KR101859200B1 - Pharmaceutical composition of monoacetyldiacylglycerol compound for oral administration and solid pharmaceutical preparation - Google Patents

Abstract

Disclosed are a composition and a solid preparation of a monoacetyl diacylglycerol compound for oral administration, in which the water solubility is improved, the bioavailability is increased and the manufacturing cost can be reduced. The composition for oral administration comprises the monoacetyl diacylglycerol compound and a surfactant, and is dissolved in water and emulsified in vivo.

Description

[0001] The present invention relates to a monoacetyldiacylglycerol compound for oral administration and a solid preparation for monoacetyldiacylglycerol compound for oral administration,

The present invention relates to a composition for oral administration of a mono acetyl diacyl glycerol compound and a solid preparation, and more particularly, to a mono acetyl diacyl glycerol monoacetyl diacyl glycerol compound which can improve water solubility, increase bioavailability, A composition for oral administration of a glycerol compound, and a solid preparation.

The mono acetyl diacyl glycerol compound contains EC-18, which is a kind of mono acetyl diglyceride, extracted / separated from deer antler, or can be prepared by a known organic synthesis method. It is known that EC-18 significantly increases the survival rate of animals in an animal model of sepsis using the cecal-ligation-puncture (CLP) method, and toxicity tests according to Good Laboratory Practice (GLP) . The mono acetyl diacyl glycerol containing EC-18 inhibits the secretion of IL-4 and the activity of STAT-6 as a drug having an oily property at room temperature, thereby destroying the microenvironment where cancer tissue can grow, Which is known to be able to be used for the prevention, treatment or inhibition of metastasis.

However, since the mono acetyl diacyl glycerol compound is a substance hardly soluble in water due to oily properties at room temperature, the elution is very poor and the bioavailability when taken orally is extremely low. Therefore, a new formulation with improved solubility and dissolution of monoacetyl diacyl glycerol is required, but studies related to it have been rarely performed. In addition, oral formulations containing oily medicines are generally difficult to develop solid preparations due to their oil properties, and are therefore produced in the form of soft capsules. However, there is a problem in that a special equipment is required in the production of a soft capsule and the unit price of the solid preparation is increased during manufacture and inconvenient for taking and storing.

Accordingly, the present inventors have developed an oral preparation containing a monoacetyl diacyl glycerol compound as a liquid and solid microemulsifying drug delivery system composition, and found that it has higher solubility and a higher bioavailability than conventional preparations. And solid microemulsifying drug delivery systems can solidify drugs that are oil-like at room temperature, thereby completing the present invention.

Accordingly, an object of the present invention is to provide a composition for oral administration of mono acetyl diacyl glycerol compound and a solid preparation, which have increased solubility as well as increased bioavailability.

In order to achieve the above object, the present invention provides a composition for oral administration comprising a mono acetyl diacyl glycerol compound and a surfactant dissolved in water and emulsified in vivo.

The present invention also provides a solid preparation for oral administration comprising the soft capsule filled with the composition for oral administration, the monoacetyl diacyl glycerol compound, the surfactant and the adsorbent, dissolved in water and emulsified in water in vivo.

The composition for oral administration of the mono acetyl diacyl glycerol compound according to the present invention shows excellent water solubility of the mono acetyl diacyl glycerol compound which is poor in solubility and is readily emulsified spontaneously in the living body to exhibit an excellent dissolution rate, The bioavailability of the silyl glycerol compound can be greatly improved. Also, by using solid microemulsifying drug delivery system, the active ingredient having oil property at room temperature can be solidified to improve the dosage, the drug storage property, and the manufacturing cost.

