KR20200095244A - A deformable liposome prepared with natural surfactants and use of the same - Google Patents

Abstract

The present invention relates to an elastic liposome prepared by using polyglyceryl-2 caprate or polyglyceryl-10-stearate as an edge activator in a phospholipid, a preparation method thereof, and a skin delivery system composition prepared by trapping a drug in the elastic liposome. The elastic liposome of the present invention has superior skin permeability and the like compared to general liposomes, and thus can be a delivery system for efficient skin delivery of various active ingredients.

Description

Elastic liposome prepared with natural surfactants and its use {A deformable liposome prepared with natural surfactants and use of the same}

The present invention relates to an elastic liposome prepared using a natural surfactant and its use.

The skin is largely composed of epidermis, dermis, and subcutaneous fat, and it plays an important role in protecting the body from harmful environments and maintaining homeostasis. The stratum corneum, which is present at the outermost part of the epidermis, protects the skin by preventing harmful substances from invading through the transdermis and acting as an antioxidant barrier. However, these skin barriers can be disrupted by air pollution and external environments such as UV rays. In particular, various reactive oxygen species (ROS) generated by ultraviolet rays damage various tissues of the body through oxidation of proteins and DNA, initiation of lipid peroxidation reaction, and destruction of antioxidants due to their high oxidative power, and skin aging. Accelerates

Therefore, various antioxidants such as vitamin C, vitamin E and flavonoids are required to remove these free radicals. Among them, flavonoids are phenolic compounds that exist in plant cells in the form of water-soluble glycosides. In general, flavonoids are called natural antioxidants and have various activities such as antioxidant, anticancer, anti-inflammatory, and anti-allergic.

Taxifolin is a peony ( paeonia lactiflora ), opuntia humifusa ) and is one of the flavonoids present in citrus fruits and onions, and has various biological effects such as antioxidant, antibacterial, anti-inflammatory, and whitening. In addition, it reduces MMP-9 and alleviates brain ischemia-reperfusion injury in rats through regulation of NF-κB activation. In addition, taxifolin glycosides were effective in skin lesions similar to atopic dermatitis in NC/Nga mice. However, taxifolin can be structurally unstable.

Taxifolin tetra octanoate, a derivative synthesized to increase the chemical stability of Taxifolin, has been reported to exhibit excellent skin whitening effects like taxifolin. However, when these antioxidant active ingredients are delivered into the skin, they must pass through the stratum corneum, the outermost layer of the skin. The stratum corneum is composed of keratinocytes and intercellular lipids that fill between them, and this structure acts as a strong barrier against foreign substances. Therefore, in order to overcome the strong skin barrier composed of the stratum corneum and deliver drugs deep into the skin, a transdermal drug delivery system is required.

Various inventions, such as liposomes, hydrogels, and nanostructured lipid carriers, have been developed as transdermal drug delivery systems. Among them, liposomes are spherical bio-like lipid membranes made by the spontaneous formation of phospholipids in aqueous solutions. Liposomes can carry a hydrophilic material inside the membrane due to the phospholipid bilayer structure, and a hydrophobic material can be carried between the bilayers, so many inventions have been made as drug delivery systems. Various liposome inventions such as ethosomes, elastic liposomes, layer by layer, cationic liposomes, and protein-coated liposomes have been actively progressed until recently in order to further enhance the skin absorption of the supported active ingredients.

Elastic liposomes are composed of phospholipids and surfactants that act as edge activators. These liposomes have elasticity and flexibility in the lipid bilayer membrane due to surfactant acting as an edge activator. Therefore, since the elastic liposome can more flexibly pass through the stratum corneum, the active ingredient can be effectively delivered deep into the skin. In the early days of the invention of elastic liposomes, surfactants having a single carbon chain such as Span 80 and Tween 80 or ionic surfactants such as sodium hexadecyl sulfates and cetylpyridinium chloride were used a lot, but these surfactants reduce the membrane stability of liposomes. There is this.

[Prior patent literature]

Korean Patent Registration 10-1684415

The present invention solves the above problems and is conceived by the necessity of the above, and an object of the present invention is to provide an elastic liposome as a carrier for efficient skin delivery of physiologically active ingredients.

In order to achieve the above object, the present invention uses an elastic liposome prepared using polyglyceryl-2 caprate or polyglyceryl-10-stearate as an edge activator. to provide.

