KR20230109028A - Mebendazole-containing solid dispersion, pharmaceutical composition comprising the solid dispersion and preparation method of the solid dispersion - Google Patents

Abstract

The present invention relates to a solid dispersion comprising mebendazole and sodium dodecyl sulfate (SDS), and a pharmaceutical composition containing the same. The solubility and dissolution rate of mebendazole are increased, and the bioavailability is remarkably improved.

Description

Mebendazole-containing solid dispersion, pharmaceutical composition comprising the solid dispersion and preparation method of the solid dispersion}

The present invention relates to a solid dispersion containing mebendazole and a method for preparing the same. In addition, the present invention relates to a pharmaceutical composition for cancer treatment containing the solid dispersion.

Mebendazole (MBZ) is a drug used to treat a number of parasitic infections, including ascariasis, urolithiasis, hookworm infection, medinaea infection, echinococcosis, trichinosis, and trichomoniasis. Mebendazole works by interfering with parasite β-tubulin polymerization and thereby inhibiting microtubule-dependent functions.

Mebendazole has a chemical structure of the following [Formula 1].

Usually, when a drug is administered orally, it is affected by two factors in the gastrointestinal tract (Gastrointestinal tract, GI tract), that is, solubility and permeability. However, mebendazole, as a drug corresponding to the Biopharmaceutical Classification System (BCS) class II, has very low aqueous solubility and shows low bioavailability. Since the bioavailability of mebendazole is only 17% when administered orally to humans (Dawson M, et al.), high doses are required to obtain the plasma concentrations required for treatment. Moreover, the absorption of mebendazole is limited by the low dissolution of mebendazole in acidic media, resulting in low bioavailability.

Through a study of the relationship between the in vitro properties and in vivo parameters of the drug, an increase in the solubility of mebendazole in an acidic medium led to an increase in the area under the curve (AUC) and maximum concentration (Cmax). was confirmed to improve bioavailability through

In addition, mebendazole is known to have anticancer activity that inhibits the proliferation of various types of cancer cells, such as colorectal cancer, stomach cancer, adrenal cancer, breast cancer, and lung cancer. It has been reported that mebendazole has strong anticancer activity against human cancer cells in in vitro and in vivo experiments, and that mebendazole exhibits an apoptotic effect in a dose- and time-dependent manner in human lung cancer cells (Mukhopadhyay et al .). In addition, mebendazole exhibits cytotoxicity with an IC50 value of 0.39 μM against gastric cancer cells, ACP-2 (cell line from gastric adenocarcinoma), and an IC50 value of 1.25 μM against ACP-03 (intestinal type) (Pinto et al. al.), and mebendazole was reported to have high inhibitory activity with an IC50 value of 0.30 to 0.32 as a result of an in vitro anticancer activity test for melanoma (Doudican et al.).

Improvement of mebendazole water solubility plays an important role in increasing the bioavailability of mebendazole and improving anticancer activity, and the increased water solubility of mebendazole can reduce side effects caused by high doses of mebendazole. .

In the case of mebendazole, it is difficult to expect high absorption in the body due to its very low solubility in water, so a method for improving the solubility and bioavailability of the drug is required.

Accordingly, as a result of research by the present inventors, it was confirmed that both the solubility and dissolution parameters of mebendazole are improved by preparing mebendazole as a solid dispersion (SD), thereby completing the present invention.

As a prior art, US Patent Publication 2017-0209372 contains 5 to 95% (w/w) of a pharmaceutically active compound (mebendazole, niclosamide, etc.), 95 to 5% (w/w) of a stabilizer (polymer and a surfactant (sodium dodecylsulfate, etc.)), but a composition in which a solid dispersion was formed with mebendazole by selecting a surfactant, SDS (sodium dodecyl sulfate), as a stabilizer. is not initiating

Korean Patent Publication No. 10-2021-0075895 discloses a pharmaceutical composition for preventing or treating cancer containing UDCA (ursodeoxycholic acid) and benzimidazole-based compounds (mebendazole, fenbendazole, etc.), but mebendazole and Implementation of an amorphous solid dispersion having excellent solubility using a specific surfactant is not disclosed.

