KR101134622B1 - Substained release hydrogels comprising amphotericin B and preparation method thereof - Google Patents

Abstract

The present invention relates to a hydrogel having solubility improvement and release rate control including amphotericin B, L-arginine, tacky polymer, and temperature sensitive polymer, wherein the hydrogel improves the aqueous solubility of poorly soluble amphotericin B. It is easy to adhere to the mucous membranes, has a gelling characteristic at a certain temperature range, and it is possible to control the release rate so that amphotericin B, which is toxic to normal cells, is gradually released depending on the composition ratio. It can improve the, and has the characteristics that can absorb body fluids, prevent infection from bacteria, transparency, ease of handling, storage and sterilization, it can be usefully used as a patch for treating fungal infections containing amphotericin B.

Description

Sustained release hydrogels of amphotericin 및 and method for preparing the same {Substained release hydrogels comprising amphotericin B and preparation method

The present invention relates to a sustained release hydrogel of amphotericin B and a method for preparing the hydrogel.

Ampotericin B is a polyene macrolide antifungal agent consisting of seven double bonds with hydrophobic properties and a hydroxyl group with hydrophilic properties and a mycosamin residue. Ampotericin B is used for the treatment of almost all fungal infections, especially for systemic fungal infections, and is a life-threatening serious infection in cancer, bone marrow transplantation, neutropenia, immunodeficiency, or immunodeficiency. Effective treatment

Amphotericin B binds to ergosterol, a membrane sterol of fungi, causes membrane rupture, increases permeability of ion channels, and leaks electrolyte (K ⁺ ) and components in the cytoplasm to kill fungal cells.

However, amphotericin B is toxic to normal cells and tissues by binding to normal cells cholesterol by the same mechanism as ergosterol upon intravenous injection, accompanied by side effects such as chills, fever, tissue necrosis, kidney toxicity. In particular, since amphotericin B is difficult to release the urinary tract by hemodialysis and very strong renal toxicity, it requires special attention when used in children, the elderly and patients with weak immunity.

In addition, the amphotericin B is insoluble in water at pH 6-7, and has a very low solubility of 0.1 mg / ml at pH 2 or pH 11, so that the salt or micelle, emulsion, nanoparticles Solubilized in the form of, or liposomes.

U.S. Patent No. 4,822,777 discloses a process for preparing amphotericin B in the form of a salt to improve solubility. Specifically, using only amphotericin B and cholesterol sulfate, nanoparticles having a size of 100 to 400 nm were prepared, thereby improving the solubility in aqueous phase by forming salts of amphotericin B in water. However, since amphotericin B is toxic to normal cells and tissues, it is important to be slowly absorbed into the body. However, the method has an effect of improving solubility, but it is difficult to control the rate of absorption into the body.

US Pat. No. 5,059,591 discloses a method for reducing the toxicity of amphotericin B using amphotericin B and cholesterol-polyethyleneglycol (PEG). Specifically, amphotericin B is combined with cholesterol-PEG in the form of a salt, wherein the characteristics of the PEG-bound PEG are used to increase the circulation time in the body to reduce toxicity. However, this method has a problem that is not sufficient to reduce the toxicity of amphotericin B.

US Patent No. 4,981,690 discloses a method for preparing liposomes encapsulated with amphotericin B. Specifically, it is prepared in the form of a multi-membrane liposome using phospholipids and cholesterol. However, the method has a problem that amphotericin B, which was easily destroyed and encapsulated, is rapidly released because the structure of the liposome is unstable during administration in the body.

U. S. Patent No. 5,965, 156 discloses a method for preparing liposomes encapsulated with amphotericin B. The above method is to ionize the amphotericin B and the anionic lipid phosphatidylglycerol in an acidic organic solvent to form liposomes to increase the drug encapsulation rate and reduce the toxicity in the body. However, since the above method uses an acidic organic solvent for ionic bonding of phosphatidylglycerol and amphotericin B, there is a problem in that the decomposition of amphotericin B is accelerated and lost.

As described above, in order to develop low solubility and highly toxic amphotericin B as a pharmaceutical preparation, it must be able to be solubilized in an aqueous medium at high concentrations, and the rate of drug release can be controlled to be slowly absorbed into the body to reduce toxicity. There is a demand for development of technology.

