KR102594715B1 - Solid dispersion comprising niclosamide with increased oral bioavailability and preparation method thereof - Google Patents

Abstract

The present invention relates to a solid dispersion containing niclosamide with increased water solubility, dissolution rate, and oral bioavailability and a method for producing the same. More specifically, it relates to a solid dispersion containing niclosamide containing niclosamide, a water-soluble polymer, and a surfactant. Dispersions and methods for producing the same are provided.
By using water-soluble polymers and surfactants in appropriate formulations and ratios according to the above manufacturing method, niclosamide is dispersed in amorphous or crystalline form to improve water solubility and dissolution rate, thereby producing a solid dispersion containing niclosamide with improved oral bioavailability. can do.

Description

Solid dispersion containing niclosamide with increased oral bioavailability and method for manufacturing same {SOLID DISPERSION COMPRISING NICLOSAMIDE WITH INCREASED ORAL BIOAVAILABILITY AND PREPARATION METHOD THEREOF}

The present invention relates to a solid dispersion containing niclosamide with increased water solubility, dissolution rate, and oral bioavailability, and a method for producing the same.

Niclosamide is a poorly soluble drug that is effective against adult tapeworms and is an orally administered anthelmintic. Recently, in addition to being an anthelmintic, the clinical and mechanism of action for niclosamide's anticancer effect have been revealed, and its COVID-19 antiviral effect has also been confirmed, making it an anticancer agent and treatment for COVID-19 (coronavirus infection-19, COVID-19). It's attracting attention.

In developing new drugs, it is important to improve the water solubility of the drug. Insufficient water solubility of a drug leads to inhibition of absorption when the drug is administered in vivo, and a decrease in in vivo absorption rate leads to a decrease in bioavailability. Niclosamide, the drug according to the present invention, also belongs to this category.

Although various solubilization techniques have been used to improve the water solubility of drugs with such low water solubility, many difficulties arise when formulating the drug considering its absorption rate, bioavailability, side effects, etc.

Accordingly, there is an urgent need to develop technology for a new formulation that can increase bioavailability by improving the water solubility of poorly soluble drugs such as niclosamide, which is attracting attention as an anticancer drug and treatment for COVID-19.

Republic of Korea Patent Publication No. 10-19980031601 (published on July 25, 1998)

The purpose of the present invention is to provide a solid dispersion containing niclosamide with improved water solubility, dissolution rate, and ultimately oral bioavailability, and a method for producing the same.

The present invention relates to niclosamide, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; One or more water-soluble polymers selected from the group consisting of sodium alginate, gelatin, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC); and at least one surfactant selected from the group consisting of poloxamer 407, Tween 80, Tween 20, and sodium lauryl sulfate (SLS). It provides a solid dispersion containing niclosamide.

The present invention relates to niclosamide; One or more water-soluble polymers selected from the group consisting of sodium alginate, gelatin, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC); and at least one surfactant selected from the group consisting of poloxamer 407, Tween 80, Tween 20, and sodium lauryl sulfate (SLS); dissolving in a solvent to prepare a mixed solution; It provides a method for producing a solid dispersion containing niclosamide, including the step of spray drying the prepared mixed solution.

The present invention includes the steps of dissolving niclosamide in a solvent to prepare a solution; and at least one water-soluble polymer selected from the group consisting of sodium alginate, gelatin, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC) in the prepared solution; and poloxamer 407, Tween 80, Tween 20, and at least one surfactant selected from the group consisting of sodium lauryl sulfate (SLS), followed by spray drying. A method for producing a solid dispersion containing niclosamide, comprising: provides.

In addition, the present invention relates to one or more water-soluble polymers selected from the group consisting of sodium alginate, gelatin, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC); and at least one surfactant selected from the group consisting of poloxamer 407, Tween 80, Tween 20, and sodium lauryl sulfate (SLS); dissolving in a solvent to prepare a mixed solution; It provides a method for producing a solid dispersion containing niclosamide, including dispersing niclosamide in the prepared mixed solution and then spray drying.

