KR20090062707A - Liposomal external preparation comprising triazole derivative antifungal agent and preparation method thereof - Google Patents

Abstract

An antifungal liposomal external agent for skin penetration, which has liposome dispersed type is provided to apply triazole based antifungal agent into topical skin, prevent the side effect of whole body and heighten the skin penetration. A liposomal external agent comprises 0.01-10 weight% of triazole based antifungal agent, 0.1-60 weight% of dissolution agent, 0.1-30 weight% of phospholipid and remaining amount of water. The liposomal external agent is used in a form of liquid, spray, liniment agent or aerosol. A method for manufacturing the liposomal external agent comprises: a step of resolving the triazole based antifungal agent with dissolution agent; a step of resolving phospholipid in dissolution agent; a step of stirring the triazole based antifungal agent in phospholipid solution to produce common solvent; and a step of stirring and adding common solvent solution in water or aqueous phase.

Description

Liposomal external preparations containing triazole-based antifungal agents and preparation methods thereof Liposomal external preparation comprising triazole derivative antifungal agent and preparation method

The present invention is to reduce the side effects caused by oral administration by developing a triazole-based antifungal agent having a high antifungal power but side effects such as hepatotoxicity and gastrointestinal disorders for long-term oral administration as a topical application applicable to topical skin, improved solubility and The present invention relates to an external preparation for liposome for skin penetration dispersed in a co-solvent system having an excellent skin penetration rate.

Triazole-based antifungal agents such as itraconazole, fluconazole, and boleyconazole are widely used for the treatment of candidiasis, early mycobacteria, dermatophytes, foot and ringworm.

Triazole antifungal agents exhibit antifungal action by inhibiting the synthesis of ergosterol, the main component of the fungal cell membrane, and have the advantage of having a large antifungal range and low toxicity compared to azole antifungal agents.

However, oral administration of gastrointestinal symptoms include systemic side effects such as nausea, abdominal pain, nausea, diarrhea, bloating, and interaction with many drugs by inducing or inhibiting liver metabolism.

Itraconazole has a broad antifungal activity and is used to treat superficial and systemic fungal infections. It is mainly used as an oral drug and is a very poorly soluble substance. The bioavailability may be changed by oral administration to the physicochemical condition of the small intestine and the food, and the individual difference is also severe.

In order to increase the bioavailability, there are disadvantages to be taken with food mainly, and even if overcome low bioavailability, side effects such as hepatotoxicity, nausea, diarrhea, abdominal pain, indigestion, headache, etc. are severe during long-term administration.

Fluconazole is also used to treat a variety of fungal infections, including mild candidiasis, early fungal infections, and yeast fungi. There are side effects, such as headaches and rashes.

Since barleyconazole is widely used for the treatment of fungi with drug resistance of fluconazole, and clinically mainly used as oral or injection, it is necessary to monitor for side effects such as liver function and renal function. Common side effects include visual field abnormalities, hypersensitivity reactions, fever, swelling, abdominal pain, chest pain, and the like.

Triazole-based antifungals have a wide range of antifungal powers and exert an excellent drug, but their use is limited due to systemic side effects and drug interactions when used orally or injectable.

In order to minimize side effects from oral administration and to efficiently deliver drugs to a desired site, drug delivery to a topical site for treatment is required. In order to develop a topical topical application for excellent skin application, it is necessary to solubilize itraconazole, fluconazole, and barleyconazole, which have very low solubility in water, and increase the skin permeability of drugs to enable effective drug expression.

On the other hand, there are precedents related to the development of external preparations aimed at reducing side effects from oral administration of antifungal agents and delivering them to topical sites.

First, considering that most of the antifungal drugs are poorly soluble, it is difficult to formulate them for external use. Examples of studies for solubilizing and preparing poorly soluble drugs include European Patent No. 515310 and European Patent No. 503988.

The patents suggest the possibility of developing a topical drug by solubilizing the drug, but it has a disadvantage in that the penetration into the skin is not effective and the excellent effect cannot be guaranteed.

In addition, the following studies have been conducted as a preceding example for effectively solubilizing poorly soluble antifungal drugs and improving penetration into the skin.

Korean Patent No. 0712734 discloses a skin external preparation that improves skin permeation of a drug by designing a formulation in which itraconazole is encapsulated inside niosome, and Korean Patent No. 0423666 discloses a fatty acid, fatty alcohol, higher fatty acid ester or lower alcohol. The external preparation which solubilized fluconazole and the external base was added using etc. was disclosed.