Therefore, the inventors of the present invention while researching a method for improving the solubility of amphotericin B and controlling the drug release rate, preparing a hydrogel containing amphotericin B, L-arginine, adhesive polymer and temperature sensitive polymer and In addition, the hydrogel dissolves amphotericin B at a high concentration without using a dissolution aid that is harmful to the human body, and can continuously release amphotericin B by controlling the release rate of amphotericin B as a patch for treating fungal infections. It was confirmed that the present invention can be usefully, and completed the present invention.

It is an object of the present invention to provide a sustained release hydrogel of amphotericin B.

Another object of the present invention is to provide a method for preparing the hydrogel.

Still another object of the present invention is to provide a patch for treating fungal infection comprising the hydrogel.

In order to achieve the above object, the present invention provides a sustained-release hydrogel of amphotericin B comprising amphotericin B, L-arginine, a tacky polymer and a temperature sensitive polymer represented by the following formula:

[Formula 1]

.

.

In addition, the present invention,

Preparing an aqueous solution by dissolving amphotericin B, L-arginine, an adhesive polymer, and a temperature sensitive polymer in a distilled shoe (step 1);

Pouring the aqueous solution into a tray to form a gel sheet (step 2); And

It provides a method for producing a sustained-release hydrogel of amphotericin B comprising the step of packaging the sheet (step 3).

Furthermore, the present invention provides a patch for treating fungal infections comprising the sustained release hydrogel of amphotericin B.

According to the present invention, the hydrogel includes L-arginine, a tacky polymer and a temperature sensitive polymer, to improve the water solubility of poorly soluble amphotericin B, and to easily adhere to mucous membranes, and to gel at a range of temperatures. According to the composition ratio, it is possible to control the release rate so that amphotericin B, which is toxic to normal cells, is gradually released, thereby improving the effect of fungal infection treatment, absorbing fluids, preventing infection from bacteria, and transparency. Because of its ease of handling, storage and sterilization, it can be usefully used as a patch for treating fungal infections containing amphotericin B.

1 is a graph measuring a calibration curve for measuring the concentration of amphotericin B according to an embodiment of the present invention.
Figure 2 is a graph showing the change in solubility according to the addition of L- arginine to amphotericin B according to an embodiment of the present invention.
FIG. 3 is a photograph showing an inverting measurement method for measuring a sol-gel-sol phase transition temperature of poloxamer 407 according to an embodiment of the present invention.
4 is a graph showing the change in the sol-gel-sol phase transition temperature of poloxamer 407 alone or poloxamer 407 according to the addition of amphotericin B and L-arginine according to an embodiment of the present invention.
FIG. 5 is a graph showing the change of the sol-gel-sol phase transition temperature of poloxamer 407 according to the addition of amphotericin B, L-arginine and carbopol 940 according to an embodiment of the present invention.
6 is a graph showing the effect of L-arginine and poloxamer 407 on the release amount of amphotericin B according to an embodiment of the present invention.
7 is a graph showing the effect of carbopol 940 on the amount of amphotericin B released according to an embodiment of the present invention.

As used herein, the term "% (W / V)" refers to the percentage of weight / volume concentration.

Hereinafter, the present invention will be described in detail.

The present invention provides a sustained-release hydrogel of amphotericin B comprising amphotericin B, L-arginine, a tacky polymer, and a temperature sensitive polymer represented by Formula 1 below:

In the hydrogel according to the present invention, the content of amphotericin B is 1 to 10% (W / V), the content of L-arginine is 1 to 20% (W / V), and the content of the tacky polymer is 0.1. It is preferably 1% (W / V), and the content of the temperature sensitive polymer is 10-50% (W / V).

In the hydrogel according to the present invention, amphotericin B represented by Chemical Formula 1 serves as an antifungal role against fungal infections, and those prepared according to methods well known in the art may be used. At this time, the content of the amphotericin B is preferably 1 to 10% (W / V), when less than 1% (W / V) there is a problem that can not sufficiently improve the therapeutic effect, 10% (W / V) in excess of the increase in the treatment effect due to the increase of amphotericin B no longer causes a problem that the amphotericin B is wasted.