The solid dispersion containing niclosamide according to the present invention can improve the bioavailability by increasing the water solubility and dissolution rate of niclosamide, a poorly soluble drug, and the solid dispersion containing niclosamide with improved bioavailability is niclosamide. It can be used more effectively in various diseases that require it.

Niclosamide has improved water solubility, dissolution rate, and oral bioavailability by dispersing niclosamide in amorphous or crystalline form by using water-soluble polymers and surfactants in appropriate formulations and ratios according to various solid dispersion production methods according to the present invention. A solid dispersion containing

Figure 1 is a list of additives for selecting additives necessary for producing a solid dispersion containing niclosamide according to an embodiment of the present invention.
Figure 2 shows the solubility evaluation results of high molecular weight polymers in the additive list of Figure 1.
Figure 3 shows the solubility evaluation results of surfactants in the additive list of Figure 1.
Figure 4 shows the results of evaluating the solubility of solvents in the additive list of Figure 1.
Figure 5 shows the main components for producing a solid dispersion selected through the solubility evaluation results in Figures 2 to 4.
Figure 6 shows the solubility analysis results for each niclosamide formulation according to Table 1.
Figure 7 shows the results of solubility analysis for each niclosamide formulation prepared according to Table 3.
Figure 8 shows the results of solubility analysis for each niclosamide formulation prepared according to Table 4.
Figure 9 shows the solubility analysis results for each niclosamide formulation prepared according to Table 5.
Figure 10 shows the solubility analysis results for each niclosamide formulation prepared according to Table 7.
Figure 11 shows the solubility analysis results for each niclosamide formulation prepared according to Table 8.
Figure 12 is a graph showing the degree of dissolution of the solvent evaporated solid dispersion prepared according to Example 1.
Figure 13 is a graph showing the degree of dissolution of the surface-attached solid dispersion prepared according to Example 2.
Figure 14 is a graph showing the degree of dissolution of the solvent-wet solid dispersion prepared according to Example 3.
Figure 15 shows the HPLC analysis conditions used in the in vivo kinetics experiment of niclosamide-containing solid dispersion.
Figure 16 is a graph showing the blood drug concentration in the body according to Experimental Example 2 of the present invention.
Figure 17 shows pharmacokinetic parameters according to Experimental Example 2 of the present invention.
Figure 18 shows the results of differential scanning calorimetry (DSC) analysis according to Experimental Example 3 of the present invention, where (A) is the drug niclosamide; (B) is a physical mixture; (C) is the solvent evaporated solid dispersion prepared according to Example 1; (D) is a solvent-wet solid dispersion prepared according to Example 3; (E) represents the surface-attached solid dispersion prepared according to Example 2.
Figure 19 shows the results of powder X-ray diffraction (XRD) analysis according to Experimental Example 3 of the present invention, where (A) is the drug niclosamide; (B) is a physical mixture; (C) is the solvent evaporated solid dispersion prepared according to Example 1; (D) is a solvent-wet solid dispersion prepared according to Example 3; (E) represents the surface-attached solid dispersion prepared according to Example 2.

Hereinafter, the present invention will be described in detail.

As a result of producing a solid dispersion containing niclosamide using a variety of methods using bioapplicable water-soluble polymers and surfactants, the present inventor found that water solubility and dissolution rate increased compared to existing niclosamide, and oral bioavailability was significantly improved. By confirmation, the present invention was completed.

The present invention provides a solid dispersion containing niclosamide.

The niclosamide-containing solid dispersion according to the present invention includes niclosamide, a poorly soluble drug; water-soluble polymer; and a surfactant.

Preferably, the solid dispersion is niclosamide, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; At least one water-soluble polymer selected from the group consisting of sodium alginate, gelatin, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC); and one or more surfactants selected from the group consisting of poloxamer 407, tween 80, tween 20, and sodium lauryl sulfate (SLS).

