KR20200085529A - Solid lipid nanoparticles for skin permeation and composition for drug delivery comprising the same - Google Patents

Abstract

The present invention relates to solid lipid nanoparticles for skin permeation, and a composition for drug delivery containing the solid lipid nanoparticles. More specifically, the solid lipid nanoparticles according to the present invention have uniform and stable size, have fast dissolution rate, penetrate the skin with high efficiency, and are evenly delivered to the stratum corneum as well as a lower part of the skin when a drug for atopy treatment is collected, thereby being able to be usefully used for delivering drugs for treating poorly soluble atopy.

Description

Skin-permeable solid lipid nanoparticles and a composition for drug delivery comprising the solid lipid nanoparticles {SOLID LIPID NANOPARTICLES FOR SKIN PERMEATION AND COMPOSITION FOR DRUG DELIVERY COMPRISING THE SAME}

The present invention relates to a skin-permeable solid lipid nanoparticle and a composition for drug delivery comprising the solid lipid nanoparticle.

Atopic dermatitis is a chronic skin disease that is frequently unexplained medically occurring in modern people. It is estimated that it is related to genetic factors and immune system deficiency, but the exact cause has not been identified. In addition, atopic dermatitis is expected to be somewhat alleviated by improving the environment and diet, and there is no fundamental treatment.

Although there are individual differences, atopic dermatitis generally involves skin irritation, rash, and sores, including severe itching, and is often accompanied by emotional anxiety, stress, tension, and other allergic diseases. Representative drugs known to be effective against atopic dermatitis so far include sedatives, antihistamines, antibiotics, nonsteroidal drugs, and other sedatives and neurostabilizers. In this regard, Korean Patent Registration No. 10-1906896 discloses a composition for the treatment of atopic dermatitis of tamol and myrcene compounds that inhibits the expression of thymus and activation-regulated chemokine (TARC), a specific factor for atopic dermatitis.

Currently, atopic dermatitis is treated through a three-step process. Firstly, as a non-drug therapy, petroleum jelly and baby powder that moisturize dry skin are used. Secondly, topical external steroids are used in combination with the first non-drug therapy. In severe atopic dermatitis patients, drugs such as tacrolimus and pimecrolimus, which are topical immunosuppressants, are used.

However, only three products are commercially available for ointments including tacrolimus and pimecrolimus. This is thought to be due to the physicochemical and difficult properties of the active ingredient. For example, tacrolimus has a large molecular weight of 882.95 g/mol, a large, poorly soluble substance, and a solubility of only 0.012 mg/ml. In addition, tacrolimus is likely to have a problem with a log P value of 3.96±0.83. Therefore, research into solving the poorly soluble characteristics of the treatment for atopic dermatitis has been continued.

Republic of Korea Patent Registration No. 10-1906896

It is an object of the present invention to provide a skin-permeable solid lipid nanoparticle and a composition for drug delivery comprising the solid lipid nanoparticle to solve the problems of the conventional poorly soluble drug.

Another object of the present invention is to provide a method for preparing the skin-permeable solid lipid nanoparticles.

In order to achieve the above object, the present invention is a lecithin; Nonionic surfactants; And it provides a skin-permeable solid lipid nanoparticles comprising any one or more selected from the group consisting of stearic acid and coco glyceride.

In addition, the present invention provides a drug delivery system comprising the skin-permeable solid lipid nanoparticles.

In addition, the present invention provides a pharmaceutical composition for the treatment of atopy comprising the skin-permeable solid lipid nanoparticles, in which a drug for treatment of atopy is captured.

In addition, the present invention provides a cosmetic composition for improving atopy comprising the skin-permeable solid lipid nanoparticles in which a drug for treatment of atopy is collected.

Furthermore, the present invention comprises the steps of dissolving stearic acid in an organic solvent to obtain a solution; Homogenizing a lecithin and a nonionic surfactant in an organic solvent to obtain a homogenate; Mixing the obtained solution and a homogeneous solution to obtain a mixed solution; Provided is a method for preparing the skin-permeable solid lipid nanoparticles, comprising the steps of adding the obtained mixed solution to a solvent in which a nonionic surfactant is dissolved while stirring to obtain solid lipid nanoparticles.

The solid lipid nanoparticles according to the present invention are uniform and stable in size when collecting drugs for the treatment of atopy, have a high dissolution rate, penetrate the skin with high efficiency, and are evenly delivered to the stratum corneum as well as the lower part of the skin, poorly soluble It can be useful for the delivery of drugs for the treatment of atopy.

