KR20210128940A - Composition for oral administration comprising niclosamide using self-nanoemulsifying drug delivery system and preparation method thereof - Google Patents

Abstract

The present invention provides: a pharmaceutical composition for oral administration containing niclosamide, comprising niclosamide and a composition for self-nano-emulsification drug delivery; and a method for manufacturing the composition using a self-nano-emulsifying drug delivery system. The pharmaceutical composition for oral administration containing niclosamide according to the present invention has an effect of remarkably increasing the aqueous solubility of niclosamide by using a self-nano-emulsifying drug delivery system that spontaneously undergoes emulsification when coming into contact with water to form nano-sized emulsion particles. Furthermore, dissolution and oral bioavailability can be increased.

Description

Composition for oral administration containing niclosamide using self-nano-emulsifying drug delivery system and manufacturing method thereof

The present invention relates to a composition for oral administration containing niclosamide using a self-nano-emulsifying drug delivery system and a method for preparing the same.

Niclosamide (Niclosamide) is a poorly soluble drug, effective against adult hookworms, and is an orally administered anthelmintic. Recently, in addition to anthelmintic drugs, niclosamide has been found not only the clinical and mechanism of action for the anticancer effect, but also the antiviral effect of Corona 19, as an anticancer agent and as a treatment for Corona 19 (coronavirus infection-19, COVID-19). is attracting attention.

Improving the aqueous solubility of drugs is important in developing new drugs. Insufficient water solubility of a drug leads to inhibition of absorption when the drug is administered in vivo, and a decrease in absorption in vivo leads to a decrease in bioavailability. Niclosamide, which is a drug according to the present invention, is also a drug belonging to this category.

Various solubilization techniques have been used to improve the aqueous solubility of drugs having such low water solubility, but there are many difficulties when formulating the drug in consideration of absorption rate, bioavailability, side effects, etc. of the drug.

A self-nanoemulsifying drug delivery system (SNEDDS) comprising an isotropic mixture of a drug, a surfactant and an oil is emerging as a means to increase the oral bioavailability of hydrophobic drugs. This system spontaneously produces (nano)emulsions in gastric fluid after contact with an aqueous medium. The emulsion particles thus formed are advantageous for drug absorption due to their large surface area, thereby improving bioavailability and reproducibility of poorly water-soluble drugs. However, liquid self-nanoemulsifying drug delivery systems have several limitations, including instability during handling and storage.

In addition, the conventional solid self-nano-emulsifying drug delivery system produces a relatively large and non-uniform emulsion upon contact with an aqueous medium, so there is a possibility that water solubility and water solubility may not be improved.

Accordingly, there is an urgent need to develop a technology for a new formulation capable of overcoming these shortcomings and improving the aqueous solubility of poorly soluble drugs such as niclosamide to increase bioavailability.

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

An object of the present invention is to provide a composition for oral administration containing niclosamide with improved aqueous solubility, dissolution, and ultimately oral bioavailability using a self-nano-emulsifying drug delivery system, and a method for preparing the same.

The present invention includes niclosamide and a composition for self-nano-emulsification drug delivery, wherein the self-nano-emulsification composition for drug delivery is selected from the group consisting of corn oil, crodamol PC and captex 355 (captex 355). one or more oils; at least one surfactant selected from the group consisting of poloxamer 407, Tween 80, Tween 20 and sodium lauryl sulfate (SLS); and cremophor RH 40 as a co-surfactant; provides a pharmaceutical composition for oral administration containing niclosamide, characterized in that it comprises.

In addition, the present invention is corn oil, crodamol PC (crodamol PC) and captex 355 (captex 355) at least one oil selected from the group consisting of; at least one surfactant selected from the group consisting of poloxamer 407, Tween 80, Tween 20 and sodium lauryl sulfate (SLS); and Cremophor RH 40 as a co-surfactant; preparing a self-nano-emulsifying composition for drug delivery by mixing; and dissolving niclosamide in the prepared self-nano-emulsifying drug delivery composition to form a liquid self-nano-emulsifying drug delivery system;

The pharmaceutical composition for oral administration containing niclosamide according to the present invention uses a self-nano-emulsifying drug delivery system that spontaneously emulsifies when in contact with water to form nano-sized emulsion particles, thereby significantly improving the aqueous solubility of niclosamide. It has an increasing effect and can further increase dissolution and oral bioavailability.