US Patent Publication 2017-0209372 (A Method of Preparing Amorphous Solid Dispersion in Submicron Range by Co-Precipitation, published on July 27, 2017) Korean Patent Publication No. 10-2021-0075895 (pharmaceutical composition for preventing or treating cancer, published on June 23, 2021)

Dawson M, Allan R, Watson T. The pharmacokinetics and bioavailability of mebendazole in man: a pilot study using [3H]-mebendazole. Br J Clin Pharmacol 1982;(14):453-5. Daniel-Mwambete K, Torrado S, Cuesta-Bandera C, Ponce-Gordo F, Torrado J. The effect of solubilization on the oral bioavailability of three benzimidazole carbamate drugs. Int J Pharm 2004;(272):29-36. Mukhopadhyay T, Sasaki J, Ramesh R, Roth JA. Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. Clin Cancer Res 2002;(8):2963-9. Doudican N, Rodriguez A, Osman I, Orlow SJ. Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells. Mol Cancer Res 2008;(6):1308-15.

An object of the present invention is to provide a solid dispersion containing mebendazole, and a pharmaceutical composition comprising the same.

Another object of the present invention is to provide a method for producing a solid dispersion containing mebendazole.

The present invention relates to a mebendazole-containing solid dispersion having improved bioavailability, including mebendazole and sodium dodecyl sulfate (SDS).

In the solid dispersion of the present invention, mebendazole is preferably present in an amorphous form.

In the solid dispersion, the weight ratio of mebendazole to sodium dodecyl sulfate (SDS) may be 1:5 to 15 (w/w).

In the solid dispersion, the weight ratio of mebendazole to sodium dodecyl sulfate may be 1:5 to 10 (w/w).

In the solid dispersion, the weight ratio of mebendazole to sodium dodecyl sulfate may be 1:7 to 10 (w/w).

According to another aspect of the present invention, it relates to a pharmaceutical composition comprising a mebendazole-containing solid dispersion, and a pharmaceutically acceptable carrier.

According to another aspect of the present invention, there is provided a method for preparing a mebendazole-containing solid dispersion, a) dissolving mebendazole in formic acid to prepare a mebendazole solution, and dissolving sodium dodecyl sulfate in distilled water to obtain sodium dodecyl sulfate preparing a seal sulfate solution; b) preparing a mixed solution by stirring while adding a mebendazole solution to the sodium dodecyl sulfate solution; and c) lyophilizing the mixed solution.

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

The solid dispersion of the present invention is characterized by containing mebendazole and sodium dodecyl sulfate (SDS) as active ingredients.

In the solid dispersion of the present invention, mebendazole as an active ingredient is changed from a crystalline form to an amorphous state, so that the solubility and dissolution rate of mebendazole are increased and the bioavailability is improved.

The solid dispersion of the present invention has a weight ratio (w/w) of mebendazole: sodium dodecyl sulfate (SDS) of 1:5 to 15, preferably 1:5 to 10, more preferably 1:5 to 15. It is 7 to 10. As such, when mebendazole:sodium dodecyl sulfate (SDS) is mixed at a specific weight ratio, the solubility and dissolution rate of mebendazole are simultaneously increased, thereby significantly increasing the bioavailability.

According to another aspect of the present invention, it relates to a pharmaceutical composition comprising a mebendazole-containing solid dispersion, and a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carrier included in the composition of the present invention includes known and used excipients, disintegrants, lubricants, and the like. Examples of the excipients include lactose, mannitol, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, calcium phosphate, silicon dioxide, cellulose, sodium bicarbonate, and mixtures thereof, and examples of the disintegrant include croscarmellose sodium, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and the like, and examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, and the like. The pharmaceutically acceptable carrier may be appropriately selected and used by those skilled in the art according to the finally obtained formulation.

The dosage form of the pharmaceutical composition may be in various forms, but includes solid preparations such as granules, tablets, capsules, dry syrups, or powders, more preferably granules, tablets, or capsules. These formulations can be prepared according to methods commonly used in the pharmaceutical field. For example, a tablet may be prepared by mixing the solid dispersion with excipients, disintegrants, lubricants, etc., or by adding excipients, etc. to the solid dispersion to prepare granules, mixing the excipients, disintegrants, lubricants, etc., and tableting. And capsules can also be prepared by filling the mixture into capsules. In addition, film-coating or enteric-coating may be performed for the purpose of improving stability, ease of administration, appearance, and the like.