In one embodiment of the present invention, the liposome is preferably a mixture of phosphatidylcholine: edge activator: cholesterol in a weight ratio of 7:3:3.5, but is not limited thereto.

In addition, the present invention provides a skin delivery system composition prepared by trapping a physiologically active substance in the elastic liposome of the present invention.

In addition, the present invention is a method of preparing an elastic liposome using polyglyceryl-2 caprate or polyglyceryl-10-stearate as an edge activator in the process of manufacturing an elastic liposome. Provides.

Hereinafter, the present invention will be described.

In the present invention, an elastic liposome was prepared by using polyglyceryl-2 caprate (PGL-2-caprate) and polyglyceryl-10 stearate (PGL-10-stearate), which are natural surfactants that do not irritate the skin, as an edge activator. As an example, taxifolin and taxifolin tetra octanoate were loaded and the loading efficiency and properties were compared. PGL-2-caprate is a natural nonionic surfactant derived from coconut and is an ester of capric acid and diglycerin. It helps to soften the skin and is known for its excellent moisturizing power. PGL-10-stearate is an ester of polyglycerin-10 and stearic acid. Compared to PGL-2-caprate, PGL-10-stearate has a higher number of glycerin and more carbon atoms in the hydrophobic tail. These two surfactants are polyglycerin fatty acid esters (PGFE), which are widely used in foods, cosmetics, toiletries, etc., and are not affected by temperature compared to the existing polyoxyethylene-based nonionic surfactants, thus preserving the environment. It is expected to be used as a useful surfactant for safety and safety.

In the present invention, an elastic liposome was prepared using two surfactants as edge activators, and by supporting taxifolin and its derivative, taxifolin tetra octanoate, properties and morphological observations such as size, zeta potential, stability, collection efficiency, and variable form factor were observed. Through in vitro skin permeation studies, we tried to enhance the transdermal delivery of taxifolin and its derivative, taxifolin tetra octanoate.

In the present invention, an elastic liposome was prepared using natural surfactants polyglyceryl-2 caprate and polyglyceryl-10 stearate, PC, and cholesterol to enhance skin penetration of taxifolin and taxifolin tetra octanoate, and various physical properties and in vitro skin penetration The ability was evaluated. The particle size of elastic liposomes using polyglyceryl-2 caprate was 64.70 ~ 91.30 nm, the collection efficiency was 77.94 ~ 79.44%, and the variable rate was 11.46 ~ 17.97. The elastic liposome using polyglyceryl-10 stearate was 90.20 ~ 110.70 nm, the collection efficiency was 77.87 ~ 78.96%, and the variation rate was 11.34 ~ 14.79. When comparing the capture efficiencies of liposomes loaded with taxifolin and taxifolin tetra octanoate, the capture efficiency and variability were increased when taxifolin tetra octanoate was loaded. CDLT3, CDLTO3 SDLT3, and SDLTO3, which have high collection efficiency, stability, and variability, were finally selected and the crystallinity and skin permeation invention were proceeded. The degree of crystallinity according to the type of surfactant and the type of drug supported was compared using DSC, and CDLTO3 showed the smallest melting point at 7.55 ℃, which was consistent with the result showing the largest variable form ratio. In addition, as a result of measurement using TEM for morphological observation of liposomes, it was confirmed that liposomes having a spherical shape were well formed. As a result of the invention of skin permeation of taxifolin and taxifolin tetra octanoate carried on liposomes using Franz cells, in the case of elastic liposomes CDLT3 and SDLT3, and CDLTO3 and SDLTO3, skin absorption of active ingredients is improved compared to 1,3 BG and general liposomes. Became. In particular, the amount of taxifolin tetra octanoate supported on CDLTO3 in the stratum corneum (Tape), epidermis and dermis (Skin), and the amount that penetrated the entire skin (Transdermal) was 7.90, 60.11, 73.43 μg/cm ³ , showing the largest amount of penetration. . In conclusion, it is suggested that elastic liposomes using polyglyceryl-2 caprate and polyglyceryl-10 stearate can be a delivery vehicle for efficient skin delivery of various active ingredients including taxifolin and taxifolin tetra octanoate.