As used herein, “niclosamide-containing solid dispersion” means that niclosamide, a drug, is evenly dispersed in a water-soluble polymer, and depending on whether it is dissolved, the crystalline form of niclosamide may be maintained or converted to an amorphous form. there is. By dispersing in a water-soluble polymer, the nature of niclosamide can change to hydrophilic, increasing the water solubility and dissolution rate. In the case of crystalline form, the stability of the drug can be maintained, and in the case of amorphous form, the water solubility and dissolution rate can be further increased. This can ultimately increase oral bioavailability.

In the present invention, the niclosamide is a compound of the following formula (1) and has the following structure and characteristics.

<Formula 1>

The compound can be used in the form of a pharmaceutically acceptable salt within the range having the same efficacy.

As used herein, “pharmaceutically acceptable” means a salt that is not toxic to cells or humans exposed to the composition and has a safety and efficacy profile suitable for administration to humans.

The salt may be used in the form of either a pharmaceutically acceptable basic salt or an acid salt. Basic salts can be used in the form of any one of organic base salts and inorganic base salts, including sodium salts, potassium salts, calcium salts, lithium salts, magnesium salts, cesium salts, amidium salts, ammonium salts, triethylaminium salts, and pyrilicate salts. It may be selected from the group consisting of dinium salts.

A useful acid salt is an acid addition salt formed by free acid. Inorganic acids and organic acids can be used as free acids. Hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, double phosphoric acid, and nitric acid can be used as inorganic acids, and citric acid, acetic acid, maleic acid, malic acid, and fumaric acid can be used as organic acids. , glucolic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, Glutamic acid, citric acid, aspartic acid, stearic acid, etc. may be used, but are not limited thereto and may include all salts formed using various inorganic acids and organic acids commonly used in the art.

In addition, the compound may include not only the above salts, but also all salts, hydrates, solvates, derivatives, etc. that can be prepared by conventional methods. Addition salts can be prepared by conventional methods, by dissolving them in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of organic base, or adding an aqueous base solution of an inorganic base and then precipitating or crystallizing. It can be manufactured by ordering. Alternatively, an addition salt can be obtained by evaporating the solvent or excess base from this mixture and drying it, or it can be prepared by suction filtration of the precipitated salt.

The water-soluble polymer is a biocompatible hydrophilic polymer and can improve its water solubility and dissolution rate by combining with the poorly soluble drug niclosamide and its salt.

The water-soluble polymer may be one or more selected from the group consisting of sodium alginate, gelatin, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC). Preferably, it may be sodium alginate, but is not limited thereto.

The surfactant is a substance that helps solubilize niclosamide, a poorly soluble drug, and may include poloxamer or Tween series, preferably poloxamer 407, tween 80, or tween 20 ( It may be one or more selected from the group consisting of tween 20) and sodium lauryl sulfate (SLS), and more preferably poloxamer 407 (poloxamer 407), but is not limited thereto.

The solid dispersion according to the present invention may be formed by containing the niclosamide, water-soluble polymer, and surfactant in a weight ratio of 1: (0.1 to 10): (0.1 to 4), but is not limited thereto. Solid dispersions prepared with the above components and contents can have improved water solubility, dissolution rate, and oral bioavailability.

The present invention provides a method for producing a solid dispersion containing niclosamide. The preferred weight composition for producing a solid dispersion with improved water solubility and dissolution rate may vary depending on the production method.

A method for producing a solid dispersion containing niclosamide according to an embodiment of the present invention includes niclosamide; One or more water-soluble polymers selected from the group consisting of sodium alginate, gelatin, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC); and at least one surfactant selected from the group consisting of poloxamer 407, Tween 80, Tween 20, and sodium lauryl sulfate (SLS); dissolving in a solvent to prepare a mixed solution; And it may include the step of spray drying the prepared mixed solution.