In the hydrogel according to the present invention, L-arginine represented by the following formula (2) serves to solubilize amphotericin B, which is very poorly soluble in an aqueous medium, and prepared or commercially available according to methods well known in the art. You can use one:

At this time, the content of L-arginine is preferably 1 ~ 20% (W / V) bar, when less than 1% (W / V) there is a problem that does not sufficiently dissolve amphotericin B, 20% (W / V) in excess of the solubility of amphotericin B no longer occurs so there is a problem that L- arginine is wasted.

In the hydrogel according to the present invention, the temperature-sensitive polymer is a polymer having a characteristic of reversibly changing in the form of a sol or a gel in accordance with a change in temperature, which is present in the state of a gel at a range of temperatures. It is characterized by maintaining the hydrogel state, and also increases the amount of amphotericin B released.

In the hydrogel according to the present invention, the temperature sensitive polymer is poloxamer, polyethylene oxide, alkyl-polyethylene oxide, irregular copolymer of poly (ethylene oxide / propylene oxide), polyvinyl methyl ether, polyphosphazene, polyethylene glycol, etc. May be used, and preferably poloxamer may be used. More preferably, in view of low toxicity, high solubility and excellent drug release properties, poloxamer 407 represented by the following formula (3) which is used as a drug delivery vehicle in various therapeutic agents may be used:

Specifically, the poloxamer 407 is a nonionic PEO-PPO-PEO triblock copolymer composed of hydrophilic polyethylene oxide (PEO) and hydrophobic polypropylene oxide (PPO) and has a molecular weight of 4400-3770-4400. The poloxamer 407 serves to maintain the hydrogel state of the present invention and to increase the release amount of amphotericin B.

In the hydrogel according to the present invention, the content of the temperature sensitive polymer is It is preferable that it is 10 to 50% (W / V). If the content of the temperature-sensitive polymer is less than 10% (W / V) there is a problem in maintaining the gel form, if it exceeds 50% (W / V) it is difficult to prepare an aqueous solution.

In the hydrogel according to the present invention, the adhesive polymer serves to impart adhesion to the hydrogel of the present invention and reduce the amount of amphotericin B released. Carbopol, chitosan, carboxymethylcellulose, polybrene, polylysine, polyvinylmethylimidazole, polyvinyl sulfate, heparin, polyethylenepyrrolidone, etc. may be used as the adhesive polymer, and preferably carbopol may be used. Can be. More preferably, Carbopol 940 represented by the following general formula (4) may be used in view of low toxicity and high viscosity even at low concentrations for the design of mucoadhesive formulations. :

In the hydrogel according to the present invention, the content of the adhesive polymer is preferably 0.1 to 1% (W / V). If the content of the adhesive polymer is less than 0.1% (W / V) there is a problem that can not sufficiently improve the adhesive force, if the content exceeds 1% (W / V) there is a problem that the viscosity is too high.

The present invention also provides a method for preparing the sustained release hydrogel of amphotericin B.

Specifically, the method for preparing a hydrogel according to the present invention comprises the steps of dissolving amphotericin B, L-arginine, adhesive polymer and temperature sensitive polymer in a distilled shoe to prepare an aqueous solution (step 1);

Pouring the aqueous solution into a tray to form a gel sheet (step 2); And

Packing the sheet (step 3).

Hereinafter, the present invention will be described in more detail step by step.

In the production method according to the present invention, step 1 is a step of dissolving amphotericin B, L-arginine, a temperature sensitive polymer and a tacky polymer in distilled water to prepare an aqueous solution.

At this time, the content of amphotericin B is 1 ~ 10% (W / V) with respect to the total aqueous solution, the content of L- arginine is 1 ~ 20% (W / V), the content of the temperature-sensitive polymer is 10 ~ It is preferably 50% (W / V), and the content of the tacky polymer is 0.1 to 1% (W / V).

In the production method according to the present invention, the temperature sensitive polymer is poloxamer, polyethylene oxide, alkyl-polyethylene oxide, irregular copolymer of poly (ethylene oxide / propylene oxide), polyvinyl methyl ether, polyphosphazene, polyethylene glycol Etc. can be used, Preferably poloxamer can be used. More preferably, in view of low toxicity, high solubility, and excellent drug release properties, poloxamer 407 represented by Formula 3, which is used as a drug delivery medium in various therapeutic agents, may be used.