1 is a SEM photograph of Example 24 according to the present invention.
FIG. 2 is a graph showing the comparison between the distilled water (A) and the distilled water (B) containing 2.5% sodium lauryl sulfate in Example 24 (composition), Example 3 (soft capsule) and Comparative Example 1 (soft capsule) Graph showing dissolution.
FIG. 3 is a graph showing the results of a comparison between the pH value of the buffer solution (A) and the pH of the buffer solution (pH 1.2) containing 2.5% of sodium lauryl sulfate (Comparative Example 1 (Soft Capsule) B). ≪ / RTI >
Figure 4 is a graph showing the results of a comparison between the pH of a 6.8 buffer solution (A) and a pH 6.8 buffer containing 2.5% sodium laurylsulfate (soft capsule) in Example 24 (composition), Example 3 (soft capsule) (B).
FIG. 5 is a graph showing the results of measuring the blood concentration of a drug after oral administration of Example 24 (composition), Example 3 (soft capsule) and Comparative Example 1 (soft capsule) according to the present invention to rats.

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings.

The oral composition using the self-emulsifying drug delivery system of the mono acetyl diacyl glycerol compound having increased solubility according to the present invention has excellent water solubility and is spontaneously emulsified in a biological fluid to exhibit an excellent dissolution rate, And monoacetyl diacyl glycerol compounds and surfactants, which have excellent bioavailability.

The mono acetyl diacyl glycerol compound acts as an active ingredient (effective ingredient) of the present invention and can be represented by the following formula (1).

[Chemical Formula 1]

In the above formula (1), R1 and R2 each independently represent a fatty acid group having 14 to 22 carbon atoms, preferably 15 to 20 carbon atoms.

The term "mono acetyl diacyl glycerol compound" in the present invention means a derivative of glycerol having one acetyl group and two acyl groups, and is also simply referred to as mono acetyl diacyl glycerol (MADG). In the above formula (1), R1 and R2 each represent a fatty acid group having 14 to 22 carbon atoms (the remaining part of the fatty acid is excluded from the hydroxyl group), and preferably palmitoyl, oleoyl, but are not limited to, linoleoyl, linolenoyl, stearoyl, myristoyl or arachidonoyl, and the like. More preferably, the combination of R1 and R2 is selected from the group consisting of oleoyl / palmitoyl, palmitoyl / oleoyl, palmitoyl / linoleoyl, palmitoyl / linolenoyl, palmitoyl / arachidonoyl, palmitoyl / Linoleyl / stearoyl, stearoyl / linoleoyl, stearoyl / oleoyl, myristoyl / linoleyl, linoleyl / palmitoyl, Oleyl or myristoyl / oleoyl, and most preferably the combination of R1 and R2 is palmitoyl / linoleoyl, respectively. Further, in optically active, the mono acetyl diacyl glycerol compound may be (R) -type, (S) -type or racemic (rac), preferably racemic, stereoisomer Are also included in the scope of the present invention.

For example, the mono acetyl diacyl glycerol compound may be a compound represented by the following formula (2).

(2)

The compound represented by the general formula (2) corresponds to 1-palmitoyl-2-linoleoyl-3-acetylglycerol, wherein R 1 and R 2 in the general formula (1) correspond to palmitoyl and linoleoyl, respectively, Quot; or "EC-18 ".

The surfactant serves to stably emulsify an oil component and a hydrophilic component such as a co-surfactant, which will be described later, in water to form a stable emulsion. The surfactant may perform the above-described function and, if it is pharmaceutically acceptable, it is preferably selected from the group consisting of Docusate sodium, emulsified wax, glyceryl monooleate, Sodium lauryl sulfate, Cetrimide, glyceryl monooleate, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene alkyl ether, Polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene stearate, Polysorbate 80, sorbic acid, sorbitan ester, sorbitan esters, Sorbitan Laurate, Triethyl citrate, Polyglycerol fatty acid ester r), and mixtures thereof, more preferably sodium lauryl sulfate, polyoxyethylene-polyoxypropylene block copolymer and mixtures thereof, and the like.

The weight ratio of mono acetyl diacyl glycerol compound and surfactant in the composition of the present invention is 1: 0.1 to 10, preferably 1: 0.1 to 5. If the content of the mono acetyl diacyl glycerol compound is too small, it may be impossible to formulate a solid preparation or increase the administration dose. If the amount is too large, dissolution of the drug is difficult and the particle size is increased, . If the content of the surfactant is too small, the drug may not be absorbed into the human body to form a stable emulsion. If the content of the surfactant is too large, the formed emulsion may aggregate and precipitate.

