WO2016052774A1 - Composition for treating tinea pedis, and method for producing therapeutic agent for tinea pedis using same - Google Patents

Abstract

A composition for treating tinea pedis and a method for producing a therapeutic agent for tinea pedis using same are disclosed. One embodiment of the present invention provides a composition for treating tinea pedis, comprising: over 0 to 0.001 wt% of a nano-ionic composite for photodynamic therapy; 0.1 to 10 wt% of an emulsifier; 0.1 to 10 wt% of a first alcohol; 0.1 to 10 wt% of a second alcohol; 0.1 to 10 wt% of a fatty acid; 1 to 40 wt% of an oil; and purified water constituting the remainder, wherein the nano-ionic composite for photodynamic therapy comprises: a copolymer formed by joining a hydrophilic cationic polymer and a photosensitizer; and a conjugate formed by joining an anionic matrix polymer and a quencher.

Description

Athlete's foot composition and method of preparing athlete's foot

One embodiment of the present invention relates to a composition for treating athlete's foot and a method for preparing athlete's foot therapeutic agent using the same.

Although skin disease does not affect life, its incidence is high, and in modern people, the frequency of occurrence is increasing due to various causes, climate, and stress.

Athlete's foot is the most common and representative form of skin disease caused by fungi, and athlete's foot, Trichophyton bacteria, damages the skin while parasitic on moist areas of skin, areas where skin overlaps, and stratum corneum. A lot of athlete's foot in the blue and old age, and narrow and tight shoes, sneakers, excessive sweating and the like act as a cause for promoting the disease.

In the case of athlete's foot, it is usually characterized by itching and pain between the toes, and after taking nutrients from skin cells, excrete (ammonia compound), causing severe odor. In addition, it is spread to various parts of the body (hands, feet, toes, toenails, nails, palms, groin) accompanied by small edema, rash, etc., and the infected part is usually white, full of smell, and odor occurs.

Athlete's foot treatment requires long-term treatment of at least 2 months to 1 year, is difficult to cure, easy to recur, so the fundamental therapeutic effect is known to be important. In addition, as a side effect of long-term treatment of athlete's foot, there are many side effects such as hepatotoxicity, so the development of a new athlete's foot treatment without side effects is required.

On the other hand, photodynamic therapy (PDT) is a kind of radical therapy such as chemotherapy that can treat lesions without surgery by using photosensitizer, which is selective and photosensitive for various lesions. For example, by administering the photosensitive material to a subject by intravenous injection and irradiating with appropriate light, the photosensitive material activates oxygen molecules to convert into singlet oxygen or create new radicals. Only lesions are selectively attacked and destroyed.

The photosensitive material is a porphyrin-like compound, and porphyrin-based compounds extracted from the powders of the latent plant, mulberry, green algae, etc. have spectroscopic properties suitable for use as a photosensitive material, and have a relatively high cell permeability. It is known that (700-900 nm) can efficiently generate an electron transition and its excited state.

One embodiment of the present invention is to provide a composition for treating athlete's foot and a method for preparing athlete's foot therapeutic agent using the same, which is harmless to human body and does not cause side effects.

In addition, an embodiment of the present invention is to provide a composition for treating athlete's foot, including a photosensitive material having optical properties and disease target properties, and a method for preparing a athlete's foot therapeutic agent using the same.

One embodiment of the invention, more than 0 and 0.001 wt% of the nano-ionic complex for photodynamic therapy; 0.1 to 10 wt% emulsifier; 0.1 to 10 wt% of a first alcohol; 0.1 to 10 wt% second alcohol; Fatty acid 0.1 to 10 wt%; Oil 1-40 wt%; And a residual amount of purified water; wherein the photodynamic therapy nano ion complex comprises: a copolymer in which a hydrophilic cationic polymer and a photosensitizer are combined; It provides a composition for treating athlete's foot comprising a; and a combination of an anionic matrix polymer and a quencher.