The method for preparing a mebendazole-containing solid dispersion of the present invention includes a) dissolving mebendazole in formic acid to prepare a mebendazole solution, and dissolving sodium dodecyl sulfate (SDS) in distilled water to obtain a sodium dodecyl sulfate solution Preparing; b) preparing a mixed solution by stirring while adding a mebendazole solution to the sodium dodecyl sulfate solution; and c) freeze-drying the mixed solution.

In step b), the weight ratio (w/w) of mebendazole:sodium dodecyl sulfate (SDS) is 1:5 to 15, preferably 1:5 to 10, more preferably 1:7 is ~10. In addition, the freeze-drying in step c) may be performed using a lyophilizer after freezing the mixed solution at about -70 ° C, but is not limited thereto and may be performed according to a conventional method known in the art. .

The solid dispersion of the present invention prepared by the above method increases the wettability of the drug due to the increase in the effective surface, the solubilization effect of the surfactant, the absence of aggregation of the drug microcrystals, and the improved dispersibility of the drug. By increasing the dissolution rate, the effect of significantly increasing the bioavailability of the drug can be obtained.

In addition, the manufacturing method has the advantage of not using an organic solvent in the process, avoiding residual solvent and toxicity problems when using an organic solvent, and providing a solid dispersion that is safe for the human body.

The solid dispersion of the present invention has an effect of remarkably improving bioavailability by increasing the solubility and dissolution rate of mebendazole because poorly soluble mebendazole exists in an amorphous state. In addition, the mebendazole solid dispersion used in the present invention exhibited higher cytotoxicity than unencapsulated mebendazole in all cancer cells tested, confirming that the anticancer effect was increased. Therefore, through the mebendazole-containing solid dispersion, absorption is improved and cytotoxicity to cancer cells is increased, thereby improving anticancer effects.

1 is a graph showing the solubility of mebendazole (MBZ) in a 1% aqueous solution of the carrier. Results are mean ± SD, (n = 3), and all analyzes show statistical significance as P < 0.05 (*), P < 0.01 (**), P < 0.001 (***).
2 is a graph showing the dissolution profile of a solid dispersion containing mebendazole (MBZ). (A) is the solubility of solid dispersions (F1-F6) prepared with mebendazole and SDS surfactant in distilled water, (B) is the solubility of mebendazole and SDS surfactant in 0.1 M HCl medium (pH 1.2). Solubility of the solid dispersions (F1-F6), (C) is a graph showing the dissolution profile of the mebendazole solid dispersion (F5) in 0.1 M HCl medium containing 0.5% SDS (sodium dodecyl sulfate). Results are mean ± SD, (n = 3), and all analyzes show statistical significance as P < 0.05 (*), P < 0.01 (**), P < 0.001 (***).
3 is a graph showing the physicochemical properties of a solid dispersion containing mebendazole (MBZ). (A) XRD, (B) DSC, and (C) FTIR spectra for mebendazole, SDS, PM, and solid dispersion (F5), respectively.
Figure 4 is a micrograph of surface morphology, which is a photograph of (A) mebendazole, (B) SDS, (C) PM, and (D) solid dispersion (F5).
Figure 5 is a graph showing the in vitro cytotoxicity evaluation results of mebendazole (MBZ) and mebendazole-containing solid dispersion (F5) in cancer cells, (A) MDA-MB-231, (B) MCF-7 , (C) A549, (D) NCI-H1299, (E) HepG2, and (F) a graph showing the evaluation results in HeLa cells. Results are mean ± SD, (n = 3), and all analyzes show statistical significance as P < 0.05 (*), P < 0.01 (**), P < 0.001 (***)
6 is a plasma concentration profile graph after oral administration of 20 mg/kg of mebendazole (MBZ) and mebendazole-containing solid dispersion (F5) to rats. Results are mean ± SD, (n = 3), and all analyzes show statistical significance as P < 0.05 (*), P < 0.01 (**), P < 0.001 (***).