In the present invention, an elastic liposome was prepared using natural surfactants PGL-2 caprate and PGL-10 stearate as edge activators in order to enhance the skin penetration of taxifolin and taxifolin tetra octanoate, and physical properties and drug penetration amount in human skin As a result of comparing the results, the stability of the prepared elastic liposomes was very high.In particular, the particle sizes of CDLT3, SDLT3, SDLTO3, and SDLTO3 showed the greatest stability due to the small size change at week 0 and week 4. Taxifolin and taxifolin tetra octanoate When comparing the trapping efficiency of liposomes carrying, the trapping efficiency was increased when taxifolin tetra octanoate was supported, and the trapping efficiency of elastic liposomes using two types of surfactants was further increased when PGL-2 caprate was used.

In conclusion, it is suggested that elastic liposomes using PGL-2 caprate and PGL-10 stearate can be a delivery vehicle for efficient skin delivery of various active ingredients including taxifolin and taxifolin tetra octanoate.

1a and b are diagrams showing the structures of taxifolin and taxifolin tetra octanoate, respectively,
Figure 2 is a picture showing the stability of elastic liposomes containing (a) taxifolin and (b) taxifolin tetra octanoate,
3 is a diagram showing the encapsulation efficiency of elastic liposomes containing taxifolin and taxifolin tetra octanoate, CDLT, CDLTO: polyglyceryl-2 caprate deformable liposomes, SDLT, SDLTO: polyglyceryl-10 stearate deformable liposomes.
Figure 4 is a picture showing the DSC thermograms of normal liposomes (LT, LTO) and elastic liposomes (CDLT3, CDLTO3, SDLT3, SDLTO3),
5 is a TEM image of (a) LT, (b) CDLT3, (c) SDLT3, (d) LTO, (e) CDLTO3, (f) SDLTO3,
Figure 6 is a 1,3-butylene glycol solution (1,3-BG), normal liposomes (LT, LTO) and elastic liposomes (CDLT3, SDLT3, CDLTO3, SDLTO3) through the in vitro skin penetration of taxifolin and taxifolin tetra octanoate Shown picture,
7 is a 1,3-butylene glycol solution (1,3-BG), normal liposomes (LT, LTO) and elastic liposomes (CDLT3, SDLT3, CDLTO3, SDLTO3) in the permeation ratio of taxifolin and taxifolin tetra octanoate after 24 hours ( %). (Tape: stratum corneum, Skin: epidermis and dermis, Transdermal: penetration through the skin).

Hereinafter, the present invention will be described in more detail through non-limiting examples.

L-α-phosphatidylcholine (from egg yolk, ≥ 99.0%), sodium phosphate monobasic (NaH ₂ PO ₄ 2H ₂ O) and sodium phosphate dibasic (Na ₂ HPO ₄ 2H ₂ O) used in cholesterol and phosphate buffer solutions All Sigma-Aldrich Co. (St. Louis, MO, USA). PGL-2-caprate, taxifolin, and taxifolin tetra octanoate were provided by Yeomyeong Biochem. Solvents such as ethanol, methanol and chloroform were manufactured by Daejung Chemical Co., Ltd (Korea), and distilled water was purified with Milli-Q.

Example 1: elasticity Liposomal Produce

The elastic liposome was prepared using a thin film hydration method, and its components and compositions are shown in Table 1. Cholesterol was added to increase the stability of liposomes. First, the constituents of Table 1 were dissolved in 25 mL of chloroform-methanol (4:1) as a solvent until completely dissolved, and then the solvent was completely removed using a rotary evaporator to form a film. 10 mL of a phosphate buffer (PB, pH 7.4) was added to the formed film to hydrate and then homogenized for 5 min using a probe sonicator. Then, it was stored by passing through a 1.2 μm filter (Minisart CA 26 mm). The content of PC and surfactant in the prepared liposome formulation was 2.5% (w/v).

Molar ratio PC: S: Chol Taxifolin (mM) Taxifolin tetra octanoate (mM) LT 10: 0: 5 0.5 - DLT1 9: 1: 4.5 0.5 - DLT2 8: 2: 4 0.5 - DLT3 7: 3: 3.5 0.5 - DLT4 6: 4: 3 0.5 - LTO 10: 0: 5 - 0.5 DLTO1 9: 1: 4.5 - 0.5 DLTO2 8: 2: 4 - 0.5 DLTO3 7: 3: 3.5 - 0.5 DLTO4 6: 4: 3 - 0.5

Table 1 shows the composition of the elastic liposome, S: polyglyceryl-2 caprate or polyglyceryl-10 stearate.