In addition, Korean Patent Publication No. 2006-0066780 discloses a fluconazole external preparation using an ionic and nonionic surfactant, an oily substance, and a fatty acid ester, and Korean Patent No. 0342945 discloses an amphiphilic solvent, a surfactant, and an oil. An external preparation in which an emulsion in which an antifungal agent is solubilized in an auxiliary solvent is uniformly dispersed in a hydrogel is disclosed.

The external preparation described in the prior art as described above may cause irritation to sensitive skin by using a solubilizing agent including a fatty acid, an oil, a surfactant, etc., and there is a problem in that the drug compliance of the patient is lowered so as not to exhibit an effective antifungal effect.

Therefore, it is urgent to develop an antifungal external preparation that solubilizes poorly soluble antifungal agents and at the same time improves penetration into the skin and minimizes skin irritation.

In order to solve the problems of the prior art, the present inventors use the phospholipids extracted from natural products without forming a solubilizing agent including fatty acid, oil, surfactant, etc. to form liposomes to form an optimal drug solubilization system. A formulation with excellent skin permeability was developed.

Accordingly, an object of the present invention is to provide an antifungal liposome external preparation for topical dermal penetration and a method of preparing the same, which effectively delivers triazole-based antifungal agents having high systemic effects but long-term oral administration and large systemic side effects. Is in.

Another object of the present invention is to provide a skin permeable antifungal liposome external preparation in a form dispersed in an oil-free co-solvent system and a preparation method thereof.

In order to achieve the above object,

The present invention (a) at least one triazole-based antifungal agent selected from the group consisting of itraconazole, fluconazole and voriconazole; (b) N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether, dimethylisosorbide, propylene glycol, propylene carbonate, tetraglycol, benzyl alcohol, ethanol, isopropyl alcohol and dimethyl sulfoxide One or more solubilizers miscible with the selected water; (c) phospholipids; And (d) provides an external preparation for liposomes comprising water.

The external preparation for the liposome is configured without an oil component, and the liposome is dispersed in a cosolvent system in which a solubilizer and water are mixed.

Liposomal external preparation according to the present invention is preferably composed of 0.01-10% by weight of triazole-based antifungal agent, 0.1-60% by weight solubilizer, 0.1-30% by weight of phospholipid and residual water.

Triazole-based antifungal agent used in the present invention may be selected from one or more of itraconazole, fluconazole or boleyconazole, and the total content thereof is preferably 0.01-10% by weight of the total weight of the liposome external preparation.

When formulated outside the above content range, the drug is not stabilized and precipitation occurs or absorption into the skin is less than desired to obtain the desired pharmacological effect.

In addition, as the solubilizer used in the present invention, N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether, dimethylisosorbide, propylene glycol, propylene carbonate, tetraglycol, benzyl alcohol, ethanol, isopropyl alcohol or At least one of dimethylsulfoxide may be selected.

These solubilizers should be miscible with water and dissolve the phospholipids used in the formation of liposomes and triazole-based antifungal agents as active ingredients, and help to permeate the drug through the skin.

The total content is preferably 0.1-60% by weight of the total weight of the liposome external preparation, which is not enough to dissolve the drug outside the above weight range, so that the precipitation of the drug does not occur or effective penetration into the skin is achieved.

In addition, the phospholipid used in the present invention is phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidyl inositol, phosphatidylserine, diphosphadidylglycerol, phosphatidylinositol, phosphatidic acid or sphingomyelin as a base for liposome formation. More than one species may be selected.

Phospholipids are constituents of biological membranes, which act as skin-friendly bases extracted from natural substances to stabilize the active ingredients in the formulation and form liposomes to increase the skin permeability of the drug.

It is preferable to contain 0.1-30% by weight of the total weight of the liposome external preparation, and if it is out of the content range, it is impossible to form liposomes, which affects the stabilization of the preparation or the degree of drug transition to the skin, thereby causing the problem of the expected pharmacological effect. May be caused.

The liposome external agent according to the present invention may be prepared as one solution selected from the group consisting of liquids, sprays, linings and aerosols.

In addition, the present invention is additionally polyacrylate-based, cellulose-based, polysaccharide-based, peptide-based, polyalkylene oxite-based, polyvinylpyrrolidone-based, polyvinyl alcohol-based or polyvinyl acetate One or more water soluble thickeners selected from the family may be added.