The solvent is water, methanol, ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol (PEG), and dimethyl sulfoxide ( It may be selected from dimethyl sulfoxide (DMSO), acetonitrile, and a mixed solution thereof, but is not limited thereto.

In the above production method, the mixed solution may be a mixture of the niclosamide, water-soluble polymer, and surfactant at a weight ratio of 1:(1 to 10):(0.25 to 4), preferably 1:(2.5 to 10). ) : (1 to 3), more preferably 1 : 2.5 : (2 to 3), but is not limited thereto.

In the above production method, niclosamide in the solid dispersion may exist in an amorphous form.

The above manufacturing method involves dissolving all of niclosamide, water-soluble polymer, and surfactant in a solvent and then drying them to evaporate the solvent, thereby converting niclosamide into an amorphous form, and the water-soluble polymer prevents its crystallization to increase the water solubility of niclosamide. can increase.

A method for producing a solid dispersion containing niclosamide according to another embodiment of the present invention includes the steps of dissolving niclosamide in a solvent to prepare a solution; and at least one water-soluble polymer selected from the group consisting of sodium alginate, gelatin, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC) in the prepared solution; and one or more surfactants selected from the group consisting of poloxamer 407, Tween 80, Tween 20, and sodium lauryl sulfate (SLS), followed by spray drying.

The solvent is water, methanol, ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol (PEG), and dimethyl sulfoxide ( It may be selected from dimethyl sulfoxide (DMSO), acetonitrile, and a mixed solution thereof, but is not limited thereto.

In the above production method, the solid dispersion may be prepared by containing the niclosamide, water-soluble polymer, and surfactant in a weight ratio of 1: (0.1 ~ 1): (0.1 ~ 0.9), preferably 1: It may be manufactured at a weight ratio of (0.5 ~ 0.8): (0.2 ~ 0.5), more preferably at a weight ratio of 1: (0.7 ~ 0.8): (0.2 ~ 0.3), but is not limited thereto.

In the above production method, niclosamide in the solid dispersion may exist in an amorphous form.

The above production method can increase the water solubility of niclosamide by dissolving niclosamide in a solvent and attaching it to the surface of a water-soluble polymer, and can lower the content of additives such as water-soluble polymers and surfactants.

A method for producing a solid dispersion containing niclosamide according to another embodiment of the present invention is one or more water-soluble materials selected from the group consisting of sodium alginate, gelatin, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC). polymer; and at least one surfactant selected from the group consisting of poloxamer 407, Tween 80, Tween 20, and sodium lauryl sulfate (SLS); dissolving in a solvent to prepare a mixed solution; and dispersing niclosamide in the prepared mixed solution and then spray drying.

The solvent is water, methanol, ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol (PEG), and dimethyl sulfoxide ( It may be selected from dimethyl sulfoxide (DMSO), acetonitrile, and a mixed solution thereof, but is not limited thereto.

In the above manufacturing method, the water-soluble polymer and the surfactant may be mixed in the mixed solution at a weight ratio of 1:(0.1 to 9), preferably at a weight ratio of 1:(0.1 to 1), more preferably at a weight ratio of 1:(0.1 to 1). : Can be mixed at a weight ratio of (0.2 to 0.4), but is not limited thereto.

In the above production method, the solid dispersion can be prepared by containing the niclosamide with the water-soluble polymer and surfactant in the prepared mixed solution at a weight ratio of 1: (0.5 to 3), preferably 1: ( It can be manufactured at a weight ratio of 1 to 3), more preferably 1:(1.5 to 2), but is not limited thereto.

In the above production method, niclosamide in the solid dispersion may exist in crystalline form.

The above manufacturing method involves dissolving only water-soluble polymers and surfactants excluding niclosamide in a solvent and then dispersing niclosamide therein, thereby attaching the water-soluble polymer to the surface of niclosamide without changing the crystal form of niclosamide. By converting to hydrophilic, the water solubility of niclosamide can be increased more stably.