Example 2: particle size and zeta Potential

The particle size of the liposome was measured using dynamic light scattering (Otsuka ELS-Z2, Otsuka Electronics, Japan). The measurement temperature was 25°C, the scattering angle was 165°, and an argon laser was used as a light source. The average particle size was expressed by the cumulative analysis method and the distribution was analyzed by the contin method. The particle size was measured three times each 70 times and indicated the average. The zeta potential was measured 3 times each 10 times using a zetasizer (Otsuka ELS-Z2, Otsuka Electronics, Japan).

Example 3: elastic Liposomal stability

In order to confirm the stability of the prepared liposome formulations, the liposome suspension was stored at 4° C. for 4 weeks and observed. Changes in particle size and polydispersity index (P.I.) values for 4 weeks were measured, and the formation of precipitates was observed. Particle size, P.I. The measurement of the value and the zeta potential was performed in the same manner as the aforementioned method.

Example 4: drugs Capture efficiency

After removing the unsupported drug using a 0.45 μm filter, take 1 mL of the liposome suspension, add 10 mL of ethanol, and sonicate to destroy the liposome membrane. After evaporating the solvent using a rotary evaporator, the drug is dissolved again in 1 mL ethanol. The concentration of the drug was measured at UV wavelength nm using a UV-vis spectrometer, and a standard calibration curve of the drug by concentration was created using a standard solution, and the concentration of the collected drug was calculated. The value obtained at this time was substituted into Equation (1) to calculate the capture efficiency of liposomes.

× 100 (1)Entrapment efficiency(%) =

× 100 (1)

C _i : Concentration of the first drug

C _e : Concentration of captured drug

Example 5: Variable rate Measure

To evaluate the variability of the prepared elastic liposomes, a mini extruder was used to measure the degree to which the elastic liposomes pass through the artificial permeation barrier. When a pressure of 0.2 MPa was applied to the elastic liposome for 1 minute, the amount of liposome liquid that passed through the polycarbonate membrane having a pore size of 0.08 um was measured, and the size of the liposome particles passed through the membrane was measured. The elasticity value of the elastic liposome membrane is proportional to Equation (1).

(1)Deformability index = J _Flux X

(One)

J _Flux : The amount of liposome that has passed through the membrane

rv: particle size of liposome after extrusion

rp: pore size of membrane

Example 6: elastic Liposomal Crystallinity ( DSC )

In order to evaluate the crystallinity of liposomes, the transition enthalpy (ΔH°) and the peak temperature (T _peak ) of general liposomes (TL, TLO) and elastic liposomes were compared using a differential scanning calorimetry (DSC-60). It was measured at a flow rate of 100 ml/min in the presence of Nitrogen.

Example 7: Morphological observation

Transmission electron microscopy (TEM) (JEOL Ltd., Tokyo, Japan) was used for morphological observation of the prepared elastic liposome. The sample was adsorbed on a 200-mesh copper grid for 2 minutes, dyed with 0.2% (w/v%) phosphotungstic acid solution for 45s and dried. Analysis was performed at 80 kV.

Example 8: elastic Liposomal Invention of In Vitro skin penetration

Invention of in vitro skin permeation of drug-captured ceramide liposomes was carried out using Franz diffusion cells (permegear, USA). In the experiment, the back skin of a 52-year-old male with subcutaneous fat and excess tissue removed was used. The skin was immobilized with the stratum corneum facing up between the donor and receptor phases. Receptor phase (HCO-60: EtOH: PBS = 2: 20: 78, weight ratio) was filled in the receptor chamber and stirred at 150 rpm for 24 h. The temperature was maintained at 37 °C using a constant temperature water bath. As a control, a drug solution dissolved in 1,3-BG/PB at the same concentration was used, respectively. The skin in the donor compartment was treated with the same concentration of liposomes. The receptor phase was collected through the sampling port for each time. After 24h, the surface of the skin was washed with a PBS solution to measure the amount of drug contained in the stratum corneum and the skin, and then the stratum corneum was removed three times by a stripping method using 3 M scotch tape (Korea 3M). After that, the tape and the drug in the skin were each dissolved in 100% ethanol using sonication. The concentration of the collected drug was measured using a UV/Vis spectrophotometer.

The results of the above example are as follows.