1 is a list of additives for selecting additives necessary for preparing an oral composition containing niclosamide according to an embodiment of the present invention.
2 is a solubility evaluation result of a surfactant in the list of additives of FIG. 1 .
3 is a result of evaluation of solubility of oil in the list of additives of FIG. 1 .
4 is a result of evaluation of solubility of a solvent in the list of additives of FIG. 1 .
5 is a three-phase diagram evaluation of surfactants, co-surfactants, and oils selected through the solubility evaluation results of FIGS. 2 to 4 .
6 is a graph showing the emulsion particle size according to the composition of corn oil and Tween 80.
7 and 8 are graphs and three-phase diagrams showing the emulsion particle size according to the composition of corn oil and Cremophor RH 40.
9 is a graph showing the emulsion size according to the composition of the surfactant with different ratios from corn oil.
10 to 12 are liquid self-nano-emulsification drug delivery system evaluation results according to operating time for each membrane pore size, FIG. 10 is 1.1 μm, FIG. 11 is 2.5 μm, FIG. 12 is 3.1 μm in size evaluated.
13 is a result of comparing the emulsion particle size for each membrane pore size at an operating time of 10 minutes.
14 is a comparison result of emulsion particle size according to temperature.
15 is a comparison result of emulsion particle size according to the stirring speed.
16 is an evaluation of the solubility of oil, surfactant, and liquid self-nano-emulsifying drug delivery system.
17 to 19 are evaluation results of the liquid self-nano-emulsification drug delivery system according to the number of repetitions for each pressure, FIG. 17 is 1000 bar, FIG. 18 is 1300 bar, FIG. 19 is the evaluation at a pressure of 1600 bar.
20 is a result of comparing the emulsion particle size for each pressure condition in 3 cycles.
21 is a solubility result of a solid self-nano-emulsifying drug delivery system prepared according to Table 1.
22 is a dissolution result of the solid self-nano-emulsifying drug delivery system prepared according to Table 1.
23 and 24 are results of solubility evaluation according to the amount of calcium silicate, and it was found that the 0.5 ratio (S-SNEDDS 1) was the most excellent.
25 is an HPLC analysis condition used for in vivo kinetics experiments of niclosamide-containing solid dispersions.
26 is a graph showing the blood drug concentration in the body according to Experimental Example 2 of the present invention, and FIG. 27 is a pharmacokinetic parameter thereof.

Hereinafter, the present invention will be described in detail.

The present inventors use the SPG membrane emulsification method and the high-pressure homogenization method to form a smaller and more uniform emulsion when redispersed in an aqueous medium. By confirming that the oral bioavailability was significantly improved, the present invention was completed.

The present invention provides a pharmaceutical composition for oral administration containing niclosamide.

The pharmaceutical composition according to the present invention may include niclosamide and a composition for self-nano-emulsifying drug delivery.

The self-nano-emulsifying composition for drug delivery may include at least one oil selected from the group consisting of corn oil, crodamol PC, and captex 355; at least one surfactant selected from the group consisting of poloxamer 407, tween 80, tween 20 and sodium lauryl sulfate (SLS); and cremophor RH 40 as a co-surfactant.

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

<Formula 1>

The compound may 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 having a safety and efficacy profile suitable for administration to humans without toxicity to cells or humans exposed to the composition.

The salt may be used in the form of any one of a pharmaceutically acceptable basic salt or an acid salt. The basic salt can be used in the form of any one of an organic basic salt and an inorganic basic salt, and includes a sodium salt, a potassium salt, a calcium salt, a lithium salt, a magnesium salt, a cesium salt, an aminium salt, an ammonium salt, a triethylamine salt, and a pyrithylamine salt. It may be selected from the group consisting of dinium salts.

As the acid salt, an acid addition salt formed by a free acid is useful. As the free acid, an inorganic acid and an organic acid can be used. As the inorganic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, double phosphoric acid, nitric acid, etc. can be used. As the organic acid, citric acid, acetic acid, maleic acid, malic acid, and fumaric acid can be used. , gluconic 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 is not limited thereto, and salts formed using various inorganic and organic acids commonly used in the art may be included.

In addition, the compound may include all salts, hydrates, solvates, derivatives, etc. that can be prepared by a conventional method as well as the above salts. The addition salt can be prepared by a conventional method, and is dissolved in a water-miscible organic solvent, for example, acetone, methanol, ethanol, or acetonitrile, and an excess of an organic base is added or an aqueous base solution of an inorganic base is added, followed by precipitation or crystallization. It can be manufactured by Alternatively, an addition salt may be obtained by evaporating the solvent or excess base from the mixture and drying, or it may be prepared by suction filtration of the precipitated salt.