The liposome external preparation according to the present invention is preferably a semisolid, and is composed of 0.01-10% by weight of a triazole antifungal agent, 0.1-60% by weight of a solubilizer, 0.1-30% by weight of a phospholipid, 0.01-10% by weight of a water-soluble thickener, and a balance of water. .

The water-soluble thickener used in the present invention is a polymer that is hydrated to increase viscosity and is a component for controlling the viscosity of the formulation and plays a role of improving viscosity and application feeling.

For example, polyacrylate type, such as polymethacrylate, polyacrylate, polyacrylamide; Cellulose series such as hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose and alkyl hydroxypropyl methyl cellulose; Polysaccharides such as starch, dextran, acacia gum, gellan gum, guar gum, tragacanth gum, xanthan gum, pectin, chitosan, alginate, carrageenan, agar; Peptide family such as gelatin, protamine, zein; Polyalkylene oxide series such as polyethylene glycol, polyethylene oxide, and poloxamer; Polyvinylpyrrolidone; Polyvinylacetate; Or one or more thickeners in polyvinyl alcohol.

When the water-soluble thickener is additionally added for semisolid properties, the total content is preferably 0.01-10% by weight of the total weight of the composition. If the content is out of the above range, the viscosity or property of the preparation may be induced, so that application to the skin may not be easy and a problem may occur that the drug is transferred to the skin.

The semi-solid may be prepared, for example, gel, cream, ointment or lotion.

In addition, the liposome external preparation according to the present invention may additionally add a pH adjusting agent, a flavoring agent, a coloring agent, a preservative, and the like within a range that does not impair the effects of the present invention.

In addition, the present invention comprises the steps of (a) dissolving a triazole-based antifungal agent as a solubilizer; (b) dissolving the phospholipid in the solubilizer; (c) adding a triazole antifungal solution to the phospholipid solution while stirring to prepare a cosolvent solution; And (d) provides a method for producing a liposome external preparation comprising the step of adding a co-solvent solution to water or water while stirring.

In order to prepare a semi-solid formulation, it is possible to use an aqueous phase instead of water during the process (d) of the manufacturing method, the aqueous phase can be prepared uniformly by adding a water-soluble thickener in water and sufficiently stirred.

Liposomal external preparation prepared in this way can maximize the physical and chemical stability of the preparation by increasing the solubility of the poorly soluble triazole-based antifungal agent as an active ingredient, and can be applied to topical skin to minimize systemic migration to avoid systemic side effects. It can effectively penetrate and deposit the drug into the skin, minimize the side effects of the skin by using a phospholipid, which is a natural substance as a base, and also has a very good feeling when applying the skin.

The liposome external preparation according to the present invention can be applied to triazole-based antifungal agents having systemic side effects upon oral administration to local skin, thereby preventing systemic transition into the blood, thereby avoiding systemic side effects, and increasing the skin permeability of the drug to enable efficient treatment. Let's do it.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for the purpose of clarifying the contents of the present invention, and the present invention is not limited by the examples.

< Example  1>

1 g of itraconazole was dissolved in 10 g of N-methyl-2-pyrrolidone. 7 g of phosphatidylcholine and 1 g of phosphatidylethanolamine were dissolved in 20 g of ethanol, and an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 0.5 g of Carbopol was dissolved in 60.1 g of water to prepare an aqueous phase, followed by stirring, a cosolvent solution was added, and 0.4 g of triethanolamine was added to prepare a semi-solid liposome external preparation.

<Example 2>

0.1 g of itraconazole was dissolved in 1 g of N-methyl-2-pyrrolidone. After dissolving 3.7 g of phosphatidylcholine and 0.3 g of diphosphatidylglycerol in 30 g of ethanol, an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 0.5 g of Carbopol was dissolved in 64 g of water to prepare an aqueous phase, followed by stirring, a cosolvent solution was added, and 0.4 g of triethanolamine was added to prepare a semi-solid liposome external preparation.

<Example 3>

1 g of itraconazole was dissolved in 10 g of N-methyl-2-pyrrolidone. After dissolving 4.6 g of phosphatidylcholine and 0.4 g of phosphatidylethanolamine in 20 g of ethanol, an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 10 g of hydroxypropyl cellulose was dissolved in 54 g of water to prepare an aqueous phase, followed by stirring to add a cosolvent solution to prepare a semi-solid liposome external preparation.