The hydrophilic cationic polymer is glycol chitosan (GC), chitosan, poly-L-lysine (PLL), poly-beta-amino ester polymer, polyethyleneimine (PEI), polyethylene glycol, poly (amidoamine) (PAMAM) At least one selected from the group consisting of dendrimers, and derivatives thereof.

The photosensitizer is a porphyrin compound, a chlorins compound, a bacteriochlorins compound, a phthalocyanine compound, a naphthalocyanine compound, and a 5-aminolevulin ester compound. (5-aminoevuline esters) compound may be at least one selected from the group consisting of.

The anionic matrix polymer is specific for esterase enzymes and cancer cells, and the anionic matrix polymer is chondroitin-6-sulfate (C6S), heparan sulfate (HS), heparan sulfate proteoglycan (HSPG), heparin, chondroitin-4 At least one selected from the group consisting of-sulfate (C4S), chondroitin-6-sulfate (C6S), dermatan sulfate (DS), keratan sulfate (KS), and hyaluronic acid (HA).

The quencher may be a blackhole quencher (BHQ) or a blackberry quencher (BBQ).

The copolymer is polyethyleneglycol-polyethylenimine-pheophorbide A, and the binder may be chondroitin sulfate-blackhole quencher (BHQ).

Another embodiment of the present invention, a method for preparing athlete's foot therapeutic agent comprising the composition for treating athlete's foot, comprising: preparing an aqueous phase material by heating an emulsifier, a first alcohol, and purified water; Heating the first alcohol, fatty acid, and oil to produce an oily raw material; Mixing the heated aqueous phase material and the oily raw material; Neutralizing the mixture and then cooling; And homogenizing the cooled mixture with the nano-ionic complexes for photodynamic therapy.

According to one embodiment of the present invention, it is possible to provide a composition for treating athlete's foot and a method for preparing athlete's foot treatment using the same, which is harmless to a human body and does not cause side effects.

In addition, according to an embodiment of the present invention, a composition for treating athlete's foot, which can be used for photodynamic therapy (PDT), including a photosensitive material having optical properties and disease target properties, and a method for preparing athlete's foot therapy using the same Can provide.

Hereinafter, embodiments of the present invention will be described in detail. However, this is presented as an example, by which the present invention is not limited and the present invention is defined only by the scope of the claims to be described later.

One embodiment of the invention, more than 0 and 0.001 wt% of the nano-ionic complex for photodynamic therapy; 0.1 to 10 wt% emulsifier; 0.1 to 10 wt% of a first alcohol; 0.1 to 10 wt% second alcohol; Fatty acid 0.1 to 10 wt%; Oil 1-40 wt%; It provides a composition for treating athlete's foot comprising a; and a residual amount of purified water.

More specifically, the photodynamic therapy nano-ion complex is a copolymer in which a hydrophilic cationic polymer and a photosensitizer are combined; And a binder in which an anionic substrate polymer and a quencher are combined.

Accordingly, the present invention is characterized in that the cationic polymer, that is, hydrophilic cationic polymer is used to impart hydrophilicity to the photosensitizer having hydrophobicity, so that the precipitate is not dissolved in the solution or water during optical treatment.

In this case, the copolymer may be, for example, polyethylene glycol-polyethyleneimine-pheophorbide A, but is not limited thereto.

Accordingly, the hydrophilic cationic polymer and the photosensitizer for forming the copolymer may be used in various modifications.

The hydrophilic cationic polymers include glycol chitosan, chitosan, poly-L-lysine (PLL), poly-beta-amino ester polymers, polyethyleneimine (PEI), poly (amidoamine) (PAMAM) dendrimers and derivatives thereof The hydrophilic cationic polymer may form ionic composite nanoparticles by an anionic substrate polymer and electrostatic attraction described below.

For example, the hydrophilic cationic polymer may include polyethylene glycol and polyethyleneimine.