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the disclosure herein is provided so that it will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

Example One. of mebendazole water solubility High carrier selection experiment

1% (w/v) carrier [PVP (polyvinylpyrrolidone), Urea, Poloxamer 188 (pol188), Poloxamer 407 (pol407), Polyethylene glycol 6000 (PEG6000), Hydroxypropyl cellulose (HPC), Hydroxypropyl-β-cyclodextrin (HP-β -CD), Hydroxypropyl methylcellulose (HPMC), Sodium dodecyl sulfate (SDS), Polyvinyl alcohol (PVA), and mannitol] by adding an excessive amount of mebendazole to a 1 ml distilled water aqueous solution containing give. The mixture was mixed on a Vortex for 1 minute and incubated for 24 hours at 37±0.5° C. in an incubator (LSI-3016A, Daihan Lab Tech Co., Ltd, Namyangju, Korea). After incubation, the sample is filtered using a 0.45 μM nylon syringe filter (Whatman, International Ltd., Maidstone, UK). Mebendazole solubility was measured using high performance liquid chromatography (HPLC) with a CAPCELL PAK C18 column (150 × 4.6 mm, 5-μm particle size, OSAKA SODA). The mobile phase contained a 50:50 (v/v) ratio of A phase and B phase. Phase A consists of methanol and acetonitrile (AcCN) in a 3:2 (v/v) ratio, respectively. Phase B is 0.05M monobasic potassium phosphate. The injection volume is 20 μL and the flow rate is 1 mL/min. Mebendazole was measured at a wavelength of 290 nm.

As shown in Figure 1, in order to select a suitable carrier for the mebendazole solid dispersion, PVP, urea, pol188, pol407, PEG6000, HPC, HP-β-CD, HPMC, SDS, PVA, and mannitol were selected and tested. As a result, since the water solubility of mebendazole was the highest in a 1% SDS (sodium dodecyl sulfate) aqueous solution (solubility, 29.7 ± 0.34 μg/mL), a solid dispersion formulation was prepared by selecting SDS as a carrier.

Example 2. of mebendazole solid dispersion formulation manufacturing

Mebendazole solid dispersion contains drug and SDS (sodium dodecyl sulfate) carrier at 1:1 (F1), 1:2 (F2), 1:3 (F3), 1:5 (F4), 1:7 ( F5), and 1:10 (F6) (w / w) ratio and then prepared by lyophilization. That is, a mixed solution is prepared by dissolving mebendazole in formic acid and dissolving the carrier (SDS) in distilled water, and then adding the mebendazole solution dropwise while stirring the carrier (SDS) solution at 500 rpm. Thereafter, the mixed solution was frozen at -70 ° C and then lyophilized using a lyophilizer (FDU-1200 EYELA, Tokyo Rikaakikai Co., Ltd, Tokyo, Japan) to obtain a mebendazole solid dispersion.

Experimental example One. of mebendazole Water solubility and in vitro dissolution test

The saturated solubility of the solid dispersion was measured in distilled water and 0.1 M HCl medium. An excess of the solid dispersion was put into a microcentrifuge tube containing 1 mL distilled water and 0.1 M HCl. The mixture was mixed for 1 minute and incubated at 37±0.5° C. for 24 hours. Then, the mixture was centrifuged at 12,000 rpm for 10 minutes, and the supernatant was analyzed by HPLC as described above to determine the solubility of mebendazole in the solid dispersion formulation.

Dissolution studies were performed in acid medium (0.1 M HCl) at 37 ± 0.5 °C according to the USP Apparatus II paddle method. The rotational speed was 75 rpm. Since the solubility of mebendazole is limited in acidic media, 0.5% sodium dodecyl sulfate (SDS) was added in 0.1 M HCl medium. Mebendazole pure drug (50 mg) and solid dispersion (amount equivalent to 50 mg of mebendazole) were added to 900 mL of medium. At appropriate time intervals of 5, 10, 15, 30, 45, 60, 90, and 120 minutes, samples were separated from the eluate and filtered using a 0.45 μm nylon syringe filter. Mebendazole concentration was measured by HPLC as previously described.

As shown in FIG. 2(A), the aqueous solubility of the mebendazole solid dispersion in distilled water is the highest in the solid dispersion F5 (MBZ: SDS, 1:7, w/w; 4,614 ± 32.8 μg/mL), Next, F6 (MBZ: SDS, 1:10, w/w; 4,310 ± 30.1 μg/mL) and F4 (1:5, w/w; 2,348 ± 4.50 μg/mL) are in order. The water solubility of the mebendazole solid dispersion of FIG. 2 (B) in 0.1 M HCl medium showed the best water solubility in F5 (MBZ: SDS, 1:7) and F6 (MBZ: SDS, 1:10). and further experiments were conducted by selecting the mebendazole solid dispersion F5. In FIG. 2(C), even in a 0.1 M HCl medium containing 0.5% SDS (sodium dodecyl sulfate), the mebendazole solid dispersion (F5) shows significantly higher dissolution of mebendazole than the mebendazole powder. Mebendazole solid dispersion (F5) shows dissolution of 87.9 ± 0.55% of mebendazole within 5 minutes, which is 1.5 times higher than mebendazole dispersal, and mebendazole solid dispersion (F5) shows dissolution within 30 minutes. It shows almost 100% mebendazole dissolution, which is expected as a result of the increase in water solubility of the mebendazole solid dispersion (F5).