In addition, the composition of the present invention may further contain, if necessary, a co-surfactant, an antioxidant, a mixture thereof, and the like.

The co-surfactant plays an auxiliary role in emulsification to dissolve the water-insoluble mono acetyl diacyl glycerol compound. The cosurfactant may perform the above-described function and, if it is pharmaceutically acceptable, it is not particularly limited, but preferably polyethylene glycol, propylene glycol, dimethylisosorbide, Diethylene glycol monoethyl ether, aliphatic ketone oil, propylene glycol monolaurate, and tetraglycolic acid, and polyoxyethylene (ethylene glycol) monoethyl ether, Fatty acid esters, mono-, di- or mono / di-glycerides, oleoyl macrogol glycerides and caprylocaproyl macrogol glycerides and mixtures thereof, more preferably polyethylene glycols, Or the like.

The antioxidant serves to further stabilize the active ingredient, and includes at least one selected from the group consisting of ascorbic acid, ascorbyl palmitate, erythorbic acid, L-cystine, But are not limited to, glutathione, sodium ethylenediaminetetraacetic acid (EDTA), butylhydroxyanisol, butylhydroxyl toluene (BHT), tocopherol acetate and mixtures thereof. , Preferably butylhydroxyanisole, tocopherol acetate and mixtures thereof.

The co-surfactant and antioxidant are added so that the weight ratio of mono acetyl diacyl glycerol compound: co-surfactant: antioxidant is 1: 0 to 20: 0.001 to 0.1, preferably 1: 0 to 10: 0.01 to 0.05 . If the content of the co-surfactant and / or antioxidant is too small, the mono acetyl diacyl glycerol compound may not be sufficiently emulsified, and if it is too large, it may be uneconomical.

In addition, the composition for oral administration according to the present invention includes an adsorbent when it is prepared as a solid preparation, and may further comprise a polymer as needed.

The adsorbent serves to solidify the self-emulsifying drug delivery system of the monoacetyl diacylglycerol compound. The adsorbent may be a silica such as silicon dioxide, magnesium metasilicate, or calcium silicate. A coating material, a resin of Amberite type, a cellulose such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose or methyl cellulose, a derivative carbomer or the like Polymers, saccharide alcohols such as kaolin, bentonite, gelatin and mannitol, maltodextrin, dicalcium phosphate and mixtures thereof and the like, Are silica-coating materials such as silicon dioxide, magnesium aluminasuma metasilicate and calcium silicate, It may be a mixture thereof.

The polymer serves to increase the drug solubility of the above-described composition and to improve the stability and solubilization ability of the active ingredient. Examples of the polymer include hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, propylene Hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose trimellidate, hydroxypropylmethylcellulose malateate, xanthan gum, xanthan gum, yudra, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, Methacrylic acid copolymers, methacrylic acid-acrylic acid ethyl ester copolymers, dimethylaminoethyl methacrylate-methacrylic acid ester copolymers, and mixtures thereof, preferably hydroxypropyl methylcellulose, carbomer And their horns Water and the like.

The adsorbent and the polymer are added so that the weight ratio of mono acetyl diacyl glycerol compound: adsorbent: polymer is 1: 0.01 to 10: 0 to 5, preferably 1: 0.5 to 5: 0 to 0.5. If the weight ratio of the adsorbent and / or the polymer is too small, the solidifying ability may be deteriorated and the preparation of the solid preparation may be difficult, while if too large, the solid preparation to be produced may become too large.

The composition for oral administration according to the present invention is a composition for oral administration which is capable of easily absorbing the active ingredient spontaneously in a living body and exhibiting an excellent dissolution rate due to the poor solubility of the mono acetyl diacyl glycerol compound, Thereby providing a pharmaceutical preparation for oral administration.

The composition according to the present invention can be prepared by mixing the above-mentioned components, preparing the mixture, dissolving the mixture in a solvent such as water, ethanol, or a mixture thereof, and then spray-drying the mixture. For example, a composition is prepared by mixing (sequentially) a surfactant, a co-surfactant and an antioxidant to a mono acetyl diacyl glycerol compound sequentially, and the composition is mixed with a soft capsule Or may be prepared in the form of a soft capsule. Alternatively, a monoacetyl diacyl glycerol compound, a co-surfactant, an antioxidant and a surfactant may be dissolved in ethanol, a polymer may be dissolved in water and ethanol mixed solution, , Followed by spray drying to obtain a solid preparation.