At this time, the polyethylene glycol (PEG) has a structural formula represented by HO- (CH ₂ CH ₂ O) nH, in this case due to the structural properties having ethylene oxide ((CH ₂ CH ₂ O)-) is connected repeatedly It shows strong hydrophilicity. In addition, these properties have characteristics that impart biocompatibility when combined with proteins or compounds.

In addition, polyethylene glycol is also present in the form of methoxy polyethylene glycol (mPEG) in which one end is substituted with a methoxy group (CH ₃ O-), and the structural formula is represented by CH ₃ O- (CH ₂ CH ₂ O) nH. do. In particular, in the case of a preparation having a form of polyethylene glycol-protein, methoxy polyethylene glycol derivatives are mostly used as polyethylene glycol. This is because the terminal of the polyethylene glycol is protected with a methoxy group, so that the stability of the structure can be maintained.

In one embodiment of the present invention, polyethylene glycol may be polyethylene glycol having a carboxyl group at the terminal having a molecular weight of 300 to 50,000. In addition, the polyethylene glycol may be methoxy polyethylene glycol in which one end is substituted with a methoxy group.

On the other hand, the polyethyleneimine is a cationic polymer electrolyte that has been utilized in the papermaking field for a long time. Generally, polyethyleneimine is divided into linear and branched forms according to its structure, and the synthesis method of the two is different. Polyethyleneimines generally used are branched, where the number of primary amines, secondary amines and tertiary amines is present in a ratio of 1: 2: 1. Branched polyethyleneimine is known to exist in about one to three branches of the main chain nitrogen atom, the polyethyleneimine is dissolved in water, alcohol, glycol, dimethylformamide, tetrahydrofuran, esters, etc. It is known to be insoluble in high molecular weight hydrocarbons, oleic acid and diethyl ether.

For example, the polyethyleneimine may be a non-toxic branched polyethyleneimine, and when the molecular weight of the polyethyleneimine is less than 100, the copolymer produced according to the present invention may not bind well with a useful bioactive substance, and the molecular weight is 25,000. If abnormal, there is a problem that is difficult to discharge out of the body through the kidneys in the body. Therefore, polyethyleneimine may have a molecular weight of 100 to 25,000, and preferably 100 to 2000.

The photosensitizer is a porphyrin compound, a chlorins compound, a bacteriochlorins compound, a phthalocyanine compound, a naphthalocyanine compound, and a 5-aminolevulin ester compound ( 5-aminoevuline esters) compounds selected from the group consisting of can be used. For example, the photosensitizer may be Chlorin e6, Zinc Phthalocyanine or Pheophorbide A.

The binder may be, for example, a chondroitin sulfate-blackhole quencher (BHQ), but is not limited thereto.

As mentioned above, the binder is formed in the form of a quencher bonded to the anionic substrate polymer. The anionic matrix polymer and the matting agent for the formation of the binder may be used in various modifications.

The anionic matrix polymer is chondroitin-6-sulfate (C6S), heparan sulfate (HS), heparan sulfate proteoglycan (HSPG), heparin, chondroitin-4-sulfate (C4S), chondroitin-6-sulfate (C6S), One selected from the group consisting of dermatan sulfate (DS), keratan sulfate (KS), and hyaluronic acid (HA) can be used.

The quencher may be selected from the group consisting of blackhole quencher (BHQ), blackberry quencher (BBQ), and derivatives thereof.

On the other hand, the emulsifier is a nonionic surfactant having a structure of hydroxyl group (-OH), ether group (-O-), amide group (-CONH), ester group (-COO-) in the molecule; Polymeric surfactants of polyoxyethylene type, polyhydric alcohol ester type, ethylene oxide and propylene oxide block copolymers, alkyl acrylate copolymers; It may be at least one selected from the group consisting of: natural surfactant of lecithin, lanolin, cholesterol, saponin.

The first alcohol may be at least one selected from the group consisting of glycerin, propylene glycol, butylene glycol, dipropylene glycol, polyethylene glycol, sorbitol, or a combination thereof.

