an auxiliary surfactant to further improve the stability of the oil-water interface as well as the surfactant When formed, it can self-associate with the first block copolymer compound, and thus can impart functionality to the emulsion composition, thereby serving as an intelligent drug delivery system.

In addition, when the first lecithin compound functions as a cosurfactant, the lecithin compound has a structure similar to that of a cell membrane, thereby improving drug delivery performance. And by generating a dipole-dipole interaction between the methoxy functional group at the end of polyethylene glycol, which is a hydrophilic group of the first block copolymer compound, and the phosphorylcholine functional group of the first lecithin compound, interaction between the droplets can be induced, which Considering the formulation stability and transdermal absorption performance, the performance of the emulsion composition as a drug carrier can be improved.

In one embodiment, the emulsion aggregate may include the first lecithin compound in a ratio of about 15 to 50 parts by weight based on 100 parts by weight of the first block copolymer compound.

The micellar linker may include an amphiphilic second block copolymer compound and a second lecithin compound, and the second block copolymer compound and the second lecithin compound are micelles having no oil therein. can be formed

In one embodiment, the second block copolymer compound is a hydrophilic polymer, polyethylene glycol (A) and a hydrophobic polymer, polycaprolactone (B) are connected to each other via a urethane linkage derived from a diisocyanate (diisocanate) compound. It may be a triblock copolymer (ABA). The second block copolymer compound may include the polyethylene glycol (A) and the polycaprolactone (B) in a molecular weight ratio of about 1: 0.1 to 1: 5. In one embodiment, the second block copolymer compound may be a triblock copolymer (A-B-A) having the molecular structure of Formula 1,

In one embodiment, the second block copolymer compound may have a molecular weight of about 3,000 to 12,000 Da.

In one embodiment, the molecular weight of the hydrophilic block of the second block copolymer compound is smaller than the molecular weight of the hydrophilic block of the first block copolymer compound, so that the hydrophilic chain length of the second block copolymer compound is the first block It may be shorter than the hydrophilic chain length of the copolymer compound. For example, the molecular weight of the second block copolymer compound may have a molecular weight of about 3000 to 9000 Da, preferably about 4,000 to 8,000 Da. In this case, compared to the case where the hydrophilic chain length of the second block copolymer compound is the same as or greater than the hydrophilic chain length of the first block copolymer compound, the emulsion composition interacts more actively with the skin layer, so that the skin Since the barrier can be effectively overcome, the skin penetration performance of the emulsion composition can be improved.

Since the second lecithin compound is substantially the same as the first lecithin compound, a redundant detailed description thereof will be omitted.

In one embodiment, the micellar linker may include the first lecithin compound in a ratio of about 15 to 50 parts by weight based on 100 parts by weight of the first block copolymer compound.

When the micellar linker includes the second lecithin compound together with the second block copolymer compound, the second lecithin compound acts as a cosurfactant and as described in the emulsion association above, the emulsion according to the present invention The drug delivery ability of the composition may be improved.

In addition, when a micellar linker comprising the second lecithin compound is included together with the emulsion aggregate, the rheological behavior can be controlled by interaction between droplets-nanolinker-droplets under the same droplet concentration, and in this case, the micelles Depending on the length of the hydrophilic polymer of the type linker, different rheological behaviors may be exhibited. For example, when the hydrophilic chain length of the micellar linker is shorter than the hydrophilic chain length of the emulsion aggregate, the dipole-dipole force between the droplet and the nanolinker acts unilaterally to weaken the gel structure, whereas the micelles When the hydrophilic chain length of the type linker is the same as the hydrophilic chain length of the emulsion aggregate, an additional crosslinking point between the droplet networks can be formed by mutually generating a dipole force between the droplet and the nanolinker under the same droplet concentration. The elastic modulus of the emulsion formulation can be increased to form a strong gel.

In one embodiment, the emulsion composition may include the emulsion aggregate and the micellar linker in a weight ratio of about 100: 1 to 100: 10.

According to the emulsion composition of the present invention, since it contains a micellar linker together with the emulsion aggregate, it is possible to control the rheological properties of a physically stable nanoemulsion fluid to improve the transdermal absorption ability of the functional drug carrier, and through this, cosmetics, pharmaceuticals, etc. Performance as a drug delivery system can be improved.