Figure 1 is a photograph confirming the size of the solid lipid nanoparticles prepared in an embodiment of the present invention.
Figure 2 is a graph confirming the dissolution rate of the solid lipid nanoparticles prepared in an embodiment of the present invention.
Figure 3 is a graph confirming the skin penetration of the solid lipid nanoparticles prepared in one embodiment of the present invention.
Figure 4 is a result of confirming the skin distribution of the solid lipid nanoparticles prepared in an embodiment of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention is lecithin; Nonionic surfactants; And it provides a skin-permeable solid lipid nanoparticles comprising any one or more selected from the group consisting of stearic acid and coco glyceride.

As used herein, the term "lecithin (lecithin)" is one of the phospholipids containing glycerin phosphoric acid, when hydrolyzed refers to a substance that produces choline, phosphoric acid, glycerol and fatty acids. The lecithin is 1 to 30 wt%, 2 to 30 wt%, 3 to 30 wt%, 4 to 30 wt%, 1 to 27 wt%, 2 to 27 wt%, 3 based on the total weight of solid lipid nanoparticles To 27%, 4 to 27%, 1 to 22%, 2 to 22%, 3 to 22%, 4 to 22%, 1 to 15%, 2 to 15%, 3 to 15% Weight percent, 4 to 15 weight percent, 1 to 12 weight percent, 2 to 12 weight percent, 3 to 12 weight percent or 4 to 12 weight percent.

As used herein, the term "nonionic surfactant" is a surfactant that does not separate into ions, and a surfactant refers to a substance that simultaneously has a hydrophilic and hydrophobic moiety in a molecule. The surfactant may be classified as a cation, anion, neutral or zwitter ionic surfactant depending on the hydrophilic portion.

Specifically, the nonionic surfactant is poloxamer, polyethylene glycol hexadecyl ether, polysorbate, sorbitan ester, polyoxyethylene castor oil derivative ), polyethylene alkyl ether (polyethylene alkyl ether) and polyoxyethylene stearate (polyoxyethylene stearate) may be any one or more selected from the group consisting of.

As used herein, the term “solid lipid nanoparticles” refers to particles having a size of nanometer (nm) in terms of morphology, and exist in a solid matrix form unlike a liposome or emulsion formulation. The solid lipid nanoparticles according to the present invention can collect a poorly water-soluble substance and greatly increase the delivery of the poorly water-soluble substance to the body, particularly to the skin. The solid lipid nanoparticles may be prepared by a conventional method, and may be performed by appropriately modifying the method as necessary.

The solid lipid nanoparticles have a diameter of 50 to 500 nm, 60 to 500 nm, 70 to 500 nm, 80 to 500 nm, 50 to 450 nm, 60 to 450 nm, 70 to 450 nm, 80 to 450 nm, 50 to 50 400 nm, 60-400 nm, 70-400 nm, 80-400 nm, 50-350 nm, 60-350 nm, 70-350 nm, 80-350 nm, 50-300 nm, 60-300 nm, 70- 300 nm, 80-300 nm, 50-250 nm, 60-250 nm, 70-250 nm, 80-250 nm, 50-200 nm, 60-200 nm, 70-200 nm, 80-200 nm, 50- It may be 150 nm, 60 to 150 nm, 70 to 150 nm, 80 to 150 nm, 50 to 100 nm, 60 to 100 nm, 70 to 100 nm or 80 to 100 nm.

In addition, the present invention provides a drug delivery system comprising the skin-permeable solid lipid nanoparticles.

The solid lipid nanoparticles included in the drug delivery system may have the characteristics as described above. In one example, the solid lipid nanoparticles include lecithin; Nonionic surfactants; And it may include any one or more selected from the group consisting of stearic acid and coco glyceride.

The drug delivery system may further include a bioactive material. The term,'bioactive substance' refers to a substance that enhances or inhibits biological functions, and is capable of maintaining its balance when a substance that regulates the function of the human body is deficient or excessively secreted and shows abnormal conditions. . The bioactive material may include all known in the art, and may be used in an appropriate amount in some cases. In one example, the bioactive material may be a drug for the treatment of atopic dermatitis.