The second alcohol may be lauryl alcohol, cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, behenyl alcohol, linoleyl alcohol, undecylyl alcohol, palmitoleyl alcohol, linolenyl alcohol, arachidonyl At least one selected from the group consisting of alcohol, erucyl alcohol, or a combination thereof.

The fatty acid may be at least one selected from the group consisting of stearic acid, lauric acid, myristic acid, behenic acid, isostearic acid, oleic acid, or a combination thereof.

The oils may be cyclodimethicone, dimethicone, diethylhexylcarbonate, hydrogenated polydesin, myritearic acid isopropyl, liquid paraffin, vegetable squalane, macadamia nut oil, jojoba oil, avocado oil, olive oil, camellia oil, or their At least one selected from the group consisting of a combination.

In one embodiment, when the content of the emulsifier, the first and second alcohols, fatty acids, oils, and purified water is the same as the above range, the effect of the athlete's foot therapeutic agent using the composition for treating athlete's foot can be further improved.

Another embodiment of the present invention, a method for preparing athlete's foot treatment agent comprising the composition for treating athlete's foot, comprising: preparing an aqueous phase material by heating an emulsifier, a first alcohol, and purified water; Heating the first alcohol, fatty acid, and oil to produce an oily raw material; Mixing the heated aqueous phase material and the oily raw material; Neutralizing the mixture and then cooling; And homogenizing the cooled mixture with the nano-ionic complexes for photodynamic therapy.

In addition, another embodiment of the present invention, as an athlete's foot treatment agent prepared according to the above-described method for preparing athlete's foot treatment agent, provides an athlete's foot treatment agent of emulsion type, gel (gel), liquid form, or powder form.

Hereinafter, examples and comparative examples of the present invention are described. However, the following examples are merely examples of the present invention and the present invention is not limited to the following examples.

Example

Example 1 Preparation of Emulsion Type Athlete's Foot Therapeutics

1. Preparation of Nano-Ion Composites

1-1. Synthesis of Copolymer (Polyethylene Glycol-Polyethyleneimine-Photosensitive Agent)

After the reflux condenser was installed, 10 g of methoxy polyethylene glycol (mPEG-COOH) (Sigma, 5000 Da) was dissolved in 50 ml of methylene chloride (CHCl ₂ ) using a 250 ml flask. Thereafter, 0.52 g of N-hydroxysuccinylimide and 0.74 g of dicyclocarbodiimide were added, followed by reaction at room temperature for 20 hours. Dicyclohexyl urea was removed through a filter process and then precipitated in diethylether to obtain activated polyethylene glycol (mPEG-NHS).

2 g of the obtained polyethylene glycol was dissolved in 200 ml of chloroform. Thereafter, 0.5 g of polyethyleneimine (Alfa Aesar, 1800da) was dissolved in 50 ml of chloroform, and then a covalent reaction of polyethylene glycol and polyethyleneimine was performed by dropping a solution of the polyethylene glycol dissolved therein drop by drop.

At this time, the reaction was carried out for 24 hours, after completion of the reaction was concentrated to a total volume of 30ml by using a vacuum concentrator, and then precipitated in diethyl ether to covalently bond the polyethylene glycol and polyethyleneimine Obtained.

1 g of the polyethyleneglycol-polyethylenimine (mPEG-PEI) obtained above was treated with pheophorbide A (eq, 0.07 mmol), dicyclohexyl carbodiimide (DCC) (1.2 * pheophorbide A in moles) and N-hydroxysuccinylimide (HOSu; 1.2 * pheophorbide A in moles) was dissolved in 20 ml of dimethyl sulfoxide (DMSO) and stirred for 3 hours. Thereafter, the two solutions were mixed and reacted at room temperature for 24 hours. In addition, the dialysis membrane (Spectra / Por; mol. Wt. Cutoff size, 1,000) was dialyzed with primary distilled water for 2 days, and then the final reaction product was dried by lyophilization to obtain polyethylene glycol-polyethylenimine-piopho. A pheophorbide A copolymer was obtained.