As used herein, "self-nano-emulsifying composition for drug delivery" refers to a composition comprising an oil, a surfactant, and a co-surfactant having an effect of increasing the bioavailability of niclosamide, a poorly soluble drug.

The oil acts as a solubilizer for the drug, thereby improving the absorption rate and solubility of niclosamide, which is a poorly soluble drug of the present invention.

The oil may be at least one selected from the group consisting of corn oil, crodamol PC, and captex 355, but is not limited thereto.

The surfactant or co-surfactant may improve absorption by stably dispersing niclosamide. The surfactant may be at least one selected from the group consisting of poloxamer 407, tween 80, tween 20, and sodium lauryl sulfate (SLS), and the co-interface The active agent may be cremophor RH 40, and if necessary, a mixture of the surfactant and the co-surfactant may be used, but is not limited thereto.

In the self-nano-emulsifying composition for drug delivery, the oil, surfactant and co-surfactant may be mixed in a weight ratio of 1: (0.2 to 18): (0.2 to 18), preferably 1: (0.6 to 6) : (1.4 to 14), more preferably 1: (1 to 2): may be mixed in a weight ratio of (2 to 3), but is not limited thereto.

More specifically, the oil and the surfactant, the co-surfactant or a mixture thereof may be mixed in a weight ratio of 1: (4 to 6), and the mixture of the surfactant and the co-surfactant is the surfactant and the co-surfactant. The surfactant may be mixed in a weight ratio of 3: 7, but is not limited thereto.

In the pharmaceutical composition, the niclosamide and the self-nano-emulsifying composition for drug delivery may be mixed in a weight ratio of 1: (40 to 60), preferably 1: 50, but limited thereto no.

The pharmaceutical composition may further include one or more silica adsorbents selected from the group consisting of calcium silicate, silicon dioxide and magnesium alumina metasilicate as a solidifying agent, but is not limited thereto.

The pharmaceutical composition including the self-nano-emulsifying drug delivery composition and the solidifying agent as described above can have improved aqueous solubility, dissolution rate and oral bioavailability.

In addition, the present invention provides a method for preparing a pharmaceutical composition for oral administration containing niclosamide.

The manufacturing method is a method using a self-nano-emulsifying drug delivery system, and more particularly, at least one oil selected from the group consisting of corn oil, crodamol PC, and captex 355 (captex 355). ; at least one surfactant selected from the group consisting of poloxamer 407, tween 80, tween 20 and sodium lauryl sulfate (SLS); and Cremophor RH 40 as a co-surfactant; preparing a self-nano-emulsifying composition for drug delivery by mixing; and dissolving niclosamide in the prepared self-nano-emulsifying drug delivery composition to form a liquid self-nano-emulsifying drug delivery system.

In the step of preparing the self-nano-emulsifying composition for drug delivery, the self-nano-emulsifying composition for drug delivery contains the oil, surfactant, and co-surfactant in a weight ratio of 1: (0.2 to 18): (0.2 to 18). may be mixed, preferably 1: (0.6 ~ 6): (1.4 ~ 14) in a weight ratio, more preferably 1: (1 ~ 2): may be mixed in a weight ratio of (2 ~ 3), It is not limited.

More specifically, the oil and the surfactant, the co-surfactant or a mixture thereof may be mixed in a weight ratio of 1: (4 to 6), and the mixture of the surfactant and the co-surfactant is the surfactant and the co-surfactant. The surfactant may be mixed in a weight ratio of 3: 7, but is not limited thereto.

In order to prepare the pharmaceutical composition, first, it is necessary to form a liquid self-nano-emulsifying drug delivery system. Forming the liquid self-nano-emulsifying drug delivery system may be performed using a shirasu-porous-glass (SPG) membrane emulsification (permeation) or a high pressure homogenizer (HPH), but is not limited thereto. .

Preferably, by performing SPG membrane emulsification (permeation) for 10 to 15 minutes in a membrane pore size of 3 to 4 μm at a temperature of 35 to 40° C. and a stirring speed of 100 to 200 rpm, liquid self-nano-emulsifying drug delivery system can form.

Alternatively, a liquid self-nano-emulsifying drug delivery system can be formed by repeating homogenization 3 to 7 times with a high pressure homogenizer (HPH) at a pressure of 1000 to 2000 bar.

A smaller and more homogeneous emulsion can be prepared by using the SPG membrane emulsification and high pressure homogenizer.