In the production method according to the present invention, the adhesive polymer can be used carbopol, chitosan, carboxymethyl cellulose, polybrene, polylysine, polyvinylmethylimidazole, polyvinyl sulfate, heparin, polyethylenepyrrolidone, etc. And preferably Carbopol. More preferably, in view of low toxicity and high viscosity even at low concentrations for the design of mucoadhesive formulations, Carbopol 940 represented by Formula 4, which is widely applied in mucoadhesive preparations, may be used. .

The prepared aqueous solution may be further centrifuged, followed by a process of taking a portion of the supernatant except for the settled precipitate, thereby preparing an aqueous solution in which amphotericin B is uniformly dissolved.

In the production method according to the invention, the step 2 is a step of pouring the aqueous solution obtained in the step 1 to a tray to form a sheet of gel state. Specifically, when the aqueous solution obtained in step 1 is poured into a tray and left in a constant temperature water bath, the gel is physically gelled by the characteristics of the temperature sensitive polymer to form a sheet in the tray.

In the manufacturing method according to the present invention, the tray may be manufactured in a general shape or various sizes, thicknesses and shapes according to the use.

In the manufacturing method according to the present invention, step 3 is a step of packaging the hydrogel in the form of a sheet obtained in step 2. Conventional packaging materials may be used for the packaging, and for example, a polymer film such as polyethylene, polypropylene, polyvinyl chloride, nylon or polyester, aluminum foil, or a laminate of aluminum and a polymer film may be used.

The hydrogel packaged as described above may further include sterilization through irradiation. In this case, the radiation used may be gamma rays, ultraviolet rays, electron beams, and the like.

Furthermore, the present invention provides a patch for treating fungal infections using a hydrogel containing amphotericin B.

The hydrogel according to the present invention contains L-arginine to improve the aqueous solubility of poorly soluble amphotericin B by about 2,600 times (see Table 1 and FIG. 2), and contains an adhesive polymer to easily adhere to the mucosa, and temperature It contains a sensitive polymer and gelled in a certain temperature range (see Tables 2, 4 and 5), and controls the release rate so that amphotericin B, which is toxic to normal cells, is gradually released depending on the composition ratio. It is possible (see Tables 3, 6 and 7) to enhance the effectiveness of fungal infection treatment. In addition, the hydrogel has a characteristic of absorbing body fluids, preventing infection from bacteria, transparency, ease of handling, storage and sterilization, and thus may be useful as a patch for treating fungal infections.

Hereinafter, an Example demonstrates this invention further in detail. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited thereto.

< Example  1> Amphotericin  B, L-arginine, Cabopol  940 and Poloxamer  Contains 407 Hydrogel  Produce

Ampotericin B was purchased from Duchefa Biochemical, L-arginine was purchased from Sigma-Aldrich, Carbopol 940 was purchased from Lubrizol Inc., and Poloxamer 407 was purchased from BASF.

Add amphotericin B 10 W / V%, L-arginine 10 W / V%, Carbopol 940 0.1 W / V%, and Poloxamer 407 20 W / V% in distilled water, and stir at room temperature for 3 days to ensure sufficient dissolution. After centrifugation at 3,000 rpm for 5 minutes, the supernatant portion, except for the settled precipitate, was taken by syringe. The solution taken was filtered with a 0.45 μm filter to prepare an aqueous solution in which amphotericin B was uniformly dissolved. The aqueous solution was poured into a mold, sealed and soaked in a constant temperature water bath at 37 ° C. for about 1 hour to prepare a hydrogel for treating fungal infections.

Example 2 Preparation of Hydrogels with Different Concentrations of Poloxamer 407

A hydrogel for treating fungal infection was prepared in the same manner as in Example 1, except that poloxamer 407 was used at 25 W / V% and 30 W / V%, respectively.

Example 3 Preparation of Hydrogels with Different Carbopol Concentrations

Carbopol 940 was used in the same manner as in Example 1 except for using 0.2 W / V% to prepare a hydrogel for treating fungal infections.