In the above manufacturing method, the spray drying step is a step involved in drying the solvent, and the method is not particularly limited. For example, other known methods such as spray drying, reduced pressure drying, hot air drying using a spray dryer, fluid bed granulator, CF granulator, reduced pressure dryer, etc. can be used.

In addition, the present invention provides a pharmaceutical composition for oral administration containing the niclosamide-containing solid dispersion or the niclosamide-containing solid dispersion prepared according to the above production method as an active ingredient.

The pharmaceutical composition can be prepared according to conventional methods in the pharmaceutical field. The composition may be mixed with an appropriate pharmaceutically acceptable carrier depending on the formulation, and, if necessary, may be prepared by further including excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc. . The appropriate carrier, etc. does not inhibit the activity and properties of the drug niclosamide according to the present invention, and may be selected differently depending on the dosage form and formulation.

Among the oral dosage forms, the solid dosage form is in the form of tablets, pills, powders, granules, capsules, etc., and contains at least one excipient, such as starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, gelatin, etc. It can be prepared by mixing, and in addition to simple excipients, lubricants such as magnesium stearate and talc may also be included. In addition, the capsule formulation may further include a liquid carrier such as fatty oil in addition to the above-mentioned substances.

Among the oral dosage forms, liquid dosage forms include suspensions, oral solutions, emulsions, syrups, etc., and may contain various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. in addition to water and liquid paraffin, which are commonly used simple diluents. there is.

Hereinafter, the present invention will be described in detail through examples to aid understanding. However, the following examples only illustrate the content of the present invention and the scope of the present invention is not limited to the following examples. Examples of the present invention are provided to more completely explain the present invention to those skilled in the art.

<Preparation Example 1> Selection of additives

Figure 1 is a list of additives for selecting additives necessary for producing a solid dispersion containing niclosamide according to an embodiment of the present invention. Through evaluation of the solubility of these additives and drugs, the optimal additives were selected as follows.

1. Selection of high molecular weight polymer

Figure 2 shows the solubility evaluation results of high molecular weight polymers among the additive list in Figure 1, including sodium alginate, gelatin, polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose (HPMC). ) was confirmed to be suitable, and sodium alginate, the best among them, was selected as the final polymer.

2. Selection of surfactant

Figure 3 shows the solubility evaluation results of surfactants among the additive list in Figure 1, including Poloxamer 407, Tween 80, Tween 20, and sodium lauryl sulfate (SLS). It was confirmed to be suitable, and among them, the excellent Poloxamer 407/Tween 80 was selected as the final surfactant.

3. Solvent selection

Figure 4 shows the solubility evaluation results of solvents among the additive list in Figure 1. Most of the solvents were confirmed to be suitable, and isopropyl alcohol/PEG was selected among them. Ethanol was used in the experiment due to its cost and ease of use.

Figure 5 shows the components according to the solid dispersion method (solvent evaporation, surface attachment, solvent wetting) selected through the solubility evaluation results in Figures 2 to 4. More details will be described later in the examples below.

<Example 1> Preparation of niclosamide-containing solvent evaporation solid dispersion

Table 1 below shows the formulation (unit: g) according to the added amount of niclosamide and sodium alginate to be used in the solvent evaporation method, and Table 2 below shows the conditions of the spray dryer.

NA 1 NA 2 NA 3 NA 4 NA 5 NA 6 NA 7 Niclosamide One One One One One One One Na-alginate 0 One 2.5 5 7.5 10 15

Inlet temperature 120℃ Outlet temperature 60~70℃ Aspirator 100% Pump 20%

NA 1 to NA 7 were completely dissolved in a solvent prepared at a ratio of ethanol:water = 2:1, and then their solubility was checked.