Particle size and zeta Potential

Taxifolin and taxifolin tetra octanoate were supported on elastic liposomes prepared by varying the ratios of surfactants PGL-2 caprate and PGL-10 stearate. As a control group, general liposomes (LT, LTO) each carrying taxifolin and taxifolin tetra octanoate were prepared and compared (Table 1). Table 2 shows the particle size, polydispersity Index (P.I.) and zeta potential after 1 day of the prepared elastic liposome. As a result of comparing the particle size of elastic liposomes using PGL-2 caprate, the particle size tended to decrease as the surfactant increased regardless of the loaded drug. On the other hand, elastic liposomes using PGL-10 stearate increased in size as the surfactant content increased, but decreased when the content reached the maximum (40%). It is believed that the lipid membrane composed of PC was collapsed due to the excessive addition of surfactant. When comparing the elastic liposomes using PGL-2 caprate and PGL-10 stearate, the particle size of the elastic liposomes using PGL-10 stearate was larger. This is thought to be due to the fact that PGL-10 stearate has more glycerin and hydrophobic tail carbons than PGL-2 caprate. When comparing the particle sizes of the elastic liposomes carrying taxifolin and taxifolin tetra octanoate, the particle size of the liposomes carrying taxifolin tetra octanoate increased slightly. Since the molecular size of taxifolin tetra octanoate is larger than that of Taxifolin, it is thought that the size of liposomes increased after loading. Liposomal P.I. A value of 0.3 or less indicates monodispersion, and a value of 0.3 or more indicates polydispersity. Zeta potential represents the surface charge of liposomes, and stability can be predicted from this value. It means that the zeta potential of liposomes is stable as all except CDLTO4 show values below -25 mV. In addition, as the content of the surfactant increased, this value tended to increase slightly.

Particle size
(nm) Polydispersity index (P. I.) Zeta potential (mV) Entrapment efficiency
(%) LT 88.40 ± 0.50 0.24 ± 0.00 -34.31 ± 2.50 78.03 ± 0.02 CDLT1 87.80 ± 0.20 0.24 ± 0.01 -29.45 ± 1.20 77.94 ± 0.03 CDLT2 80.10 ± 1.20 0.24 ± 0.00 -27.92 ± 1.33 78.34 ± 0.04 CDLT3 74.70 ± 1.50 0.24 ± 0.00 -26.42 ± 0.32 78.76 ± 0.12 CDLT4 64.70 ± 2.50 0.23 ± 0.00 -25.41 ± 0.20 79.10 ± 0.09 SDLT1 90.20 ± 0.20 0.19 ± 0.00 -34.87 ± 1.22 77.87 ± 0.02 SDLT2 100.60 ± 1.30 0.20 ± 0.01 -30.29 ± 0.50 78.22 ± 0.04 SDLT3 103.20 ± 0.50 0.22 ± 0.01 -28.57 ± 0.35 78.43 ± 0.17 SDLT4 101.60 ± 0.60 0.22 ± 0.01 -26.22 ± 0.25 78.38 ± 0.13 LTO 91.30 ± 0.30 0.23 ± 0.01 -35.99 ± 1.23 80.23 ± 0.24 CDLTO1 88.00 ± 0.50 0.23 ± 0.00 -31.32 ± 0.30 79.44 ± 0.06 CDLTO2 81.80 ± 0.20 0.22 ± 0.01 -27.42 ± 0.52 79.29 ± 0.04 CDLTO3 75.50 ± 1.30 0.25 ± 0.01 -25.23 ± 0.32 79.17 ± 0.08 CDLTO4 70.00 ± 0.30 0.26 ± 0.00 -22.86 ± 0.26 78.84 ± 0.06 SDLTO1 95.50 ± 0.20 0.21 ± 0.01 -30.12 ± 0.22 78.67 ± 0.09 SDLTO2 109.60 ± 1.20 0.22 ± 0.02 -29.35 ± 0.13 78.73 ± 0.04 SDLTO3 110.70 ± 1.50 0.23 ± 0.01 -28.23 ± 0.35 78.96 ± 0.01 SDLTO4 103.40 ± 0.50 0.23 ± 0.00 -27.56 ± 0.55 78.66 ± 0.10 CDLT: Taxifolin loaded polyglyceryl-2 caprate deformable liposomes, SDLT: Taxifolin loaded polyglyceryl-10 stearate deformable liposomes, CDLTO: Taxifolin tetra octanoate loaded polyglyceryl-2 caprate deformable liposomes, SDLTO: Taxifolin tetra octanoate loaded polyglyceryl-10 stearate deformable liposomes.

Table 2 is a table showing the average particle size, polydispersity index, Zeta Potential, and collection efficiency of elastic liposomes.