<Example 4>

1.5 g of itraconazole was dissolved in 10 g of benzyl alcohol and 20 g of diethylene glycol monoethyl ether was added thereto. After dissolving 7 g of phosphatidylcholine and 1 g of phosphatidylethanolamine in 12 g of ethanol, the solution in which itraconazole was dissolved was added with stirring to prepare a cosolvent solution. 0.7 g of xanthan gum was dissolved in 47.8 g of water to prepare an aqueous phase, followed by stirring and adding a cosolvent solution to prepare a semi-solid liposome external preparation.

<Example 5>

0.01 g of itraconazole was dissolved in 1 g of benzyl alcohol, and 0.3 g of diethylene glycol monoethyl ether was added thereto. 3.5 g of phosphatidylcholine and 0.5 g of sphingomyelin were dissolved in 10 g of ethanol, and then the solution in which itraconazole was dissolved was added with stirring to prepare a cosolvent solution. A water solid was prepared by dissolving 5 g of poloxamer in 79.69 g of water, followed by stirring and adding a cosolvent solution to prepare a semi-solid liposome external preparation.

<Example 6>

0.1 g of itraconazole was dissolved in 9 g of N-methyl-2-pyrrolidone. 16 g of phosphatidylcholine, 2 g of phosphatidylethanolamine, 0.3 g of diphosphatidylglycerol, and 1.7 g of sphingomyelin were dissolved in 30 g of ethanol, followed by stirring with N-methyl-2-pyrrolidone solution to prepare a cosolvent solution. 0.5 g of xanthan gum was dissolved in 40.4 g of water to prepare an aqueous phase, followed by stirring to add a cosolvent solution to prepare a semi-solid liposome external preparation.

<Example 7>

0.5 g of itraconazole was dissolved in 5 g of N-methyl-2-pyrrolidone. 2 g of phosphatidylcholine was dissolved in 17 g of ethanol, and then an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. A water phase was prepared by dissolving 0.01 g of poloxamer in 75.49 g of water, followed by stirring to add a cosolvent solution to prepare a semi-solid liposome external preparation.

<Example 8>

1 g of itraconazole was dissolved in 9 g of N-methyl-2-pyrrolidone. 4 g of phosphatidylcholine was dissolved in 35 g of ethanol, and then an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 51 g of water was added to the cosolvent solution to prepare a liquid liposome external preparation.

Example 9

1 g of itraconazole was dissolved in 9 g of N-methyl-2-pyrrolidone, and then 10 g of diethylene glycol monoethyl ether was added thereto. After dissolving 8 g of phosphatidylcholine and 2 g of sphingomyelin in 20 g of ethanol, the solution in which itraconazole was dissolved was added with stirring to prepare a cosolvent solution. 50 g of water was added to the cosolvent solution to prepare a liquid liposome external preparation.

<Example 10>

0.5 g of itraconazole was dissolved in 5 g of N-methyl-2-pyrrolidone and then 2 g of diethylene glycol monoethyl ether was added. 4.8 g of phosphatidylcholine, 0.1 g of phosphatidylethanolamine, and 0.1 g of diphosphatidylglycerol were dissolved in 20 g of ethanol, followed by stirring and adding the solution in which itraconazole was dissolved to prepare a cosolvent solution. 67.5 g of water was added to the cosolvent solution to prepare a liquid liposome external preparation.

<Example 11>

0.1 g of itraconazole was dissolved in 1 g of N-methyl-2-pyrrolidone. After dissolving 2 g of phosphatidylcholine in 5 g of ethanol, an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 91.9 g of water was added to the cosolvent solution to prepare a liquid liposome external preparation.

<Example 12>

1 g of fluconazole was dissolved in 20 g of diethylene glycol monoethyl ether. 3.9 g of phosphatidylcholine and 0.1 g of phosphatidylethanolamine were dissolved in 12 g of ethanol, followed by stirring with diethylene glycol monoethyl ether solution to prepare a cosolvent solution. 1.5 g of Carbopol was dissolved in 60.3 g of water to prepare an aqueous phase, followed by stirring, a cosolvent solution was added, and 1.2 g of triethanolamine were added to prepare a semi-solid liposome external preparation.