In addition, the present invention provides a pharmaceutical composition for the treatment of atopy comprising the skin-permeable solid lipid nanoparticles, in which a drug for treatment of atopy is captured.

Solid lipid nanoparticles included in the pharmaceutical composition may have the characteristics as described above. In one example, the solid lipid nanoparticles include lecithin; Nonionic surfactants; And it may include any one or more selected from the group consisting of stearic acid and coco glyceride.

The drug for the treatment of atopy may include any commonly known substance, and may be any one or more selected from the group consisting of tacrolimus, dexpanterol, and allantoyl. In one embodiment of the present invention, the drug for the treatment of atopy may be tacrolimus. The atopy treatment drug is 0.01 to 1% by weight, 0.05 to 1% by weight, 0.08 to 1% by weight, 0.01 to 0.7% by weight, 0.05 to 0.7% by weight based on the total weight of the skin-permeable solid lipid nanoparticles according to the present invention %, 0.08 to 0.7% by weight, 0.01 to 0.5% by weight, 0.05 to 0.5% by weight, and 0.08 to 0.5% by weight.

The pharmaceutical composition of the present invention may also include carriers, diluents, excipients, or combinations of two or more of those commonly used in biological agents. The pharmaceutically acceptable carrier is not particularly limited as long as it is suitable for delivering the composition in vivo, for example, Merck Index, 13th ed., Merck & Co. Compounds described in Inc., saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these components may be used. At this time, other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary.

When formulating the composition, it may be prepared by using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are usually used.

The composition of the present invention may be formulated as oral preparations or parenteral preparations. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, etc. These solid preparations include at least one excipient in one or more compositions, such as starch, calcium carbonate, sucrose, It can be prepared by mixing lactose and gelatin. Also, lubricants such as magnesium stearate and talc may be added. On the other hand, the liquid preparation includes a suspension, an intravenous solution, an emulsion or a syrup, and may include excipients such as wetting agents, sweeteners, fragrances, preservatives, and the like.

Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspension solutions, injections such as emulsions. As the non-aqueous solvent and suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.

The composition of the present invention may be administered orally or parenterally depending on the desired method, and parenteral administration may be for external application to the skin or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. Can be selected.

The composition according to the invention is administered in a pharmaceutically effective amount. This may vary depending on the type of disease, severity, drug activity, sensitivity to the drug, administration time, administration route and discharge rate, treatment duration, and drugs used simultaneously. The composition of the present invention may be administered alone or in combination with other therapeutic agents. In combination administration, administration can be sequential or simultaneous.

However, for a desired effect, the amount of active ingredient contained in the pharmaceutical composition according to the present invention may be 0.001 to 10,000 mg/kg, specifically 0.1 g to 5 g/kg. The administration may be once a day, or divided into several times.

In addition, the present invention provides a cosmetic composition for improving atopy comprising the skin-permeable solid lipid nanoparticles in which a drug for treatment of atopy is collected.

Solid lipid nanoparticles included in the cosmetic composition may have the characteristics as described above. In one example, the solid lipid nanoparticles include lecithin; Nonionic surfactants; And it may include any one or more selected from the group consisting of stearic acid and coco glyceride. In addition, the drug for the treatment of atopy may be any one or more selected from the group consisting of tacrolimus, dexpanterol and allantoyl.

The cosmetic composition containing solid lipid nanoparticles, in which the drug for treatment of atopy according to the present invention is collected, may be formulated into a conventionally prepared cosmetic formulation. The cosmetic composition may be formulated as a solution, suspension, emulsion, paste, gel, lotion, cream, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation and spray, and the like. Specifically, it may be a flexible lotion, nutrition lotion, nutrition cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.

When the formulation of the cosmetic composition of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide or Mixtures thereof. In addition, when the formulation of the cosmetic composition is a powder or a spray, it may include lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder or a mixture thereof. In particular, in the case of a spray, chlorofluorohydrocarbon, propane/butane or dimethyl ether may be further included.

When the formulation of the cosmetic composition of the present invention is a solution or an emulsion, a carrier, a solvating agent, an emulsifying agent, or a mixture thereof may be included as a carrier. Examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol, sorbitan fatty acid ester, and the like.

When the formulation of the cosmetic composition of the present invention is a suspension, a liquid diluent such as water, ethanol or propylene glycol as a carrier, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, or mixtures thereof. In addition, when the formulation of the cosmetic composition is a surfactant-containing cleansing agent, as a carrier, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, Fatty acid amide ethersulfide, alkalamidobetaine, aliphatic alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, ethoxylated glycerol fatty acid ester or mixtures thereof.