As a result, as shown in Figure 6, the solubility increased until the ratio of niclosamide and sodium alginate was 1:10, but after that, the solubility did not increase any further. NA 6 had a problem with high viscosity due to too much sodium alginate, so subsequent experiments were conducted only with NA 3 and NA 6.

Table 3 below shows a niclosamide formulation (unit: g) in which poloxamer, a surfactant, is added to the ratio of niclosamide and sodium alginate in NA 3 and NA 6 in Table 1. At this time, the conditions of the spray dryer are: is as shown in Table 2 above.

NA8 NA9 NA10 NA11 NA12 NA13 Niclosamide One One One One One One Na-alginate 2.5 2.5 2.5 2.5 10 10 Poloxamer 407 0.25 0.5 One 2 0.5 One Niclosamide: Na-alginate 1:2.5 1:10 Niclosamide: Poloxamer 407 1:0.25 1:0.5 1:1 1:2 1:0.5 1:1

NA 8 to NA 13 were also completely dissolved in a solvent prepared at a ratio of ethanol:water = 2:1, and then their solubility was checked.

As a result, as shown in Figure 7, NA 11 and NA 13 were found to be the highest. NA 12 and NA 13 have the problem of high solution viscosity due to the high proportion of sodium alginate, and there is little difference in solubility from NA 11, so further experiments were conducted by adding more poloxamer to NA 11.

Table 4 below shows a niclosamide formulation (unit: g) in which poloxamer is added to the niclosamide and sodium alginate ratio of NA 3 in Table 1, and the conditions of the spray dryer are the same as Table 2 above.

NA 3 NA 8 NA 9 NA 10 NA 11 NA 14 NA 15 Niclosamide One One One One One One One Na-alginate 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Poloxamer 407 - 0.25 0.5 One 2 3 4 70% EtOH (L) 1.4 1.4 1.4 1.4 1.4 1.4 1.4

As a result, as shown in Figure 8, NA 14 was found to have the highest solubility, and there was no significant difference from NA 15.

< Example 2> Niclosamide surface attached solid dispersion manufacturing

Table 5 below shows the formulation (unit: g) according to the addition amount of niclosamide, sodium alginate, and poloxamer to be used in the surface attachment method, and Table 6 below shows the conditions of the spray dryer.

NSA 1 NSA 2 NSA 3 NSA 4 NSA 5 NSA 6 Niclosamide One Na-alginate 0.1 0.25 0.5 0.75 0.9 One Poloxamer 407 0.9 0.75 0.5 0.25 0.1 0

Inlet temperature 150℃ Outlet temperature 65~75℃ Aspirator 100% Pump 20%

The solvent used was water only, sodium alginate and poloxamer were dissolved, and niclosamide was prepared without being dissolved.

As a result, as shown in Figure 9, NSA 4 was confirmed to be the best.

Table 7 below shows niclosamide formulations (unit: g) prepared by varying the ratio of drug and additives based on NSA 4 in Table 5, and the spray dryer conditions are as shown in Table 6.

NSA 4 NSA 7 NSA 8 NSA 9 NSA 10 NSA 11 Niclosamide One Na-alginate 0.75 0.375 0.5625 1.125 1.5 2.25 Poloxamer 407 0.25 0.125 0.1875 0.375 0.5 0.75 Drug: Carrier 1:1 1:0.5 1:0.75 1:1.5 1:2 1:3

In this case too, only water was used as the solvent, and sodium alginate and poloxamer were dissolved, but niclosamide was not dissolved.

As a result, as shown in Figure 10, NSA 9 was confirmed to be the best.

<Example 3> Preparation of solvent wetted solid dispersion containing niclosamide

Table 8 below shows the formulation (unit: g) according to the added amount of niclosamide, sodium alginate, and poloxamer to be used in the solvent wetting method, and Table 9 below shows the conditions of the spray dryer.