Since the composition for oral administration according to the present invention is made of soft capsules, solid preparations and the like and uses a self-nanoemulsifying drug delivery system (SNEDDS), it is possible to elute the drug more rapidly than a commercially available formulation Do. The self-emulsification drug delivery system can be used as a microemulsification drug delivery system in the form of a uniform mixture of liquid components (soft capsules, solid preparations, etc.) in which the water phase is removed from the components of the microemulsion, When they meet with the awards, they quickly emulsify themselves and disperse quickly, so you can expect rapid drug elution. Specifically, the ultrafine particles formed by the self-emulsification drug delivery system can easily pass through the mucous membrane in the gastrointestinal tract, and the digested superfine particles can flow into the blood and exhibit significantly increased physiological and chemical activities. Here, the gastrointestinal tract refers to a gastrointestinal tract including both stomach and intestines.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by the following Examples.

EXAMPLES 1 TO 10 Preparation of an oral preparation using a monoacetyl diacyl glycerol compound self-emulsifying drug delivery system

A mixture of monoacetyl diacyl glycerol compound (PLAG), a surfactant, a co-surfactant and an antioxidant was mixed in the composition shown in the following Table 1 in order to prepare a self-emulsifying drug delivery system mixture. This mixed solution was filled into soft capsules according to the manufacturing method of the soft capsules in the General Rules of Pharmacopoeia and was formulated. In Table 1 below, Tween 80 means Polysorbate 80 and Span 20 means Sorbitan Laurate.

division Example One 2 3 4 5 6 7 8 9 10 PLAG (g) One One One One One One One One One One Interface
Activator (g) Twin 80 One 2 5 10 - 5 5 5 5 5 Span 20 - - - - 5 - - - - - Ball interface
Activator (g) La Brasol 10 10 10 10 10 - - 2.5 5 20 Polyethylene
Glycol 400 - - - - - 10 - - - - Oxidation
(G) Tocopheryl acetate 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02

[Examples 11 to 24] Preparation of oral solid preparation using mono acetyl diacyl glycerol compound self-emulsifying drug delivery system

The monoacetyl diacyl glycerol compound (PLAG), the co-surfactant, the antioxidant and the surfactant were dissolved in ethanol with the composition shown in the following Table 2, the polymer and the like were dissolved in a water / ethanol mixed solvent, and the two solutions were mixed Then, the adsorbent was added thereto and stirred, followed by spray drying (Mini-spray dryer, Buchi, Germany) at a solution speed of 5 ml / min and an inlet temperature of 55 to 65 ° C.

division Example 11 12 13 14 15 16 17 18 19 20 21 22 23 24 PLAG One One One One One One One One One One One One One One Surfactants Lauryl sulfate
salt 0.1 0.25 0.5 2 - 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 Poloxamer 407 - - - - 0.25 - - - - - - - - - Co-surfactant La Brasol - - - - - 5 - - - - - - - - Polymer HPMC15000 - - - - - - 0.05 0.1 - 0.1 0.1 0.1 0.1 0.1 Carbomer - - - - - - - - 0.1 - - - - - absorbent Silicon dioxide - - - - - - - - - - - 0.5 - - Meta silicon alumina magnesium - - - - - - - - - - - 0.5 - Calcium silicate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 One 1.5 - - 0.5 Antioxidant BHA - - - - - - - - - - - - - 0.0002 Tocopheryl acetate 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 -

[Comparative Example 1] Preparation of PLAG-containing soft capsule preparation

Monacoacetyl diacylglycerol compound (PLAG) was mixed with tocopherol acetate by the same composition as shown in the following Table 3, and filled in soft capsules according to the manufacturing method of soft capsules in the General Rules of Pharmacopoeia.