The cosmetic composition of the present invention, in addition to the carrier component, may include antioxidants, stabilizers, solubilizers, moisturizers, pigments, fragrances, sunscreens, colorants, surfactants, or mixtures thereof as adjuvants. The adjuvant can be used as long as it is a substance commonly used in the preparation of cosmetic compositions.

Furthermore, the present invention comprises the steps of dissolving stearic acid in an organic solvent to obtain a solution; Homogenizing a lecithin and a nonionic surfactant in an organic solvent to obtain a homogenate; Mixing the obtained solution and a homogeneous solution to obtain a mixed solution; Provided is a method for preparing the skin-permeable solid lipid nanoparticles, comprising the steps of adding the obtained mixed solution to a solvent in which a nonionic surfactant is dissolved while stirring to obtain solid lipid nanoparticles.

In the preparation method, stearic acid, lecithin, nonionic surfactant and organic solvent may be used in appropriate amounts known in the art, and may be modified as necessary. In one example, the process of homogenizing or mixing in the manufacturing method may be performed using a high pressure homogenizer, which may be performed at an appropriate rate.

The nonionic surfactant may be any one or more selected from the group consisting of poloxamer, polyethylene glycol hexadecyl ether, polysorbate, sorbitan ester, polyoxyethylene castor oil derivative, polyethylene alkyl ether and polyoxyethylene stearate. . In addition, the organic solvent may be any one or more selected from the group consisting of methylene chloride, ethyl alcohol, dichloromethane, methyl alcohol and isopropyl alcohol.

The manufacturing method may further include the step of cooling the obtained solid lipid nanoparticles.

Hereinafter, the present invention will be described in detail by the following examples, provided that the following examples are only for illustrating the present invention, and the present invention is not limited by them. Anything that has substantially the same configuration and the same working effect as the technical idea described in the claims of the present invention is included in the technical scope of the present invention.

Example 1. Preparation of solid lipid nanoparticles-1

First, 0.102 g of tacrolimus hydrate (0.1 g of tacrolimus) and 0.4 g of stearic acid were placed in a beaker containing 25 ml of methylene chloride, heated to 35° C., and completely dissolved for 5 minutes. Meanwhile, 0.05 g of lecithin and 1 g of Brij 93 were placed in a beaker containing 50 ml of ethyl alcohol, heated to 50°C, and uniformly dispersed at 5,000 rpm for 10 minutes using a high pressure homogenizer. The solution containing the dissolved tacrolimus hydrate and the homogeneous solution containing the dispersed lecithin were mixed in total and uniformly prepared at 5,000 rpm for 10 minutes using a high pressure homogenizer under a temperature of 50°C. 1 g of Phloxamer 188 was placed in a beaker containing 100 ml of distilled water, heated to 70° C. and uniformly mixed for 15 minutes at 7,000 rpm using a high pressure homogenizer. The prepared mixture was quickly added while maintaining the solution containing the uniformly mixed phloxamer at 70°C. Thereafter, an emulsion was prepared by strongly mixing at 15,000 rpm for 20 minutes using a high pressure homogenizer under the same temperature. The prepared emulsion was cooled to 0° C. and mixed thoroughly using a sonicator. As a result, solid lipid nanoparticles containing tacrolimus as an active ingredient were obtained.

Example 2. Preparation of solid lipid nanoparticles-2

Solid lipid nanoparticles containing tacrolimus as an active ingredient were prepared in the same conditions and methods as in Example 1, except that 0.15 g of lecithin was added instead of 0.05 g of lecithin.

Example 3. Preparation of solid lipid nanoparticles-3

Solid lipid nanoparticles containing tacrolimus as an active ingredient were prepared in the same conditions and methods as in Example 1, except that 0.3 g of lecithin was added instead of 0.05 g of lecithin.

Example 4. Preparation of solid lipid nanoparticles-4

Solid lipid nanoparticles containing tacrolimus as an active ingredient were prepared in the same conditions and methods as in Example 1, except that 0.6 g of lecithin was added instead of 0.05 g of lecithin.

Example 5. Preparation of solid lipid nanoparticles-5

Solid lipid nanoparticles containing tacrolimus as an active ingredient were prepared in the same conditions and methods as in Example 1, except that 0.75 g of lecithin was added instead of 0.05 g of lecithin.