In the liquid self-nano-emulsifying drug delivery system, the niclosamide and the self-nano-emulsifying drug delivery composition may be mixed in a weight ratio of 1: (40 to 60), preferably 1: 50, but may be mixed. , but is not limited thereto.

The liquid self-nano-emulsification drug delivery system of the above composition spontaneously undergoes emulsification when in contact with water to form nano-sized emulsion particles to easily permeate the fat-soluble biological membrane, so that absorption in the body is very fast and high bioavailability can be expected. .

The manufacturing method may further include adding a solidifying agent to the formed liquid self-nano-emulsifying drug delivery system and spray-drying to form a solid self-nano-emulsifying drug delivery system.

Forming the solid self-nano-emulsifying drug delivery system may be performed by adding 0.5 to 2 parts by weight of the solidifying agent with respect to 1 part by weight of the formed liquid self-nano-emulsifying drug delivery system, and the solidifying agent is calcium silicate, It may be one or more silica adsorbents selected from the group consisting of silicon dioxide and alumina magnesium metasilicate, but is not limited thereto.

In addition to this, the step of forming the solid self-nano-emulsifying drug delivery system may be performed according to a conventional method known to those skilled in the art.

According to the above preparation method, the aqueous solubility and dissolution rate of the pharmaceutical composition for oral administration containing niclosamide can be improved, and thus the oral bioavailability can be significantly improved.

The spray drying is a step involved in drying the solvent, and the method is not particularly limited. For example, other known methods such as spray drying using a spray dryer, fluidized bed granulator, CF granulator, reduced pressure dryer, reduced pressure drying, and hot air drying may be used.

The pharmaceutical composition may be combined with a suitable pharmaceutically acceptable carrier according to the formulation, and if necessary, excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, and the like may be prepared. have. The appropriate carrier and the like do 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 dosage form.

Hereinafter, to help the understanding of the present invention, examples will be described in detail. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

<Preparation Example 1> Additive selection

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

1. Selection of surfactant

Figure 2 is the solubility evaluation result of the surfactant in the additive list of Figure 1, poloxamer 407 (Poloxamer 407), Tween 80 (Tween 80), Tween 20 (Tween 20), sodium lauryl sulfate (sodium lauryl sulfate, SLS) It was confirmed to be suitable, and among them, excellent poloxamer 407/Tween 80 was selected as the final surfactant.

2. Oil selection

3 is a result of evaluating the solubility of oil in the list of additives of FIG. 1 , and it was confirmed that most of the oils were suitable, and corn oil was selected among them.

3. Selection of solvent

FIG. 4 is a result of evaluating the solubility of solvents in the additive list of FIG. 1 , and it was confirmed that most of the solvents were suitable, and among them, isopropyl alcohol/polyethylen glycol (PEG) was selected. Ethanol was used in the experiment due to its price and ease of use.

5 is a three-phase diagram evaluation of Tween 80, a cosurfactant Cremophor RH 40, and corn oil selected as a surfactant of the self-nano-emulsifying drug delivery system (SNEDDS) through the solubility evaluation results of FIGS. 2 to 4 , thereby establishing a stable emulsion region.

<Example 1> Preparation of liquid self-nano-emulsifying drug delivery system (liquid-SNEDDS, L-SNEDDS)

1. Composition of oil, surfactant and cosurfactant

After dispersing the oil, surfactant, and cosurfactant in 10 mL of distilled water, the emulsion particle size and polydispersity evaluation machine (Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK) at 25 ° C. , emulsion particle size and polydispersity (PDI) evaluations were performed in the same manner.

6 is a graph showing the emulsion particle size according to the composition of corn oil and Tween 80, and FIGS. 7 and 8 are graphs and three-phase diagrams showing the emulsion particle size according to the composition of corn oil and Cremophor RH 40.

Referring to this, when corn oil and Tween 80 have a composition of 15/85 and corn oil and Cremophor RH 40 have a composition of 20/80, absorption enhancement can be increased by showing the smallest emulsion particle size and PDI value. After selection, the experiment was carried out.

9 is a graph showing the emulsion size according to the composition of the surfactant in different ratios from corn oil. The composition of the oil and the surfactant is 20/80, and the surfactant is Cremophor RH 40 and Tween 80 in a 3:7 ratio. Since the absorption enhancement can be increased by showing the smallest emulsion particle size and PDI value in the case of , this was selected.