Example 4 Preparation of Hydrogels with Different L-Arginine Concentrations

A hydrogel for treating fungal infection was prepared by the same method as in Example 1 except for using 20 W / V% of L-arginine.

Experimental Example 1 Measurement of Solubility of Ampoterisin B

Experimental Example 1-1 Calibration curve for measuring the concentration of amphotericin B

In order to measure the concentration of amphotericin B, amphotericin B was completely dissolved in dimethyl sulfoxide (DMSO) solvent, followed by serial dilution to prepare a standard solution having a concentration of 1, 5, 10, 25 mg / ml. Prepared. The absorbance at wavelength 405 nm was measured using a UV-VIS spectrometer (Mini 1240, Schimadzu, Japan), and the results are shown in FIG. 1. The linear regression equation of the calibration curve obtained in FIG. 1 is represented by Equation 1 below, and used to calculate the concentration of amphotericin B in the following experiments.

Experimental Example 1-2 Measurement of Solubility of Ampoterisin B in Water

An aqueous solution in which an amphotericin B was added to distilled water was stirred at room temperature for 3 days, and centrifuged at 3,000 rpm for 5 minutes. After centrifugation, 0.8 to 0.9 ml of the supernatant except for the settled precipitate was taken with a syringe to prepare a sample of amphotericin B, and the solubility of amphotericin B was measured by the same method as Experimental Example 1-1. 1 μg / ml was found to be very poorly soluble in aqueous media.

Experimental Example 1-3 Measurement of Solubility of Ampoterisin B with Addition of L-Arginine

A solution sample was prepared by the same method as Experimental Example 1-2, except that an aqueous solution in which excess amphotericin B and 0.1 M, 0.2 M, 0.5 M, and 1.0 M of L-arginine was added to distilled water was used. The results of measuring the solubility of amphotericin B by the same method as in Experimental Example 1-1 are shown in Table 1 and FIG. 2.

Concentration of R (m) Solubility of AmB (mg / ml) 0.1 0.2 0.2 0.5 0.5 1.3 1.0 2.6  R: L-arginine, AmB: amphotericin B

As shown in Table 1 and Figure 2, it was confirmed that the solubility of amphotericin B was linearly proportional to the concentration of L-arginine added. From this result, when 1M of L-arginine was added, the solubility of amphotericin B was about 2.6 mg / ml, and the solubility of amphotericin B in water of Experimental Example 1-2 was about 1 µg / ml. 2,600 times increase was confirmed.

< Experimental Example  2> according to additives Hydrogel  Phase transition temperature measurement

20% (W / V), 25% (W / V) and 30% (W / V) of Poloxamer 407 (BASF, Germany) were added to distilled water and then stored in a water bath at 4 ° C for 2 days to completely dissolve. Poloxamer 407 solution samples were prepared and subjected to the following treatment.

Group 1) Poloxamer 407 solution alone

Group 2) Add 1 mg / ml of amphotericin B to poloxamer 407 solution

Group 3) Add 1 mg / ml of amphotericin B and 1 M of L-arginine to poloxamer 407 solution

Group 4) Add 1 mg / ml of amphotericin B, 1 M of L-arginine and 0.1% (W / V) of Carbopol 940 to poloxamer 407 solution.

Group 5) Add 1 mg / ml of amphotericin B, 1 M of L-arginine and 0.2% (W / V) of Carbopol 940 to poloxamer 407 solution.

The treated poloxamer 407 solution samples were placed in a constant temperature water bath at 10 ° C. and the phase transition temperature was measured while increasing the temperature. The method of measuring the phase transition temperature was measured by the inverting method of FIG. 3. In order to reduce the error of the phase transition temperature, a thermometer was directly inserted into the gel and measured, and the results are shown in Tables 2, 4, and 5. .

division Pol (W / V%) AmB (mg / ml) R (M) C (W / V%) Gelation temperature (℃)
Group 1
20 - - - 28-60 25 - - - 23-79 30 - - - 20.5-84.5
Group 2
20 One - - 23-57 25 One - - 19-73 30 One - - 15.5 ~ 8
Group 3
20 One One - 25.8-58 25 One One - 20-70 30 One One - 17-80
4th group
20 One One 0.1 24 ~ 62 25 One One 0.1 18.5-74 30 One One 0.1 12-86
5 groups
20 One One 0.2 23-68 25 One One 0.2 16-75 30 One One 0.2 9-88  AmB: amphotericin B, R: L-arginine, Pol: poloxamer 407, C: carbopol 940

FIG. 4 is a graph showing the change of sol-gel-sol phase transition temperature of poloxamer 407 with poloxamer 407 alone or with addition of amphotericin B and L-arginine, and FIG. 5 is amphotericin B, L-arginine and carbo It is a graph showing the sol-gel-sol phase transition temperature of poloxamer 407 with the addition of the pole 940.