Liposomal stability

In order to evaluate the stability of the prepared elastic liposome, the change in particle size of the liposome was measured after storage at 4°C for 4 weeks (FIG. 2). In general, when the liposome is unstable, the particles aggregate with each other to increase the average particle size. After 4 weeks, the particle size of the liposomes slightly increased, but there was no significant change, and the absolute value of the zeta potential was also slightly increased, confirming that the stability of the liposomes was very high. Particularly, the particle size of CDLT3, SDLT3, SDLTO3, and SDLTO3 showed the greatest stability due to small changes in week 0 (74.70, 103.20, 75.50, 110.70 nm) and week 4 (74.80, 104.30, 75.90, 111.80 nm).

drug Capture efficiency

Tables 2 and 3 show the drug encapsulation efficiency of elastic liposomes loaded with taxifolin and taxifolin tetra octanoate. The trapping efficiency of general liposomes (LT) carrying taxifolin was 78.03%, and the value of PGL-2 caprate elastic liposomes (CDLT) carrying taxifolin increased as the surfactant increased. On the other hand, in the case of general liposome (LTO) carrying taxifolin tetra octanoate, the collection efficiency increased to 80.23%, and the value of PGL-2 caprate elastic liposome (CDLTO) decreased as the surfactant increased. In the case of elastic liposomes (SDLT, SDLTO) using PGL-10 stearate, the collection efficiency increases as the surfactant content increases, and then in the liposomes (SDLT4, SDLTO4) using the maximum content (40%) of surfactants to 78.38, 78.66% again. Decreased. It is believed that the micelles formed due to an excessive amount of surfactant disperse the drug in the solvent, resulting in a relatively reduced drug capture efficiency.

Variable rate

The greater the variability, the more easily the liposome can pass through the stratum corneum of the skin due to its elasticity, which has the advantage of being able to deliver the active ingredient deep into the skin. To evaluate the variability of liposomes, an extrusion method was used, and the Deformability Index was measured using Equation (1) (Table 3). The deformability index of LT and LTO were 6.40 and 6.79, respectively. On the other hand, the deformability index of elastic liposomes was about 2 times higher than that of general liposomes. In particular, CDLTO showed the highest deformability index, followed by SDLTO, CDLT, and SDLT. In addition, this value increased with increasing surfactant content in the elastic liposome using PGL-2 caprate, and increased with the surfactant content in the elastic liposome using PGL-10 stearate, but rather decreased in the maximum surfactant content (SDLT4, SDLTO4). Showed a tendency to do. In consideration of these results, collection efficiency, and stability, CDLT3, CDLTO3 SDLT3 and SDLTO3 with high variability and stability were finally selected to conduct crystallinity and skin permeation studies.

Deformability index Deformability index LT 6.40 ± 0.12 LTO 6.79 ± 0.01 CDLT1 11.46 ± 0.15 CDLTO1 11.67 ± 0.36 CDLT2 12.94 ± 0.19 CDLTO2 13.27 ± 0.24 CDLT3 14.58 ± 0.20 CDLTO3 14.92 ± 0.13 CDLT4 17.33 ± 0.09 CDLTO4 17.97 ± 0.19 SDLT1 11.34 ± 0.50 SDLTO1 11.46 ± 0.33 SDLT2 12.13 ± 0.23 SDLTO2 12.82 ± 0.21 SDLT3 13.99 ± 0.22 SDLTO3 14.79 ± 0.12 SDLT4 12.55 ± 0.35 SDLTO4 13.56 ± 0.52 CDLT: Taxifolin loaded polyglyceryl-2 caprate deformable liposomes, SDLT: Taxifolin loaded polyglyceryl-10 stearate deformable liposomes, CDLTO: Taxifolin tetra octanoate loaded polyglyceryl-2 caprate deformable liposomes, SDLTO: Taxifolin tetra octanoate loaded polyglyceryl-10 stearate deformable liposomes.

Table 3 is a table showing the variation ratio of general liposomes (LT, LTO) and elastic liposomes

Shout Liposomal Crystallinity ( DSC )

Surfactants added to liposomes reduce the degree of crystallinity by interfering with the binding between lipids. This means that the variability of liposomes is increased by increasing the fluidity of the liposome lipid membrane. Therefore, to compare the change in crystallinity according to the type of surfactant and the type of drug supported, the transition enthalpy (△H°) of general liposomes (LT, LTO) and elastic liposomes (CDLT3, CDLTO3, SDLT3, SDLTO3) and The peak temperature (T _peak ) was compared (FIG. 4).