Experimental example 2. Mebendazole solid dispersion PXRD , DSC , and FTIR analyze

For comparison with the mebendazole solid dispersion (F5) formulation, as a physical mixture (PM), the same composition ratio as F5, that is, the weight ratio of mebendazole drug and SDS of 1:7 (w/w) It was mixed in a mortar and prepared as a powder.

The structural characteristics of mebendazole, SDS, PM (physical mixture) and mebendazole solid dispersion formulation (F5) were determined using powder X-ray diffraction (PXRD, X-Pert PRO MPD, Rigaku International Corp., Tokyo Japan). was measured. The sample's data was collected at the diffraction angle 2θ with an angular range comprised between 5° and 50°. Differential scanning calorimetry (DSC) of mebendazole, SDS, PM (physical mixture) and solid dispersion (F5) was performed at 10 °C using TGA/DSC1 (Mettler-Toledo International Inc., Greifensee, Switzerland). /min rate was measured at 30 ~ 300 ℃. Possible interaction between the drug mebendazole and the polymer in the solid dispersion was determined using Fourier-transform infrared spectroscopy (FTIR, Alpha-P, Brucker Optik, Ettligen, Germany). It was measured in the 500 to 4000 cm ^{- 1} wavelength range.

Figure 3 (A) shows the PXRD results of mebendazole, SDS, PM (physical mixture) and solid dispersion (F5), and the 2θ values of mebendazole crystals are 12.2, 14.4, 16.3, 17.2, 18.2, 19.7, 21.4, 23.4, 24.7, 26.8, 28.6, 29.1, and the 2θ values of the SDS were 8.2, 9.0, 11.3, 13.7, 18.2, 20.3, 20.7, 21.8, 22.9, 27.5, 29.9, 32.3, 34.6, and the PM sample was mebenda. sol and There is an SDS peak, and in the solid dispersion (F5), a peak shift is observed due to the interaction between mebendazole and SDS. confirmed to be FIG. 3(B) is a DSC result of mebendazole, SDS, PM (physical mixture) and solid dispersion (F5). The melting point of mebendazole is 258°C and the melting point of SDS is 198°C. In the solid dispersion (F5), the melting points of mebendazole and SDS are lost, indicating that there is an interaction between the mebendazole drug and the carrier SDS. Figure 3 (C) shows the FTIR results of mebendazole, SDS, PM (physical mixture) and the solid dispersion (F5), and the shift from the original peak position of mebendazole and SDS in the solid dispersion (F5) is mebendazole represents the interaction between and SDS.

Experimental example 3. Mebendazole solid dispersion SEM analyze

The sample is fixed in the sample holder and coated with gold for 1 minute. The surface morphology of mebendazole (MBZ), SDS, PM (physical mixture), and solid dispersion (F5) was examined by Field Emission Scanning Electron Microscopy (FE-SEM III Merlin Compact, Carl Zeiss, Oberkochen, Germany) was used. The analysis voltage is 10 kV.

Figure 4 is a SEM result of mebendazole (A), SDS (B), PM (physical mixture) (C) and solid dispersion (F5) (D), mebendazole solid dispersion (D ) shows the interaction between mebendazole and SDS.