In addition, in the emulsion composition of the present invention, since the formulation can be prepared through a simple emulsification method, it is suitable for solubilization and mass production, and various active ingredients such as various drugs can be simultaneously supported according to the solubilization conditions, and furthermore, the polymer It can lead to diversification of nano-linker-based drug delivery system formulations that can control the dipole-dipole interaction between phospholipids according to polymer properties.

Hereinafter, embodiments of the present invention will be described in detail. However, the following examples are merely some embodiments of the present invention, and the scope of the present invention is not limited to the following examples.

<Example 1>: Preparation of micellar nanolinker

A triblock polymer (PEO-b-PCL-b-PEO) and lecithin (P75-3) having a molecular weight of 6,000 Da were completely dissolved in THF. The triblock polymer and the lecithin were mixed in a weight ratio of 8:2.

Then, the solution was stirred at 750 rpm and distilled water was added at a rate of 100 ul/min. Then, after evaporating the solvent using a rotary fractionator of THF, a micelle-type nanolinker was prepared.

<Example 2>: Preparation of micelle-type nanolinker-based nanoemulsion fluid

A triblock polymer (PEO-b-PCL-b-PEO) having a molecular weight of 20,000 Da and lecithin (P75-3) were mixed in 1,3-butylene glycol and then completely dissolved by heating at 80°. At this time, the triblock polymer and the lecithin were mixed in a weight ratio of 8:2.

Then, after adding 60 wt% of water, it was dispersed using a homogenizer, and then after adding 40 wt% of oil, the first emulsification was performed with a homogenizer, and then the second emulsification was performed at 1,000 bar using a high pressure homogenizer a total of 5 times. Proceeding to prepare a micelle-type nanolinker induction-based nanoemulsion fluid.

<Comparative Example 1>

A gel structure with a high storage modulus was formed by dipole interaction between the droplets without introducing a nanolinker into the nanoemulsion fluid having the same droplet concentration.

<Comparative Example 2>

A gel structure with high storage elastic modulus was formed by introducing a micelle-type nanolinker having the same hydrophilic chain length as the hydrophilic chain length along with the nanoemulsion.

<Experimental example>

2 is a particle size distribution ('A') measured using a particle size analyzer (ELS-Z2, Otsuka, Japan) using dynamic light scattering for the micellar nanolinker prepared according to Example 1; , average particle size ('■') and zeta potential ('●') ('B') measured using ELS-Z2 (Otsuka, Japan) and nanoemulsion fluid, hydrophilic micelle type with short length Electron microscopy images ('C', 'D', 'E') of the nano-linker and the long hydrophilic micelle-type nano-linker are shown.

Referring to FIG. 2 , the average particle size of the micellar nanolinker was about 80 to 90 nm for the nanolinker containing 3 wt% surfactant, regardless of the length of the hydrophilic polymer, and the surface charge was about -25 to -15 mV. was measured. In addition, the average particle size of the nanoemulsion was about 400 nm, and the surface charge was measured to be about -35 mV.

3 is a graph showing the storage modulus (closed symbol) and loss modulus (open symbol) distribution ('B') according to the vibrational strain ('A') and vibration frequency of the nanoemulsion fluid into which the micellar nanolinker is introduced.

Referring to FIG. 3 , it can be seen that different rheology control behaviors are exhibited according to the introduction of the micellar nanolinker under the same droplet concentration. Specifically, by the introduction of a nanolinker with a short hydrophilic polymer chain length ('NE+short-NL'), the force between the droplet and the nanolinker acts unilaterally to interfere with the network between the droplets. It has been shown to form a gel.

In contrast, the composition ('NE') in which the nanolinker was not introduced was found to form a strong gel with a high storage modulus due to the dipole interaction between droplets. In addition, the composition ('NE+long-NL') introduced with a nanolinker with a long hydrophilic polymer chain length generates an additional crosslinking point between the droplet networks by mutually generating a dipole force between the droplet and the nanolinker under the same droplet concentration. It has been shown to form a strong gel with a relatively high storage modulus.