1-2. Synthesis of Binder (Quatcher Conjugate Chondroitin Sulfate)

0.1 g of chondroitin sulfate was dissolved in 20 ml of distilled water. After dissolving BHQ3 in dried DMSO, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimine hydrochloride (EDC) and 4-dimethylaminopyridine (DMAP) were each added 1.5-fold to the molar ratio of BHQ. . Then, the two solutions were each stirred at room temperature for 3 hours, then mixed and reacted for 24 hours. Removal of unreacted quencher (BHQ3) was removed by dialysis using primary distilled water for 2 days using a dialysis membrane (Spectra / Por; mol. Wt. Cutoff size, 1,000), and the final reaction product was freeze-dried after dialysis. Drying through gave a quencher conjugated chondroitin sulfate conjugate.

1-3. Synthesis of Copolymers and Binders

1-1. The polyethyleneglycol-polyethylenimine-pheophorbide A copolymer prepared in 1-2 and the quencher conjugated chondroitin sulfate conjugate were dissolved in tertiary distilled water, respectively, and then 1.0: 0.0 and 1.0: 0.3, 1.0: 0.6, 1.0: 1.2, 1.0: 2.5, and 1.0: 5.0 in proportions. After 2 hours, the mixture was filtered using a 0.8 μm syringe filter to prepare a nano ion composite.

2. Mixing of raw materials

Purified water, glycerin, and raw materials were water phases, and emulsifiers, polyhydric alcohols, higher fatty acids, and oils were used as oil phases according to the compositions shown in Table 1 below, and each phase was heated and dissolved to 80 ° C. The oil phase or the oil phase was slowly added to the water phase and uniformly mixed with a mixer to emulsify at 80 ° C for 10 minutes. The emulsion was neutralized with a pH adjuster at 70 ° C. or lower and then cooled to 45 ° C. to obtain a mixture of raw materials.

3. Preparation of athlete's foot treatment

Into the mixture of the raw material obtained by cooling to 45 ℃ was added to the nano ion composite prepared by the above process as shown in Table 1 below, and then homogenized to prepare an emulsion-type athlete's foot.

Table 1

	ingredient	Content (wt%)
Award raw material	Purified water	Remaining amount
	Glycerin (polyhydric alcohol)	10
	Xanthan Gum	10
Oily raw material	Polysorbate 80 (emulsifier)	2
	Cetyl Alcohol (Advanced Alcohol)	One
	Stearic acid (high fatty acid)	One
	Dimethicone (oil)	0.5
	Macadamia Nut Oil (Oil)	One
	Cyclodimethicone (oil)	3
	Liquid paraffin (oil)	2
	Hydrogenated Polydesine (Oil)	10
additive	Triethanolamine (pH regulator)	Quantity
	Nano ion composite	Less than 1mg / 100gr
	antiseptic	a very small amount

Example 2 Preparation of Gel-type Athlete's Foot Treatment

Purifying gel-type athlete's foot athlete's foot in the same manner as in Example 1, except that purified water, glycerin, hydrophilic polymer compound, and ethanol were dispersed by heating to 40 ° C. in an aqueous phase to prepare a mixture of raw materials. Was prepared.

TABLE 2

	ingredient	Content (wt%)
Award raw material	Purified water	Remaining amount
	Glycerin (polyhydric alcohol)	10
	Hydrophilic polymer	2
	ethanol	30
additive	Nano ion composite	Less than 1mg / 100gr
	antiseptic	a very small amount

Example 3: Preparation of Liquid Athlete's Foot Treatment

According to the composition of [Table 3] below, except for preparing a mixture of raw materials with purified water, polyhydric alcohol, ethanol in the water phase, a liquid type athlete's foot treatment was prepared in the same manner as in Example 1.