NSW 1 NSW 2 NSW 3 NSW 4 NSW 5 NSW 6 Niclosamide One Na-alginate 0.1 0.25 0.5 0.75 0.9 One Poloxamer 407 0.9 0.75 0.5 0.25 0.1 0

Inlet temperature 90℃ Outlet temperature 65~75℃ Aspirator 100% Pump 15%

Only ethanol was used as a solvent, niclosamide was dissolved in the solvent, and sodium alginate and poloxamer were prepared without being dissolved.

As a result, as shown in Figure 11, it was confirmed that NSW 4 had the best solubility.

<Comparative Example 1> Niclosamide raw material

The niclosamide raw material itself was used as a comparative example.

< Experiment example 1> In aqueous solution Niclosamide and Niclosamide contain Acceptability of formulation and dissolution evaluation

The drugs of the examples and comparative examples were added to 1 mL of purified water in excess of the saturated solubility, stirred at 25°C and 100 rpm in a thermostat for 3 days, and then niclosamide was quantified using the following high-performance liquid chromatography (HPLC) system.

* HPLC conditions

Column: Inertsil ^® ODS-2 (4.6×250mm, 5μm)

Flow rate: 1.0mL/min

Injection volume: 20μL

Detection wavelength: 254nm

Mobile phase: Mobile phase A - pH 3.6 buffer, Mobile phase B - methanol (10:90 v/v)

pH 3.6 buffer = 5.75 g of monobasic ammonium phosphate dissolved in 1 L of water, adjusted to pH 3.6 with phosphoric acid.

In addition, 25 mg of the Example and Comparative Example drugs were tested according to the elution conditions below, and niclosamide was quantified using the eluate using the high-performance liquid chromatography (HPLC) system described above.

* Dissolution conditions

Eluent: 900ml water

Elution temperature: 37℃

Dissolution method: Method 2 (paddle method)

Paddle rotation speed: 50rpm

Figure 12 is a graph showing the degree of dissolution of the solvent evaporated solid dispersion prepared according to Example 1. The dissolution rate of the drug itself was 0%, and similar to the solubility results, the degree of dissolution of NA 14 and NA 15 was observed over 15 minutes. There was no significant difference, and the initial dissolution was highest at NA 14. That is, in the case of solvent evaporation solid dispersion, NA 14 was confirmed to have the best solubility and elution.

Figure 13 is a graph showing the degree of dissolution of the surface-attached solid dispersion prepared according to Example 2. The dissolution rate of the drug itself was 0%, and similar to the solubility results, there was a significant difference in the dissolution results of NSA 9 and NSA 10. In the case of NSA 9, solubility and dissolution were confirmed to be the best even with minimal use of additives.

Figure 14 is a graph showing the degree of dissolution of the solvent-wet solid dispersion prepared according to Example 3. Similar to the solubility results, NSW 4 showed the highest degree of dissolution.

<Experimental Example 2> In vivo kinetics experiment (Pharmacokinetics, PK test) of solid dispersion containing niclosamide

To evaluate oral bioavailability, the niclosamide-containing solid dispersion prepared according to the above Examples and Comparative Examples was orally administered to SD rats at 30 mg/kg, and blood was collected from the femoral artery using a heparinized disposable syringe. The collected blood was separated into plasma and analyzed by HPLC under the following conditions (FIG. 15).

* HPLC conditions

Column: Capcell Pak C18 (4.6×150mm, 5μm)

Flow rate: 0.5mL/min

Injection volume: 50μL

Detection wavelength: 332nm

Mobile phase: mobile phase A - 0.005M phosphate buffer, mobile phase B - acetonitrile (30:70 v/v)

Internal standard: indomethacin

Figure 16 is a graph showing the blood drug concentration in the body according to Experimental Example 2 of the present invention, and Figure 17 is a graph showing its pharmacokinetic parameters. Referring to this, it can be seen that superior bioavailability appears in all cases of solvent evaporation (SE), surface attached (SA), and solvent wetted (SW) compared to the raw niclosamide.