Example 13

0.01 g of fluconazole was dissolved in 0.015 g of N-methyl-2-pyrrolidone. 0.1 g of phosphatidylcholine was dissolved in 0.15 g of ethanol, and then an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. A water solid was prepared by dissolving 10 g of poloxamer in 89.725 g of water, followed by stirring to add a cosolvent solution to prepare a semi-solid liposome external preparation.

<Example 14>

0.01 g of fluconazole was dissolved in 0.015 g of N-methyl-2-pyrrolidone. 28 g of phosphatidyl choline and 2 g of sphingomyelin were dissolved in 30 g of ethanol, followed by stirring with an N-methyl-2-pyrrolidone solution to prepare a cosolvent solution. A semi-solid liposome external preparation was prepared by dissolving 0.01 g of poloxamer in 39.965 g of water, followed by stirring to add a cosolvent solution.

<Example 15>

0.01 g of fluconazole was dissolved in 1 g of N-methyl-2-pyrrolidone. 0.1 g of phosphatidylcholine was dissolved in 59 g of ethanol, and then an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 0.5 g of Carbopol was dissolved in 38.99 g of water to prepare an aqueous phase, followed by stirring, a cosolvent solution was added, and 0.4 g of triethanolamine was added to prepare a semi-solid liposome external preparation.

<Example 16>

2 g of fluconazole was dissolved in 10 g of benzyl alcohol and 20 g of diethylene glycol monoethyl ether was added thereto. After dissolving 7 g of phosphatidylcholine and 1 g of phosphatidylethanolamine in 12 g of ethanol, the solution in which fluconazole was dissolved was added with stirring to prepare a cosolvent solution. 0.7 g of xanthan gum was dissolved in 47.3 g of water to prepare an aqueous phase, followed by stirring and adding a cosolvent solution to prepare a semi-solid liposome external preparation.

<Example 17>

10 g of fluconazole was dissolved in 15 g of N-methyl-2-pyrrolidone. 0.1 g of phosphatidylcholine was dissolved in 40 g of ethanol, and then an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. After dissolving 1 g of Carbopol in 33.1 g of water to prepare an aqueous phase, agitated, adding a cosolvent solution, and adding 0.8 g of triethanolamine to prepare a semi-solid liposome external preparation.

Example 18

0.1 g of fluconazole was dissolved in 1 g of benzyl alcohol, and then 2 g of diethylene glycol monoethyl ether was added. After dissolving 1 g of phosphatidylcholine in 40 g of ethanol, the solution in which fluconazole was dissolved was added with stirring to prepare a cosolvent solution. 1 g of Carbopol was dissolved in 54.1 g of water to prepare an aqueous phase, followed by stirring, a cosolvent solution was added, and 0.8 g of triethanolamine was added to prepare a semi-solid liposome external preparation.

Example 19

1 g of fluconazole was dissolved in 5 g of N-methyl-2-pyrrolidone. After dissolving 3.8 g of phosphatidylcholine and 0.2 g of diphosphatidylglycerol in 30 g of ethanol, an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 60 g of water was added to the cosolvent solution to prepare a liquid liposome external preparation.

Example 20

0.5 g of fluconazole was dissolved in 4 g of N-methyl-2-pyrrolidone, followed by addition of 1 g of diethylene glycol monoethyl ether. After dissolving 3.9 g of phosphatidylcholine and 0.1 g of sphingomyelin in 20 g of ethanol, the solution in which fluconazole was dissolved was added with stirring to prepare a cosolvent solution. 70.5 g of water was added to the cosolvent solution to prepare a liquid liposome external preparation.

Example 21

0.5 g of fluconazole was dissolved in 8 g of N-methyl-2-pyrrolidone. After dissolving 2 g of phosphatidylcholine in 5 g of ethanol, an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 84.5 g of water was added to the cosolvent solution to prepare a liquid liposome external preparation.

<Example 22>

1 g of barleyconazole was dissolved in 10 g of N-methyl-2-pyrrolidone. After dissolving 7.8 g of phosphatidylcholine and 0.2 g of diphosphatidylglycerol in 20 g of ethanol, an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 0.5 g of Carbopol was dissolved in 60.1 g of water to prepare an aqueous phase, followed by stirring, a cosolvent solution was added, and 0.4 g of triethanolamine was added to prepare a semi-solid liposome external preparation.

<Example 23>

1 g of boriconazole was dissolved in 9 g of N-methyl-2-pyrrolidone. 4 g of phosphatidylcholine was dissolved in 35 g of ethanol, and then an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 51 g of water was added to the cosolvent solution to prepare a liquid liposome external preparation.