As shown in Table 2, Figures 4 and 5, the gelation temperature in the poloxamer 407 20% (W / V) alone solution was 28 ~ 60 ℃, poloxamer 407 20% with amphotericin B added The gelation temperature in the (W / V) solution ranged from 23 to 57 ° C. It is considered that the hydrophobic association of the polymer is further enhanced due to the presence of the hydrophobic drug, thereby lowering the phase transition temperature.

In addition, the range of gelation temperature in poloxamer 407 20% (W / V) solution to which amphotericin B and L-arginine was added was 25.8 to 58 ° C, resulting in L-arginine used as a solubilizer for amphotericin B. It was confirmed that the phase transition temperature was increased.

Furthermore, the gelation temperature in poloxamer 407 20% (W / V) solution with amphotericin B, L-arginine and Carbopol 940 did not change significantly, but the gelation temperature was proportional to the concentration of carbopol. It can be seen that is slightly expanded.

Accordingly, it can be seen that poloxamer 407 used in the present invention can be usefully used as a hydrogel, even though amphotericin B, L-arginine, and carbopol 940 are always present in the body temperature (37 ° C.).

< Experimental Example  3> Amphotericin  B's In in vitro  Drug Release Behavior Measurement

An aqueous solution in which an amphotericin B was added to distilled water was stirred at room temperature for 3 days, and centrifuged at 3,000 rpm for 5 minutes. After centrifugation, take 0.8-0.9 ml of syringe from the supernatant except for the settled precipitate, soak 2 ml of amphotericin B saturated solution in a membrane of MWCO (molecular weight cut off) 6000-8000, and then PBS 40 at 37 ° C. It was placed in a conical tube containing ml.

Shaking the centrifuge tube in an incubator (SI-300, Lab Companion, Korea) at a temperature of 37 ° C. for a predetermined time interval (1 hour, 6 hours, 12 hours, 18 hours, 1 day, 2 days, On days 3, 6, 7, 9, 10, 11 and 14), the membrane containing the amphotericin B saturated solution was removed from the centrifuge tube and transferred to a centrifuge tube containing 40 ml of fresh PBS. .

The concentration of amphotericin B released from the membrane was measured in the same manner as in Experimental Example 1-1, and the drug release amount was determined from the concentration of amphotericin B initially introduced into the membrane. The concentration of amphotericin B released compared is expressed in%.

Next, L-arginine, poloxamer 407, and Carbopol 940 were added to the amphotericin B saturated solution, and the amount of amphotericin B was measured by the method described above. The measurement results are shown in Tables 3, 4, 6, and 7 below.

% AmB released by additive time
AmB AmB + R AmB + R + Pol 0 hours 0 0 0 2 hours 0.35 19.33 6.29 4 hours 0.47 30.73 14.06 8 hours 0.71 41.40 21.35 12 hours 0.91 45.88 53.96 1 day 1.03 49.80 70.14 2 days 1.52 52.02 76.04 3 days 2.04 54.69 80.04 4 days 2.45 56.63 82.46 6 days 3.30 58.69 86.24 8 days 4.10 60.95 87.34 10 days 4.91 62.85 87.27 14 days 6.53 65.32 85.31  AmB: amphotericin B, R: L-arginine, Pol: poloxamer 407, C: carbopol 940

% AmB released by additive time
AmB + R + Pol AmB + R + Pol + C 0.1 W / V% AmB + R + Pol + C 0.2 W / V% 0 hours 0 0 0 1 hours 6.45 7.37 6.58 4 hours 14.61 14.70 14.89 8 hours 22.53 21.01 22.40 1 day 52.68 45.67 38.46 2 days 70.49 56.70 49.25 3 days 75.93 58.89 54.10 6 days 80.15 67.07 57.19 7 days 82.64 68.46 57.80 9th 86.40 73.92 60.40 10 days 88.84 75.01 64.10 11th 87.93 74.34 63.92 14 days 85.17 72.77 63.67  AmB: amphotericin B, R: L-arginine, Pol: poloxamer 407, C: carbopol 940

FIG. 6 is a graph showing the effect of L-arginine and poloxamer 407 on the amount of amphotericin B released, and FIG. 7 is a graph showing the effect of carbopol 940 on the amount of amphotericin B released.