< Experiment example 3> Niclosamide contain solid dispersion Check physical and chemical changes

To confirm the physicochemical changes in the niclosamide-containing solid dispersions prepared according to Examples 1 to 3, they were analyzed by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD).

As a result, as shown in Figures 18 and 19, the solvent-evaporated solid dispersion (C) prepared according to Example 1 and the solvent-wet solid dispersion (D) prepared according to Example 3 are amorphous, and Example 2 It was confirmed that the surface-attached solid dispersion (E) prepared according to maintained its crystalline form and that there was no interaction between the drug and excipients.

As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. do. That is, the practical scope of the present invention is defined by the appended claims and their equivalents.

Claims (13)

niclosamide;
Sodium alginate as a water-soluble polymer; and
As a surfactant, [poly(ethylene oxide)] _a -[poly(propylene oxide)] _b -[poly(ethylene oxide)] _a block copolymer (a=101, b=56) (PEO-PPO-PEO block copolymer) Includes,
Characterized in that it is prepared by dissolving any one or more selected from the above niclosamide, sodium alginate, or PEO-PPO-PEO block copolymer in a solvent selected from water, ethanol, or a mixed solution thereof, and then spray drying. Solid dispersion containing niclosamide. According to claim 1,
The solid dispersion is,
A solid dispersion characterized by improved water solubility, dissolution rate, and oral bioavailability. Niclosamide, sodium alginate as a water-soluble polymer, and [poly(ethylene oxide)] _a -[poly(propylene oxide)] _b -[poly(ethylene oxide)] _a block copolymer as a surfactant (a=101, b= 56) Preparing a mixed solution by dissolving (PEO-PPO-PEO block copolymer) in an aqueous ethanol solution; and
It includes the step of spray drying the prepared mixed solution,
The mixed solution is characterized in that niclosamide, sodium alginate, and PEO-PPO-PEO block copolymer are mixed in a weight ratio of 1: (1 ~ 10): (0.25 ~ 4), producing a solid dispersion containing niclosamide. method. delete According to claim 3,
The solid dispersion is,
A production method, characterized in that niclosamide in the solid dispersion exists in an amorphous form. Preparing a solution by dissolving niclosamide in water; and
[Poly(ethylene oxide)] _a -[poly(propylene oxide)] _b -[poly(ethylene oxide)] _a block copolymer (a=101, b= After mixing 56), it includes the step of spray drying,
A method for producing a solid dispersion containing niclosamide, characterized in that the niclosamide, sodium alginate and PEO-PPO-PEO block copolymer are included in a weight ratio of 1: (0.1 ~ 1): (0.1 ~ 0.9). delete According to claim 6,
The solid dispersion is,
A production method, characterized in that niclosamide in the solid dispersion exists in an amorphous form. [Poly(ethylene oxide)] _a -[poly(propylene oxide)] _b -[poly(ethylene oxide)] _a block copolymer (a=101, b=56) as a water-soluble polymer and a surfactant were dissolved in ethanol. Preparing a mixed solution by dissolving; and
It includes the step of dispersing niclosamide in the prepared mixed solution and then spray drying,
In the mixed solution, sodium alginate and PEO-PPO-PEO block copolymer are mixed at a weight ratio of 1: (0.1 to 9), and the niclosamide is mixed with sodium alginate and PEO-PPO-PEO block copolymer in the prepared mixed solution. A method for producing a solid dispersion containing niclosamide, characterized in that it is contained in a weight ratio of 1: (0.5 to 3). delete delete According to clause 9,
The solid dispersion is,
A production method, characterized in that niclosamide in the solid dispersion exists in crystalline form. According to any one of claims 3, 5, 6, 8, 9 and 12,
The manufacturing method is,
A production method characterized by improved water solubility, dissolution rate, and oral bioavailability of the niclosamide.