In order to evaluate the transdermal absorption performance of the nanoemulsion fluid through the micellar nanolinker, an ex vivo skin absorption test (OECD guideline TG. No. 428) based transdermal absorption test was performed, and FIG. 4 shows the in vitro skin of the nanoemulsion fluid. It is a graph showing the results of the absorption test method. In FIG. 4, '■''▲' and '●' denotes a nanoemulsion fluid into which a micellar nanolinker is not introduced, a nanoemulsion fluid into which a micellar nanolinker having a long hydrophilic chain is introduced, and a micelle having a short hydrophilic chain. The degree of permeation of the nano-emulsion fluid into which the nano-type nano-linker is introduced is respectively indicated.

Referring to FIG. 4, for the test of FIG. 4, 0.1 wt% of pseudoceramide (Hydroxypropyl Bispalmitamide MEA) was added in the surfactant composition of Example 1 to prepare a sample in the same manner. After applying the sample to the Franz cell, samples were collected and analyzed after 3 hours, 6 hours, 9 hours, and 24 hours, respectively. As a result, the transdermal absorption performance of the nanoemulsion fluid sample containing the micellar nanolinker with a short hydrophilic polymer chain was the best. Excellent was confirmed. This is a result of the increase in the skin activation power of the nanoemulsion fluid, which has weakened the force between the gel droplets due to the introduction of the nanolinker with a short hydrophilic polymer length, and thus the percutaneous absorption performance is increased.

When compared with the results of <Comparative Example 1> or <Comparative Example 2> in which the same amount of pseudoceramide was added, it was confirmed that the nanolinker having a short hydrophilic chain effectively overcomes the skin barrier. This is explained by the improved skin permeation performance by allowing the weak nanoemulsion gel formed by the nanolinker with a short hydrophilic polymer chain to more actively interact with the skin layer.

Although the above has been described with reference to the preferred embodiment of the present invention, those skilled in the art can variously modify and change the present invention without departing from the spirit and scope of the present invention as set forth in the following claims. You will understand that you can.

does not exist

Claims (12)

an emulsion aggregate comprising a first block copolymer compound and a first lecithin compound and forming spherical micelles containing an active ingredient-containing oil therein; and
The second amphiphilic block copolymer compound and the second lecithin compound include a micelle-type linker that forms a micelle form that does not support oil therein,
The first and second block copolymer compounds are each independently connected to each other through a urethane linkage derived from a diisocyanate compound in which polyethylene glycol (A), a hydrophilic polymer, and polycaprolactone (B), a hydrophobic polymer, are each independently connected to each other. An emulsion composition, characterized in that it is a triblock copolymer. According to claim 1,
Each of the first and second lecithin compounds is a compound exhibiting zwitterionic ionicity independently of each other, and comprises at least one selected from the group consisting of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides and phospholipids. , emulsion composition. 3. The method of claim 2,
The first and second lecithin compounds are each independently from each other, characterized in that it comprises phosphatidylcholine, phosphatidylethanolamine or phosphatidylinositol, the emulsion composition. According to claim 1,
The emulsion aggregate is characterized in that it comprises 15 to 50 parts by weight of the first lecithin compound with respect to 100 parts by weight of the first block copolymer compound, the emulsion composition. According to claim 1,
The micellar linker is an emulsion composition, characterized in that it contains the second lecithin compound in a ratio of 15 to 50 parts by weight based on 100 parts by weight of the second block copolymer compound. According to claim 1,
The first lecithin compound is self-associated with the first block copolymer compound,
The second lecithin compound is characterized in that self-associated with the second block copolymer compound, the emulsion composition. According to claim 1,
The first block copolymer compound has a molecular weight of 10,000 to 30,000 Da,
The second block copolymer compound is characterized in that it has a molecular weight of 3,000 to 12,000 Da, the emulsion composition. 8. The method of claim 7,
Since the molecular weight of the hydrophilic block of the second block copolymer compound is smaller than the molecular weight of the hydrophilic block of the first block copolymer compound, the hydrophilic chain length of the second block copolymer compound is the hydrophilic chain of the first block copolymer compound. An emulsion composition, characterized in that it is smaller than the length. 9. The method of claim 8,
The second block copolymer compound has a molecular weight of 3000 to 9000 Da, characterized in that the emulsion composition. The method of claim 1,
An emulsion composition comprising the emulsion aggregate and the micellar linker in a weight ratio of 100: 1 to 100: 10. delete A cosmetic composition comprising the emulsion composition of any one of claims 1 to 10.

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