Example 6. Preparation of solid lipid nanoparticles-6

Solid lipid nanoparticles containing tacrolimus as an active ingredient were prepared in the same conditions and methods as in Example 3, except that 0.4 g of cocoglyceride was added instead of 0.4 g of stearic acid.

Example 7. Preparation of solid lipid nanoparticles-7

Solid lipid nanoparticles containing tacrolimus as an active ingredient were prepared in the same conditions and methods as in Example 6, except that 1 g of Brij 58 was added instead of 1 g of poloxamer 188.

Example 8. Preparation of solid lipid nanoparticles-8

Solid lipid nanoparticles containing dexpanthenol as an active ingredient were prepared in the same conditions and methods as in Example 6, except that 0.1 g of dexpanthenol was added instead of 0.102 g of tacrolimus hydrate.

Example 9. Preparation of solid lipid nanoparticles-9

Solid lipid nanoparticles containing dexpanthenol as an active ingredient were prepared in the same conditions and methods as in Example 8, except that 0.2 g of dexpanthenol was added instead of 0.1 g of dexpanthenol.

Example 10. Preparation of solid lipid nanoparticles-10

Solid lipid nanoparticles containing dexpanthenol as an active ingredient were prepared in the same conditions and methods as in Example 8, except that 0.4 g of dexpanthenol was added instead of 0.1 g of dexpanthenol.

Example 11. Preparation of solid lipid nanoparticles-11

Solid lipid nanoparticles containing allantoyl as an active ingredient were prepared in the same conditions and methods as in Example 6, except that 0.1 g of allantoyl was added instead of 0.102 g of tacrolimus hydrate.

Example 12. Preparation of solid lipid nanoparticles-12

Solid lipid nanoparticles containing allantoyl as an active ingredient were prepared in the same conditions and methods as in Example 11, except that 0.2 g of allantoyl was added instead of 0.1 g of allantoyl.

Example 13. Preparation of solid lipid nanoparticles-13

Solid lipid nanoparticles containing allantoyl as an active ingredient were prepared in the same conditions and methods as in Example 11, except that 0.4 g of allantoyl was added instead of 0.1 g of allantoyl.

Experimental Example 1. Comparison of lecithin content with different particle sizes

According to the content of lecithin used in the preparation of solid lipid nanoparticles, the size of the nanoparticles was compared by the following method.

Specifically, 1 ml of solid lipid nanoparticles prepared in Examples 1 to 5 were added to a 1.5 ml cuvette, and a polydispersity index value for measuring particle size and particle size dispersion was measured using a Zeta sizer analyzer. Obtained and shown in Table 1 below.

Weight ratio of lecithin (% by weight) Average particle size (nm) Polydispersity Index Example 1 2 409.9 0.510 Example 2 5 265.7 0.399 Example 3 10 150.3 0.233 Example 4 20 147.7 0.275 Example 5 25 149.5 0.299

As shown in Table 1, as the content of lecithin added to the solid lipid nanoparticles increased, the size of the solid lipid nanoparticles decreased. However, when lecithin was added in an amount of 10% by weight or more, the size of the solid lipid nanoparticles was not significantly affected, and it was found that the size of the solid lipid nanoparticles prepared by containing 5 or 10% by weight of lecithin was most appropriate. there was.

Experimental Example 2. Comparison of particle size according to the type of surfactant

The size of nanoparticles according to the type of surfactant used in the preparation of solid lipid nanoparticles was compared. The experiment was performed in the same manner as in Experimental Example 1 using the solid lipid nanoparticles prepared in Examples 6 and 7, and the results are shown in Table 2 below.

Surfactants Average particle size (nm) Polydispersity Index Example 6 Poloxamer 188 89.6±21.5 0.279 Example 7 Brij 58 94.1±22.6 0.327

As shown in Table 2, in the case of using poloxamer 188 or Brij 58 as a surfactant, small particles of 100 nm or less were all produced, and it was confirmed that nanoparticles of this size were uniformly distributed.

Experimental Example 3. Comparison of particle size according to the content of the active ingredient

The size of the nanoparticles according to the content of the active ingredient included in the preparation of the solid lipid nanoparticles was compared. The experiment was carried out in the same manner as in Experiment 1 using the solid lipid nanoparticles prepared in Examples 8 to 13, and the results are shown in Table 3 below.