Experimental example 4. In vitro anti-cancer effect test

Cytotoxicity of mebendazole against various cancer cells, such as breast cancer cells (MDA-MB-231 and MCF-7), lung cancer cells (NCI-H1299 and A549), liver cancer cells (HepG2), and cervical epithelial cancer cells (HeLa) The in vitro anticancer effect was measured. MDA-MB-231, MCF-7, NCI-H1299, and A549 cells were grown in 5% CO ₂ in RPMI medium containing 10% (v/v) FBS and 1% (v/v) antibiotics (penicillin/streptomycin). And incubated at 37 ± 0.5 ℃ conditions. Cells are seeded in 96-well plates at a concentration of 1×10 ⁴ cells per well in complete medium. Upon cell attachment, cells were added to fresh medium containing mebendazole alone and mebendazole solid dispersion (F5) at concentrations of 0.5, 1, 2, 5, 10, 20, and 30 μg/mL mebendazole. will be put After 24 hours of incubation at 37 ± 0.5°C, the medium is removed and 100 μL of MTT solution (0.5 mg/mL) is added. After further incubation for 3 hours, the supernatant was removed and 100 μL of DMSO was added to dissolve purple formazan crystals. Sample absorbance was measured using a microplate reader (Infinite M200 PRO; Tecan Trading AG, M nnedorf, Switzerland) at 570 nm. Cell viability (%) is calculated using the formula below.

Figure 5 shows the in vitro cytotoxicity results by MTT assay. Figure 5 (A) is the cell viability (%) of MDA-AB-231 cancer cells, Figure 5 (B) is the cell viability (%) of MCF-7 cancer cells, Figure 5 (C) is the cell viability (%) of A549 cancer cells , Figure 5 (D) shows the cell viability (%) of NCI-H1299 cancer cells, Figure 5 (E) shows the cell viability (%) of HepG2 cancer cells, and Figure 5 (F) shows the cell viability (%) of HeLa cancer cells, respectively. . Mebendazole solid dispersion (F5) at 30 μg/mL was effective against these cancer cells (breast cancer cells: MDA-MB-231 and MCF-7; lung cancer cells: NCI-H1299 and A549; liver cancer cells: HepG2; cervical epithelial cancer cell: HeLa) shows about 7 times stronger cytotoxicity. Table 1 below shows IC ₅₀ (Half maximal inhibitory concentration) values of mebendazole and mebendazole solid dispersion (F5) against cancer cells using GraphPad Prism 5 software (San Diego, CA, USA). am.

IC ₅₀ of Mebendazole and Mebendazole Solid Dispersion (F5) on Cancer Cells cell line IC ₅₀ (μg/mL) (mean ± SD, 95% CI) Mebendazole (MBZ) Mebendazole Solid Dispersion (F5) MDA-MB-231 29.9 ± 1.06 (26.3-34.0) 6.57 ± 1.09 (5.40-7.98)*** MCF-7 12.2 ± 1.10 (9.93-15.0) 3.88 ± 1.14 (2.96-5.10)*** NCI-H1299 6.69 ± 1.06 (5.95-7.53) 2.43 ± 1.08 (2.05-2.87)*** A549 44.9 ± 1.12 (35.7-56.6) 12.6 ± 1.19 (8.81-18.0)*** Hela 6.22 ± 1.09 (5.15-7.51) 1.83 ± 1.19 (1.27-2.64)*** HepG2 26.3 ± 1.06 (23.0-29.9) 5.03 ± 1.11 (4.05-6.26)*** * P < 0.05, ** P < 0.01, and *** P < 0.001

Experimental example 5. pharmacokinetics ( Pharmacokinetics ) Experiment

Pharmacokinetic experiments were conducted according to the protocol approved by the Ethics Committee of the Chungnam National University, South Korea (No. 202003A-CNU-057). Male Sprague-Dawley rats (220 ± 10 g) were obtained from Samtako Bio Korea. Animals were housed at 22 ± 2 °C, 50-60% relative humidity, and a 12-hour light/dark cycle, and rats were provided with food and water ad libitum. After one week, the animals were divided into two groups for the experiment. After fasting for one day, mebendazole and mebendazole solid dispersion (F5) were orally administered at a dose of 20 mg/kg (3 mice in each group). Blood samples were taken from rats every 0, 0.5, 1, 2, 4, 8, 12, and 24 hours by posterior orbital plexus and stored in tubes containing heparin. Plasma samples are obtained by centrifuging blood samples at 12,000 rpm for 10 minutes in a centrifuge (Hanil micro-12, Hanil Scientific Inc., Gimpo, Korea), and the obtained plasma samples are stored at -70°C before analysis.

Add 500 μL of AcCN to a microcentrifuge tube containing 100 μL plasma sample for analysis and vortex mix for 2 minutes for protein precipitation. Then, the sample is centrifuged at 12,000 rpm for 10 minutes to separate the precipitated proteins. Transfer the upper layer to a new tube and evaporate in a vacuum desiccator. The dried residue was added to 100 μL mobile phase for reconstitution and vortexed for 1 minute. The sample is centrifuged at 12,000 rpm for 10 minutes, and a 20 μL sample is injected into the HPLC system as previously described.