2. SPG Liquid using membrane emulsification method Jagano Nano Oil Painting Drug delivery system manufacturing

In order to reduce the particle size and polydispersity (PDI) of the emulsion formed in the composition of the liquid self-nano-emulsifying drug delivery system selected in step 1, the SPG (shirasu-porous-glass) membrane emulsification (membrane permeation) method was used. To optimize the method, the conditions with the smallest emulsion particle size and polydispersity were selected by evaluating the emulsion particle size and polydispersity while changing the operating time and membrane size.

* SPG Membrane Emulsification Method Basic Conditions

1) Machine : MC Tech

2) Agitation rate: 100 rpm

3) Temperature: 37℃

4) Sampling point (min): 10, 20, 30, 40, 50, 60 min

5) Membrane pore size: 1.1, 2.5, 3.1 μm

10 to 12 are liquid self-nano-emulsification drug delivery system evaluation results according to operating time for each membrane pore size, FIG. 10 is 1.1 μm, FIG. 11 is 2.5 μm, and FIG. 12 is 3.1 μm in size evaluated.

As a result, stable L-SNEDDS was obtained by showing the smallest emulsion particle size and PDI value at 10 minutes of operation time.

13 is a result of comparing the emulsion particle size by membrane pore size at 10 minutes of operation, and it was found to be the smallest and most stable at 3.1 μm, and FIG. It was found to be stable, and FIG. 15 shows that there is no significant difference in the evaluation results according to the stirring speed, but 100 rpm was found to be safe.

Through this, the optimum conditions for the SPG membrane emulsification method in the preparation of L-SNEDDS as follows were selected.

* Optimal conditions for SPG membrane emulsification method

1) Machine : MC Tech

2) Agitation rate: 100 rpm

3) Temperature: 37℃

4) Sampling point (min): 10 min

5) Membrane pore size: 3.1 μm

16 is an evaluation of the solubility of oil, surfactant, and liquid self-nano-emulsification drug delivery system, and it can be confirmed that solubility is significantly improved when prepared with a liquid self-nano-emulsification drug delivery system than each component.

3. Manufacture of liquid self-nano-emulsifying drug delivery system using high pressure homogenizer

A high-pressure homogenizer was used to reduce the emulsion particle size and polydispersity formed in the composition of the liquid self-nano-emulsifying drug delivery system selected in 1, and to optimize this method, the two parameters of pressure and number of repetitions were changed and the most Conditions with a small emulsion particle size and polydispersity were selected.

17 to 19 are evaluation results of the liquid self-nano-emulsification drug delivery system according to the number of repetitions for each pressure, FIG. 17 is 1000 bar, FIG. 18 is 1300 bar, FIG.

As a result, it was confirmed that all of them showed the smallest emulsion particle size and PDI value in 3 cycles.

20 is a comparison of the emulsion particle size for each pressure condition in 3 cycles, and although there is no significant difference, it was confirmed that the emulsion was stable at 1300 bar.

<Example 2> Preparation of a solid self-nano-emulsifying drug delivery system (Solid-SNEDDS, S-SNEDDS)

Table 1 below is a solid self-nano-emulsifying drug delivery system using Aerosil® (silicon dioxide) AEROPERL® (silicon dioxide) Neusilin® US2 (magnesium alumina metasilicate) and calcium silicate as adsorbents (unit: g), and Table 2 below shows the conditions of the spray dryer.

Ingredient NS1 NS2 NS3 NS4 Niclosamide (mg) 20 L-SEDDS One Aerosil® One - - - AEROPERL® - One - - Neusilin® US2 - - One - Ca silicate - - - One DW (ml) 100

Inlet temperature 140 ℃ Outlet temperature 65~75℃ Aspirator 100% Pump 15%

21 shows the solubility results of the solid self-nano-emulsifying drug delivery system prepared according to Table 1, showing that calcium silicate is the most excellent.

22 is a dissolution result of the solid self-nano-emulsifying drug delivery system prepared according to Table 1, and it was found that calcium silicate was the most excellent.

23 and 24 are results of solubility evaluation according to the amount of calcium silicate, and it was found that the 0.5 ratio (S-SNEDDS 1) was the most excellent.

<Comparative Example 1> Niclosamide raw material

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

<Experimental Example 1> Evaluation of aqueous solubility and dissolution of niclosamide and niclosamide-containing formulations in aqueous solution

The drugs of Examples and Comparative Examples were added to 1 mL of purified water in excess of saturated solubility, respectively, and stirred at 25° C. and 100 rpm in a constant temperature bath for 3 days, and then niclosamide was quantified by 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 monobasic ammonium phosphate dissolved in 1 L water, adjusted to pH 3.6 with phosphoric acid.