<Example 24>

0.1 g of boriconazole was dissolved in 9 g of N-methyl-2-pyrrolidone. 18 g of phosphatidylcholine, 1 g of phosphatidylethanolamine, and 1 g of sphingomyelin were dissolved in 30 g of ethanol, and an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 0.5 g of xanthan gum was dissolved in 40.4 g of water to prepare an aqueous phase, followed by stirring to add a cosolvent solution to prepare a semi-solid liposome external preparation.

<Example 25>

0.01 g of barleyconazole was dissolved in 1 g of benzyl alcohol, and 0.3 g of diethylene glycol monoethyl ether was added thereto. 4.8 g of phosphatidylcholine and 0.2 g of phosphatidylethanolamine were dissolved in 12 g of ethanol, and the co-solvent solution was prepared by stirring the solution in which voriconazole was dissolved. A water solid was prepared by dissolving 10 g of poloxamer in 71.69 g of water, followed by stirring and adding a cosolvent solution to prepare a semi-solid liposome external preparation.

Example 26

0.5 g of boriconazole was dissolved in 5 g of N-methyl-2-pyrrolidone. 4 g of phosphatidylcholine was dissolved in 17 g of ethanol, and then an N-methyl-2-pyrrolidone solution was added with stirring to prepare a cosolvent solution. 2 g of hydroxypropyl cellulose was dissolved in 71.5 g of water to prepare an aqueous phase, followed by stirring to add a cosolvent solution to prepare a semi-solid liposome external preparation.

Example 27

0.5 g of barleyconazole was dissolved in 5 g of N-methyl-2-pyrrolidone and then 2 g of diethylene glycol monoethyl ether was added. 3.8 g of phosphatidylcholine and 0.2 g of phosphatidylethanolamine were dissolved in 20 g of ethanol, and the co-solvent solution was prepared by stirring the solution in which voriconazole was dissolved. 68.5 g of water was added to the cosolvent solution to prepare a liquid liposome external preparation.

Experimental Example 1 Using Male Hairless Mouse In vitro  Skin permeation experiment

In order to measure the skin permeability of the antifungal liposome external preparation according to the present invention, a skin permeation experiment was conducted using the preparations prepared in Examples 1, 4 and 12.

The skin used for the experiment was cut out of the back skin of the male hairless mouse, and the amount of permeation and the rate of permeation were measured using a Keshary-Chien skin permeation system (vertical diffusion cell).

Fresh skin that was quickly removed was placed between each half-cell, 0.5 mL of the formulation prepared in Examples was applied to the donor cell in contact with the stratum corneum, and the receptor cell in contact with the dermal layer was used as a receptor solution as a medium (benzyl alcohol). , A mixture of PBS and PEG400 (3: 8: 4 (v / v / v)) was prepared and added.

At this time, the area of the skin coated with external preparation was filled with 2.01 cm ² , the volume of the receptor phase (content of the diffusion cell) was 12 mL, the temperature of the medium and the cell was maintained at 37 ± 0.5 ° C., and the stirrer was constantly stirred at 600 rpm. It was.

After a certain period of time (3, 4, 5, 6, 7, 8 hours) from the time of application, the receptor solution was taken and supplemented with fresh medium equal to the amount collected (1.0 mL). Subsequently, the concentration of drug in the collected sample was measured by HPLC, and the skin permeation amount (cumulative value) of the drug permeated by the receptor solution was calculated.

In Examples 1 and 4, which are external preparations for liposomes containing itraconazole as active ingredients, the skin permeation amount per unit area after 8 hours after application of the external preparation was about 5 ㎍ / cm ² and about 7 ㎍ / cm ^{2, respectively,} as shown in FIG. 1. .

Since the minimum inhibition concentration (MIC) of itraconazole against fungi such as skin filamentous fungi is about 0.1 µg / cm ^3, it was confirmed that the skin permeation amount of itraconazole in the external preparations according to the present invention was sufficient to inhibit fungi ( J. Am. Acad. Dermato. 38, S42-S47).

In the case of Example 12, a liposome external preparation containing fluconazole as an active ingredient, the skin permeation amount per unit area 8 hours after application of the external preparation was about 50 μg / cm ^2, as shown in FIG. 2. Since the bacterium minimum inhibitory concentration of fluconazole was about 4 µg / cm ^3, it was confirmed that the skin permeation amount of fluconazole in the external preparation according to the present invention was an amount sufficient to inhibit fungi.