TABLE 3

	ingredient	Content (wt%)
Award raw material	Purified water	Remaining amount
	ethanol	50
	Polyhydric alcohol	10
additive	Nano ion composite	Less than 1mg / 100gr

Example 4 Preparation of Powdered Athlete's Foot Treatment

According to the composition of [Table 4] below, the starch or dextrin, glucose was used as an excipient, except that it was homogenized by impregnating the polyhydric alcohol and nano-ion complex, the liquid athlete's foot athletes therapeutic agent in the same manner as in Example 1 It was.

Table 4

	ingredient	Content (wt%)
Excipient	Starch or dextrin or glucose	Remaining amount
Award raw material	Polyhydric alcohol	10
additive	Nano ion composite	Less than 1mg / 100gr

The present invention is not limited to the above embodiments, but may be manufactured in various forms, and a person skilled in the art to which the present invention pertains has another specific form without changing the technical spirit or essential features of the present invention. It will be appreciated that the present invention may be practiced as. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

According to one embodiment of the present invention, it is possible to provide a composition for treating athlete's foot and a method for preparing athlete's foot treatment using the same, which is harmless to a human body and does not cause side effects.

In addition, according to an embodiment of the present invention, a composition for treating athlete's foot, which can be used for photodynamic therapy (PDT), including a photosensitive material having optical properties and disease target properties, and a method for preparing athlete's foot therapy using the same Can provide.

Claims (7)

1. Greater than 0 and 0.001 wt% of a nano-ionic complex for photodynamic therapy;

   0.1 to 10 wt% emulsifier;

   0.1 to 10 wt% of a first alcohol;

   0.1 to 10 wt% second alcohol;

   Fatty acid 0.1 to 10 wt%;

   Oil 1-40 wt%; And

   Including remaining amount of purified water;

   The photodynamic therapy nano-ion complex is a copolymer in which a hydrophilic cationic polymer and a photosensitizer are combined; And an conjugate in which an anionic matrix polymer and a quencher are combined.
2. The method of claim 1,

   The hydrophilic cationic polymer is glycol chitosan (GC), chitosan, poly-L-lysine (PLL), poly-beta-amino ester polymer, polyethyleneimine (PEI), polyethylene glycol, poly (amidoamine) (PAMAM) At least one selected from the group consisting of a dendrimer, and derivatives thereof.
3. The method of claim 1,

   The photosensitizer is a porphyrin compound, a chlorins compound, a bacteriochlorins compound, a phthalocyanine compound, a naphthalocyanine compound, and a 5-aminolevulin ester compound. At least one selected from the group consisting of (5-aminoevuline esters) compounds for treating athlete's foot.
4. The method of claim 1,

   The anionic matrix polymer is specific for esterase enzymes and cancer cells, and the anionic matrix polymer is chondroitin-6-sulfate (C6S), heparan sulfate (HS), heparan sulfate proteoglycan (HSPG), heparin, chondroitin-4 At least one selected from the group consisting of sulfate (C4S), chondroitin-6-sulfate (C6S), dermatan sulfate (DS), keratan sulfate (KS), and hyaluronic acid (HA).
5. The method of claim 1,

   The quencher is a black hole quencher (blackhole quencher, BHQ) or blackberry quencher (blackberry quencher, BBQ) composition for treating athlete's foot.
6. The method of claim 1,

   The copolymer is polyethyleneglycol-polyethylenimine-pheophorbide A,

   The conjugate is chondroitin sulfate-black hole quencher (blackhole quencher, BHQ) composition for treating athlete's foot.
7. As a method for producing a therapeutic agent for athlete's foot comprising the composition for treating athlete's foot of any one of claims 1 to 6,

   Heating the emulsifier, the first alcohol, and purified water to produce an aqueous phase material;

   Heating the first alcohol, fatty acid, and oil to produce an oily raw material;

   Mixing the heated aqueous phase material and the oily raw material;

   Neutralizing the mixture and then cooling; And

   Homogenizing the cooled mixture with a nano-ionic complex for photodynamic therapy

   Athlete's foot manufacturing method comprising a.