As shown in Table 3, Figure 6, the amount of amphotericin B in the saturated solution of amphotericin B to which nothing was added showed a linear release, but less than 7% release for 2 weeks, so that the solubility was not improved. In the state, it was confirmed that the release of amphotericin B is not easy.

However, the amount of amphotericin B released by L-arginine addition was about 50% within 1 day, and the cumulative release amount was about 65% for 2 weeks, indicating that L-arginine improved the solubility of amphotericin B. Improved.

In addition, the amount of amphotericin B released by the addition of L-arginine and poloxamer 407 was released by about 20% until 12 hours, and the cumulative amount of release over two weeks increased to about 85%. Indicated.

Furthermore, as shown in Table 4 and FIG. 7, the cumulative release of amphotericin B for two weeks following the addition of L-arginine, poloxamer 407 and carbopol 940 is 0.1% (W / V) of carbopol 940. At 73% and Carbopol 940 was 0.2% (W / V), it decreased to 64%, indicating that the amount of amphotericin B decreased as the concentration of Carbopol 940 increased.

From this, it can be seen that the solubility and release amount of amphotericin B is improved by L-arginine and poloxamer 407, and the amount of release of amphotericin B is reduced by carbopol 940. Therefore, since the release rate of amphotericin B can be controlled by adjusting the concentration of the composition, a hydrogel that can be used as a patch for treating fungal infection can be prepared.

Claims (18)

Including amphotericin B, L-arginine, an adhesive polymer and a temperature sensitive polymer represented by Formula 1,
The adhesive polymer is carbopol,
The sustained-release hydrogel of amphotericin B, characterized in that the temperature sensitive polymer is poloxamer:
[Formula 1]

.
According to claim 1, wherein the content of amphotericin B is 1 ~ 10% (W / V), the content of L- arginine is 1 ~ 20% (W / V), the content of the adhesive polymer is 0.1 ~ 1 A sustained release hydrogel of amphotericin B, which is% (W / V), and the content of the temperature-sensitive polymer is 10-50% (W / V).
delete delete The sustained-release hydrogel of amphotericin B according to claim 1, wherein the poloxamer is poloxamer 407 represented by the following Chemical Formula 2:
(2)

.
delete delete The sustained release hydrogel of amphotericin B according to claim 1, wherein the carbopol is Carbopol 940.
The sustained-release hydrogel of amphotericin B according to claim 1, wherein the hydrogel solubilizes poorly soluble amphotericin B and has drug release control ability.
Dissolving amphotericin B, L-arginine, a temperature sensitive polymer and a tacky polymer in a distilled shoe to prepare an aqueous solution (step 1);
Pouring the aqueous solution into a tray to form a gel sheet (step 2); And
Packing the sheet (step 3),
The adhesive polymer is carbopol,
The temperature-sensitive polymer is a method for producing a hydrogel according to claim 1, characterized in that the poloxamer.
The method of claim 10, wherein the content of the amphotericin B relative to the total aqueous solution is 1 to 10% (W / V), the content of L- arginine is 1 to 20% (W / V), the temperature-sensitive polymer The content is 10 to 50% (W / V), the content of the adhesive polymer is 0.1 to 1% (W / V) method for producing a hydrogel, characterized in that.
delete delete The method of claim 10, wherein the poloxamer is a poloxamer 407 manufacturing method characterized in that the molecular weight of PEO-PPO-PEO is 4400-3770-4400.
delete delete The method of claim 10, wherein the carbopol is carbopol 940, characterized in that the manufacturing method of the hydrogel.
A patch for treating fungal infections comprising the sustained release hydrogel of claim 1 amphotericin B.

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