Experimental Example 2 Using Male Hairless Mouse In vivo  Skin deposition amount confirmation experiment

Male hairless mice were fixed and 0.3 mL of the formulations prepared in Examples 1 and 4 were applied to the back skin of 3.0 cm ² area. The hairless mouse was lethal to the cervical vertebra at each sampling time, and the amount of drug deposited in the skin was measured in the same manner as in Experimental Example 1.

As shown in FIGS. 3 and 4, in Examples 1 and 4, the amount of itraconazole deposited in the exfoliated skin was about 4 μg / cm ^{2 on} average for 1 hour, 4 hours, and 8 hours after skin application. Appeared.

This is an amount sufficient to inhibit the fungi and it was confirmed that a constant concentration is maintained to suppress the fungi for 1 hour, 4 hours, 8 hours after skin application.

Figure 1 shows the results of the skin permeation amount of the active ingredient when the in vitro skin permeation experiment using the formulations prepared in Examples 1 and 4,

Figure 2 shows the results of the skin permeation amount of the active ingredient when the in vitro skin permeation experiment using the formulation prepared in Example 12,

Figure 3 shows the results of the skin deposition amount of the active ingredient when the in vivo skin deposition confirmation test using the formulation prepared in Example 1,

4 is In using the formulation prepared by Example 4 It shows the result of the skin deposition amount of the active ingredient in the experiment of confirming the skin deposition amount in vivo .

Claims (10)

At least one triazole-based antifungal agent selected from the group consisting of itraconazole, fluconazole, and boleyconazole; Water selected from the group consisting of N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether, dimethylisosorbide, propylene glycol, propylene carbonate, tetraglycol, benzyl alcohol, ethanol, isopropyl alcohol and dimethyl sulfoxide At least one miscible solvent; Phospholipids; And Liposomal external preparations comprising water. The external preparation for liposome according to claim 1, wherein the external preparation for liposome is composed of 0.01-10% by weight of triazole antifungal agent, 0.1-60% by weight of solubilizer, 0.1-30% by weight of phospholipid and residual amount of water. The liposomal external preparation according to claim 1, wherein the phospholipid is at least one selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, diphosphatidylglycerol, phosphatidic acid and sphingomyelin. The external preparation for liposome according to claim 1, wherein the liposome external preparation is one solution selected from the group consisting of a liquid, a spray, a lining agent, and an aerosol. The liposome external preparation is a polyacrylate-based, cellulose-based, polysaccharide-based, peptide-based, polyalkylene-oxite-based, polyvinylpyrrolidone-based, or polyvinyl alcohol. A liposome external preparation further comprising at least one water-soluble thickener selected from the group consisting of a series and a polyvinylacetate series. The method of claim 5, wherein the external preparation for liposomes is composed of 0.01-10% by weight of triazole antifungal agent, 0.1-60% by weight solubilizer, 0.1-30% by weight phospholipid, 0.01-10% by weight water-soluble thickener and the balance of water Liposomal external preparations. The method of claim 5, wherein the water-soluble thickener is selected from the group consisting of polymethacrylate, polyacrylate and polyacrylamide; Cellulose series selected from the group consisting of hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose and alkyl hydroxypropyl methyl cellulose; Polysaccharides selected from the group consisting of starch, dextran, acacia gum, gellan gum, guar gum, tragacanth gum, xanthan gum, pectin, chitosan, alginate, carrageenan and agar; Peptide family selected from the group consisting of gelatin, protamine and zein; Polyalkylene oxide series selected from the group consisting of polyethylene glycol, polyethylene oxide and poloxamer; Polyvinylpyrrolidone; Polyvinyl alcohol; And at least one member selected from the group consisting of polyvinylacetate. The liposome external preparation according to claim 5, wherein the liposome external preparation is one semi-solid agent selected from the group consisting of a gel, a cream, an ointment, and a lotion. Dissolving the triazole antifungal agent with a solubilizer; Phospholipids are dissolved in a dissolving agent; Preparing a cosolvent solution by adding triazole-based antifungal solution to the phospholipid solution with stirring; And Adding cosolvent solution to water or water phase with stirring Method for producing a liposome external preparation, characterized in that comprising a. The method of claim 9, wherein the aqueous phase is homogenized by sufficiently adding a water soluble thickener to water and stirring the mixture.

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