Pharmacokinetic parameters of mebendazole and mebendazole solid dispersion were calculated using the non-compartmental model of the WinNonLin program. C _max and the time to reach C _max (T _max ) are obtained directly from the plasma concentration curve. The area under the curve (AUC) is calculated according to the linear trapezoidal rule (a method of calculating the area by assuming that the area between the point where the concentration is measured on the concentration-time curve is a trapezoid). The terminal half-life (T _1/2 ) is calculated as 0.693/ λ _z , where λ _z (K _el ) is the terminal elimination rate constant calculated by log concentration linear regression )am.

6 is a plasma concentration profile of mebendazole after oral administration of mebendazole to rats. The mebendazole solid dispersion (F5) shows superior mebendazole plasma concentrations at all points compared to mebendazole alone. Drug absorption depends on the rate and degree of drug absorption and is determined by several factors such as solubility, pearmeability, pKa, or lipophilicity. In the present invention, mebendazole is a hydrophobic drug and poorly soluble drug corresponding to BCS Class II, and bioavailability is maximized by increasing solubility and dissolution rate by preparing a selected SDS carrier and mebendazole solid dispersion. Table 2 shows the pharmacokinetic parameters after oral administration of mebendazole powder and mebendazole solid dispersion (F5) to rats (20 mg/kg). Mebendazole solid dispersion (F5) is mebendazole powder It shows about 4 times better bioavailability than

Rat Pharmacokinetic Parameters of Mebendazole and Mebendazole Solid Dispersion (F5) Parameters MBZ SD (F5) AUC _{0 -24} (μg h mL ^-1 ) 32.3 ± 0.54 115.1 ± 1.44*** AUC _{0 -∞} (μg h mL ^-1 ) 33.8 ± 0.52 136.0±1.25*** C _max (μg mL ^-1 ) 2.20 ± 0.14 7.28±0.23*** T _max (h) 8.00 ± 0.00 2.00 ± 0.00 T _1/2 (h) 4.66 ± 0.14 9.49 ± 1.27** K _el (h ^-1 ) 0.15 ± 0.00 0.07 ± 0.01*** MRT _last (h) 9.54 ± 0.04 9.59 ± 0.20 Relative bioavailability (%) 100 402*** * P < 0.05, ** P < 0.01, *** P < 0.001, AUC: area under the curve, T _1/2 : half-life, C _max : maximum plasma concentration, T _max : the time taken to reach maximum concentration, _Kel : elimination rate constant, MRT: mean residence time.

Experimental example 6. Statistical analysis

Data are presented as mean ± standard deviation (SD). One-way analysis of variance (ANOVA) in SigmaPlot 12.5 (SYSTAT Software, Inc., San Jose, CA, USA) was used for statistical analysis. P < 0.05 (*), P < 0.01 (**), and P < 0.001 (***) indicate significant differences.

Claims (7)

A solid dispersion containing mebendazole with improved bioavailability comprising mebendazole and sodium dodecyl sulfate (SDS). According to claim 1,
Mebendazole-containing solid dispersion, characterized in that mebendazole in the solid dispersion exists in an amorphous form. According to claim 1,
In the solid dispersion, the weight ratio of mebendazole: sodium dodecyl sulfate is 1: 5 to 10 (w / w), characterized in that the mebendazole-containing solid dispersion. According to claim 3,
In the solid dispersion, the weight ratio of mebendazole: sodium dodecyl sulfate is 1: 7 to 10 (w / w), characterized in that the mebendazole-containing solid dispersion. A pharmaceutical composition comprising the mebendazole-containing solid dispersion according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier. An anticancer agent composition comprising the mebendazole-containing solid dispersion according to any one of claims 1 to 4. A method for producing the mebendazole-containing solid dispersion according to any one of claims 1 to 4,
a) preparing a mebendazole solution by dissolving mebendazole in formic acid, and dissolving sodium dodecyl sulfate in distilled water to prepare a sodium dodecyl sulfate solution;
b) preparing a mixed solution by stirring while adding a mebendazole solution to the sodium dodecyl sulfate solution; and
c) freeze-drying the mixed solution; method for producing a mebendazole-containing solid dispersion comprising the.