division Comparative Example 1 PLAG (g) One Tocopherol acetate (g) 0.02

[Experimental Example 1] Evaluation of solubility of mono acetyl diacyl glycerol compound in aqueous solution

The excess (about 200 mg as active ingredient) prepared in Examples 1 to 24 and Comparative Example 1 was added to purified water (10 ml), and the mixture was sealed in a vial, stirred at room temperature for 7 days, filtered, The solubility of the silyl glycerol compound was measured using high performance liquid chromatography (HPLC) under the conditions shown in Table 4, and the results are shown in Table 5 below.

division Condition column C18 column (25 cm x 0.46 cm I.D., particle size 5.0 μm) Dose 20 μl UV wavelength 210 nm Mobile phase Acetonitrile / 2-propanol (55/45)

division Water solubility (mg / ml) Comparative Example 1 0 Example 1 1.912 + 0.078 Example 2 2.491. + -. 0.307 Example 3 4.381 + 1.023 Example 4 4.635 ± 1.131 Example 5 3.124 0.894 Example 6 3.824 0.621 Example 7 3.757 + - 0.254 Example 8 3.894 + 0.648 Example 9 4.015 ± 0.567 Example 10 4.412 ± 1.106 Example 11 1.837 + 0.271 Example 12 3.125 + 0.801 Example 13 3.472 + 0.612 Example 14 7.051 + 1.547 Example 15 1.137 + 0.179 Example 16 3.234 + - 0.923 Example 17 3.916 + 0.467 Example 18 4.740 ± 1.174 Example 19 4.102 + 0.657 Example 20 4.214 + 0.847 Example 21 4.314 ± 1.527 Example 22 4.631 + 1.341 Example 23 4.445 + 1.471 Example 24 4.613 + - 1.239

As shown in Table 5, in Examples 1 to 10 prepared from soft capsules in an autologous microemulsified drug delivery system composition of the mono acetyl diacyl glycerol compound of the present invention, the active drug (mono acetyl diacyl glycerol compound) When the amount of surfactant was increased, the solubility was also increased. However, when the amount of tween 80 was more than 500% as compared with the active drug, there was no significant increase in solubility. The amount of surfactant is increased by 500% or more of the active drug without increasing the solubility, and the optimum amount of the surfactant is 200-500% of the drug. The water solubility of the drug is 2 mg / ml or more . Also, as shown in the results of water solubility in Examples 3, 7, and 8 to 10, the amount of co-surfactant was increased, but the water solubility was increased as the amount increased, but the statistically significant solubility was not increased.

When the water solubilities of the surfactant in Examples 11 to 15 were compared according to the amount and type in the solid self-emulsifying drug delivery system composition using spray drying of Examples 11 to 24, as the surfactant, sodium lauryl sulfate, was increased Although the water solubility of the drug was increased, the higher the concentration of sodium lauryl sulfate, the more toxic problems such as local toxicity might occur. When sodium lauryl sulfate was 25 to 50% of the active drug, there was no significant difference in water solubility. Was determined at 25% concentration relative to the active drug. Comparing Examples 12 and 15, it was confirmed that sodium laurylsulfate further increases the water solubility of the drug compared to poloxamer.

In addition, although the influence of the co-surfactant was confirmed through the comparison of Examples 12 and 16, it was confirmed that the water solubility does not greatly affect the water solubility. As a result of examining the effect of the polymer through the comparison of Examples 12 and 17 to 19, it was found that HPMC 15,000 was not completely dissolved in the solvent when it exceeded 10% of the active drug. As the amount of polymer increased, the water solubility of the drug was increased. When the HPMC 15,000 was contained, the water solubility of the drug was higher than that of the cabomer.

In Examples 18 and 19 to 23, solubilizer drug delivery system preparations were prepared by varying the amount and kind of the adsorbent, and the water solubility of the drug was evaluated. It was confirmed that the calcium silicate of Example 18 Was found to exhibit increased water solubility of the drug as compared to the case of containing other calcium silicate ratios or using other adsorbents.

Finally, when the antioxidants were evaluated differently in Examples 18 and 24, it was confirmed that the water solubility of the drug was not significantly different.