Active ingredient (g) Average particle size (nm) Polydispersity Index Dexpanthenol Allantoin Example 8 0.1 - 114 0.333 Example 9 0.2 - 274 0.317 Example 10 0.4 - 384 0.322 Example 11 - 0.1 266 0.209 Example 12 - 0.2 275 0.194 Example 13 - 0.4 355 0.246

As shown in Table 3, as the content of the active ingredient dexpanthenol or allantoyl increased, the size of the solid lipid nanoparticles increased.

Experimental Example 4. Confirmation of sealing rate

The encapsulation rate of the active ingredient contained in the prepared solid lipid nanoparticles was confirmed by an HPLC analysis method.

Specifically, 500 μL of solid lipid nanoparticles prepared in Examples 6 to 13 were respectively placed in a filter tube (a pore size of about 10 kDa) manufactured by Amicon. Thereafter, the filter tube was centrifuged for 50 minutes under conditions of 4°C and 17,000 rpm to remove the active ingredient not captured inside the nanoparticles. After injecting the solid lipid nanoparticles from which the active ingredient was removed into HPLC, it was analyzed under the conditions shown in Table 4 below, and the results are shown in Table 5 below.

Mobile phase Mix acetonitrile and water in a volume ratio of 70:30 column C18 150×4.6 mm Column temperature 50℃ Detector UV (210 nm) Holding time 8 minutes Flow rate 1.1 ml/min Injection volume 20 μl

Active ingredients Encapsulation rate (%) Standard Deviation Example 6 0.102 g tacrolimus hydrate
(0.1 g tacrolimus, 0.1 wt%) 88.9 0.7 Example 7 0.102 g tacrolimus hydrate
(0.1 g tacrolimus, 0.1 wt%) 88.5 0.2 Example 8 0.1 g dexpanthenol (0.1 wt%) 35.5 0.4 Example 9 0.2 g dexpanthenol (0.2 wt%) 43.2 0.4 Example 10 0.4 g dexpanthenol (0.4 wt%) 37.2 2.7 Example 11 0.1 g allantoin (0.1 wt%) 62.7 0.8 Example 12 0.2 g allantoin (0.2 wt%) 37.1 2.6 Example 13 0.4 g allantoin (0.4 wt%) 34.5 4.0

As shown in Table 5, solid lipid nanoparticles in which tacrolimus hydrate was collected as an active ingredient had excellent sealing rate. On the other hand, the amount of dexpanthenol and allantoyl increased during the preparation of solid lipid nanoparticles, and the variation in the encapsulation rate increased.

Experimental Example 5. Morphological analysis of solid lipid nanoparticles

The shape of the prepared solid lipid nanoparticles was observed using a transmission electron microscopy.

Specifically, after the solid lipid nanoparticles prepared in Examples 6 and 7 were placed on a copper grid, the nanoparticles were dyed by putting them in a 2% phosphotungustic acid solution. After staining, solid lipid nanoparticles were washed in distilled water for 2 seconds, dried, and the results observed with a transmission electron microscope are shown in FIG. 1.

As shown in Figure 1, it was found that the solid lipid nanoparticles prepared in Examples 6 and 7 were small and uniform in size.

Experimental Example 6. Dissolution test of solid lipid nanoparticles

Dissolution test of the prepared solid lipid nanoparticles was performed under the conditions as shown in Table 6 below using a Franz diffusion cell. Then, the elution rate was confirmed by performing HPLC under conditions and methods as described in Experimental Example 4, and the results are shown in FIG. 2. At this time, 0.1% (w/w) of prototype ointment (Astellas pharmaceutical) was used as a control.

Membrane Artificial membrane (particle size: 12,000 to 14,000 kDa) Temperature Water tank: 37℃, Franz cell box: 32℃ Experimental volume 500 μl of solid lipid nanoparticles, 500 mg of prototype ointment interval 0, 1, 2, 4, 6, 8, 12, 24 hours Volume Injection of 200 μl of the extracted receptor phase Receptor phase Physiological saline: ethyl alcohol = 70:30 (v/v)

As shown in FIG. 2, the dissolution rates of solid lipid nanoparticles of Examples 6 and 7 were superior to that of the control group, Protopic Ointment.