The transition enthalpy (ΔH°) of LT and LTO were 45.27 and 48.26 cal/g, respectively, and the peak temperatures (Tpeak) were 8.35 and 8.70 °C. The peak temperature decreased in the order of SDLT3, CDLT3, SDLTO3, and CDLTO3, and the lowest was 7.55 °C in CDLTO3. Therefore, it was confirmed that the decrease in the melting point of the liposome by the surfactant weakens the crystallinity, thereby increasing the membrane fluidity of the liposome, and thereby increasing the variability of the liposome.

Morphological observation

Taxifolin and taxifolin tetra octanoate were measured using TEM for morphological observation of the general liposomes and elastic liposomes supported (FIG. 5). The particle size of general liposomes and elastic liposomes was similar to the results measured using dynamic light scattering. It was confirmed that liposomes having a spherical shape were well formed through TEM images.

In Vitro skin penetration study using Franz Cell

Skin penetration studies of taxifolin and taxifolin tetra octanoate carried on liposomes were conducted using Franz cells (FIGS. 6 and 7). The skin penetration amount of taxifolin per time was 1,3 BG <normal liposome (LT) <PGL-10 stearate elastic liposome (SDLT3) <PGL-2 caprate elastic liposome (CDLT3) (Fig. 6). The skin penetration amount of taxifolin tetra octanoate over time was significantly increased compared to taxifolin, and 1,3 BG <normal liposome (LTO) <PGL-10 stearate elastic liposome (SDLTO3) <PGL-2 caprate elastic liposome (CDLTO3) was found ( Fig. 6). After 24 h, the skin penetration of taxifolin and taxifolin tetra octanoate showed a similar trend (Fig. 7). In the case of Taxifolin's skin penetration invention, in the case of 1,3 BG, which is a control group, the amount present in the stratum corneum (Tape), epidermis and dermis layer (Skin) after 24 h, and the amount that penetrated the entire skin (Transdermal) was 2.51, 16.20, 15.97 μg/g/, respectively. cm ³ It was this. In the case of taxifolin loaded on a general liposome (LT), the amount present in the stratum corneum (Tape), the epidermis, and the dermal layer (Skin), and the amount that penetrated the entire skin (Transdermal) was 5.50, 23.55, 24.46 μg/cm ³ As compared to 1,3 BG, the amount of drug permeation was increased. The amount of taxifolin loaded on the elastic liposomes CDLT3 and SDLT3 was further increased compared to taxifolin loaded on 1,3 BG and normal liposomes. In particular, the amount of taxifolin supported on CDLT3 in the stratum corneum (Tape), epidermis, and dermis (Skin), and the amount that penetrated the entire skin (Transdermal) was 14.86, 35.53, 36.68 μg/cm ³ Increased significantly. This is thought to be due to the smaller size of elastic liposomes using PGL-2 caprate compared to PGL-10 stearate. In the skin permeation study of Taxifolin tetra octanoate, the amount of permeation was higher than that of taxifolin. In the case of 1,3 BG, which is a control group, the amounts present in the stratum corneum (Tape), epidermis and dermis layers (Skin), and the amount that penetrated the entire skin (Transdermal) were 8.81, 30.77, and 57.63 μg/cm ³ , respectively. The amount of permeation of taxifolin tetra octanoate supported on normal liposomes (LTO) and elastic liposomes (CDLTO3, SDLTO3) was remarkably increased. In particular, the amount of taxifolin tetra octanoate supported on CDLTO3 in the stratum corneum (Tape), epidermis and dermis (Skin), and the amount that penetrated the entire skin (Transdermal) was 7.90, 60.11, 73.43 μg/cm ³ , showing the largest amount of penetration. .

Claims (4)

An elastic liposome prepared by using polyglyceryl-2 caprate or polyglyceryl-10-stearate as an edge activator in phospholipids. The elastic liposome according to claim 1, wherein the liposome has a mixture weight ratio of phosphatidylcholine: edge activator: cholesterol of 7:3:3.5. A skin delivery system composition prepared by trapping a physiologically active substance in the elastic liposome of claim 1 or 2. A method of preparing an elastic liposome by using polyglyceryl-2 caprate or polyglyceryl-10-stearate as an edge activator as a phospholipid in the process of manufacturing an elastic liposome.

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