In addition, 25 mg of the drugs of Examples and Comparative Examples were tested according to the following dissolution conditions, and niclosamide was quantified using the high-performance liquid chromatography (HPLC) system with the eluate, respectively.

* Elution conditions

Eluate: 900ml water

Elution temperature: 37℃

Dissolution method: 2nd method (paddle method)

Paddle rotation speed: 50rpm

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

In order to evaluate the oral bioavailability, the composition containing niclosamide 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 with a heparin-treated disposable syringe. The collected blood was analyzed by HPLC under the following conditions (FIG. 25) after plasma separation.

* HPLC conditions

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

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 substance: indomethacin

26 is a graph showing the blood drug concentration in the body according to Experimental Example 2 of the present invention, and FIG. 27 is a pharmacokinetic parameter thereof. Referring to this, there was a significant increase in the area under the blood concentration-time curve, which is an index of oral bioavailability, in the case of S-SNEDDS 1 compared to the raw material of niclosamide. Also, a significant increase was observed in the highest blood concentration. Therefore, it was confirmed that the composition of the present invention exhibits excellent oral bioavailability.

As described above in detail a specific part of the content of the present invention, for those of ordinary skill in the art, it is clear that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (12)

Including niclosamide and self-nano-emulsifying composition for drug delivery,
The self-nano-emulsifying composition for drug delivery may include at least one oil selected from the group consisting of corn oil, crodamol PC, and captex 355;
at least one surfactant selected from the group consisting of poloxamer 407, Tween 80, Tween 20 and sodium lauryl sulfate (SLS); and
Cremophor RH 40 as a co-surfactant; The method of claim 1,
The self-nano-emulsifying composition for drug delivery,
The oil, surfactant and co-surfactant 1: (0.2 ~ 18): characterized in that mixed in a weight ratio of (0.2 ~ 18), pharmaceutical composition. The method of claim 1,
The pharmaceutical composition is
The niclosamide and the self-nano-emulsifying composition for drug delivery are 1: (40 to 60), characterized in that mixed in a weight ratio, a pharmaceutical composition. The method of claim 1,
The pharmaceutical composition is
A pharmaceutical composition, characterized in that it further comprises one or more silica adsorbents selected from the group consisting of calcium silicate, silicon dioxide and magnesium metasilicate as a solidifying agent. The method of claim 1,
The pharmaceutical composition is
A pharmaceutical composition, characterized in that water solubility, dissolution rate and oral bioavailability are improved. at least one oil selected from the group consisting of corn oil, crodamol PC, and captex 355; at least one surfactant selected from the group consisting of poloxamer 407, Tween 80, Tween 20 and sodium lauryl sulfate (SLS); and Cremophor RH 40 as a co-surfactant; preparing a self-nano-emulsifying composition for drug delivery by mixing; and
Dissolving niclosamide in the prepared self-nano-emulsifying drug delivery composition to form a liquid self-nano-emulsifying drug delivery system; comprising, a method for preparing a pharmaceutical composition for oral administration containing niclosamide. 7. The method of claim 6,
The self-nano-emulsifying composition for drug delivery,
The oil, the surfactant and the co-surfactant are 1: (0.2 ~ 18): (0.2 ~ 18), characterized in that mixed in a weight ratio of the manufacturing method. 7. The method of claim 6,
The liquid self-nano-emulsifying drug delivery system,
The manufacturing method, characterized in that the niclosamide and the self-nano-emulsifying composition for drug delivery are mixed in a weight ratio of 1: (40 to 60). 7. The method of claim 6,
Forming the liquid self-nano-emulsifying drug delivery system,
A manufacturing method, characterized in that it is carried out using a shirasu-porous-glass (SPG) membrane emulsification or a high pressure homogenizer (HPH). 7. The method of claim 6,
The manufacturing method is
Forming a solid self-nano-emulsification drug delivery system by adding a solidifying agent to the formed liquid self-nano-emulsification drug delivery system and spray-drying; 11. The method of claim 10,
Forming the solid self-nano-emulsifying drug delivery system comprises:
Based on 1 part by weight of the formed liquid self-nano-emulsifying drug delivery system, 0.5 to 2 parts by weight of the solidifying agent is added to the prepared method. 11. The method of claim 10,
The solidifying agent,
A method for producing, characterized in that at least one silica adsorbent selected from the group consisting of calcium silicate, silicon dioxide and magnesium alumina metasilicate.

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