Experimental Example 7. Skin penetration test of solid lipid nanoparticles

The skin penetration test of the prepared solid lipid nanoparticles was performed under the conditions as described in Table 7 below using Franz Diffusion Cell. Thereafter, the degree of skin penetration was confirmed by performing HPLC under conditions and methods as described in Experimental Example 4, and the results are shown in FIG. 3. At this time, 0.1% (w/w) of prototype ointment (Astellas pharmaceutical) was used as a control.

Membrane SD rat skin Temperature Water tank: 37℃, Franz cell box: 32℃ interval Skin analysis after application for 24 hours Receptor phase Physiological saline: ethyl alcohol = 70:30 (v/v)

As shown in FIG. 3, it was confirmed that the solid lipid nanoparticles of Examples 6 and 7 penetrated to a deeper skin layer than the control group, and in particular, the solid lipid nanoparticles of Example 6 were excellent.

Experimental Example 8. Confirmation of skin distribution of solid lipid nanoparticles

The skin distribution of the prepared solid lipid nanoparticles was confirmed by an FT-IR imaging method.

First, as described in Experimental Example 7, solid lipid nanoparticles of Examples 6 and 7 were applied to the skin. After application, the skin was cut to a thickness of 150 μm using a microtome to obtain a section. The skin section was placed on a slide glass, the distribution of the drug was confirmed by FT-IR imaging, and the results are shown in FIG. 4. At this time, 0.1% (w/w) of prototype ointment (Astellas pharmaceutical) was used as a control.

As shown in Fig. 4, both the solid lipid nanoparticles of Example 6 and 7 and the protopic ointment remained the most in the stratum corneum, from which the properties of the active ingredient tacrolimus drug itself remained unchanged within the solid lipid nanoparticles And it was found. However, compared to the control group, the solid lipid nanoparticles of Examples 6 and 7 delivered the drug through the stratum corneum to the deeper skin layer. In particular, the solid lipid nanoparticles of Example 6 delivered the drug to the relatively deep skin layer.

Claims (11)

lecithin;
Nonionic surfactants; And
Skin permeable solid lipid nanoparticles comprising any one or more selected from the group consisting of stearic acid and cocoglycerides.
The method of claim 1, wherein the nonionic surfactant is poloxamer, polyethylene glycol hexadecyl ether, polysorbate, sorbitan ester, polyoxyethylene castor oil derivative (polyoxyethylene) Castor oil derivative, polyethylene alkyl ether (polyethylene alkyl ether) and polyoxyethylene stearate (polyoxyethylene stearate) any one or more selected from the group consisting of, skin permeable solid lipid nanoparticles.
According to claim 1, The lecithin is contained in 1 to 30% by weight based on the total weight of the solid lipid nanoparticles, skin-permeable solid lipid nanoparticles.
The solid lipid nanoparticle of claim 1, wherein the solid lipid nanoparticle has a diameter of 50 to 500 nm.
A drug delivery system comprising the skin-permeable solid lipid nanoparticle of claim 1.
A pharmaceutical composition for the treatment of atopy comprising the skin-permeable solid lipid nanoparticle of claim 1, in which the drug for treatment of atopy is collected.
The pharmaceutical composition for treating atopy according to claim 6, wherein the drug for treating atopy is at least one selected from the group consisting of tacrolimus, dexpanterol, and allantoyl.
A cosmetic composition for improving atopy comprising the skin-permeable solid lipid nanoparticle of claim 1, in which a drug for treatment of atopy is collected.
Dissolving stearic acid in an organic solvent to obtain a solution;
Homogenizing a lecithin and a nonionic surfactant in an organic solvent to obtain a homogenate;
Mixing the obtained solution and a homogeneous solution to obtain a mixed solution;
A method for preparing skin-permeable solid lipid nanoparticles according to claim 1, comprising adding and stirring the obtained mixed solution in a solvent in which a nonionic surfactant is dissolved to obtain solid lipid nanoparticles.
The method of claim 9, wherein the organic solvent is at least one selected from the group consisting of methylene chloride, ethyl alcohol, dichloromethane, methyl alcohol, and isopropyl alcohol.
10. The method of claim 9, wherein the nonionic surfactant is selected from the group consisting of poloxamers, polyethylene glycol hexadecyl ether, polysorbate, sorbitan esters, polyoxyethylene castor oil derivatives, polyethylene alkyl ethers and polyoxyethylene stearate. The method of manufacturing a skin-permeable solid lipid nanoparticle of claim 1, which is at least one.

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