[Experimental Example 2] Evaluation of antioxidative activity of mono acetyl diacyl glycerol compound under 0.1% hydrogen peroxide

The solid preparations prepared in Examples 18 and 24 were stored in a 0.1% hydrogen peroxide solution at a temperature of 40 ° C. for 4 days, and the content of mono acetyl diacylglycerol was measured by high performance liquid chromatography (HPLC) , And the results are shown in Table 6 below.

division content (%) Example 18 63.5 ± 3.8 Example 24 96.9 ± 4.2

As shown in Table 6, the butylhydroxyanisole of Example 24 showed excellent antioxidative effects when evaluated with tocopherol acetate and butylhydroxyanisole in the oral solid preparation composition of the mono acetyl diacyl glycerol compound of the present invention Able to know.

[Experimental Example 3] Test for confirming the formation of a solid preparation

The solid preparation prepared in Example 24 was photographed using an SEM (Scanning Electron Micrograph) to obtain the results shown in Fig. As a result of the experiment, it was confirmed that the novel monoacetyl diacyl glycerol compound oral solid preparation composition had a self-emulsifying drug delivery system inserted into the porous adsorbent.

[Experimental Example 4] Evaluation of dissolution

The compositions prepared in Examples 3 and 24 and Comparative Example 1 were taken in hard capsules in an amount corresponding to 300 mg of the mono acetyl diacyl glycerol compound and subjected to elution tests according to the Korean Pharmacopoeia dissolution assay Method 2. At this time, the eluate was water, 900 ml of pH 1.2 and pH 6.8 buffer, 2.5% of sodium laurylsulfate, pH 1.2 and pH 6.8 buffer solution, the temperature was 37 ° C and the rotation speed was 100 rpm. 1 ml of the sample was filtered at a constant time, and quantified using high performance liquid chromatography (HPLC). The results are shown in FIGS. 2 to 4.

FIG. 2 is a graph showing the comparison between the distilled water (A) and the distilled water (B) containing 2.5% sodium lauryl sulfate in Example 24 (composition), Example 3 (soft capsule) and Comparative Example 1 (soft capsule) FIG. As shown in FIG. 2, the compositions of Examples 3 and 24 started elution without delay time in distilled water (water). In Example 45, the elution rate was about 7% in 45 minutes, , And the dissolution rate of Comparative Example 1 was almost 0% (Fig. 2A). In addition, in Example 3, the dissolution rate was about 37% in Example 45, about 65% in Example 24, and about 10% in Comparative Example 1, in a solvent containing 2.5% sodium lauryl sulfate at 45 minutes (Fig. 2B). From these results, it can be seen that the dissolution of the self-emulsifying drug system composition of the present invention is significantly increased as compared with the simple composition of Comparative Example 1. [

FIG. 3 is a graph showing the results of a comparison between the pH value of the buffer solution (A) and the pH of the buffer solution (pH 1.2) containing 2.5% of sodium lauryl sulfate (Comparative Example 1 (Soft Capsule) B). ≪ / RTI > As shown in FIG. 3, Example 3 showed a dissolution rate of about 1.5% in pH 1.2 buffer, and Example 24 showed about 2.5% dissolution. In comparison, 1 showed a dissolution rate of almost 0% 3 A). In Example 3, the dissolution rate was about 17% in Example 3, about 20% in Example 24, and about 21% in Comparative Example 1 (Comparative Example 1) in which 2.5% of sodium lauryl sulfate was added 3B). In the pH 1.2 buffer, the self-emulsifying drug system composition of the present invention showed higher elution than the simple composition of Comparative Example 1, but elution similar to Comparative Example 1 was observed in the pH 1.2 buffer added with 2.5% sodium lauryl sulfate.

Figure 4 is a graph showing the results of a comparison between the pH of a 6.8 buffer solution (A) and a pH 6.8 buffer containing 2.5% sodium laurylsulfate (soft capsule) in Example 24 (composition), Example 3 (soft capsule) (B). ≪ tb > < TABLE > As shown in FIG. 4, Example 3 showed a dissolution rate of about 3% and Example 24 showed a dissolution rate of about 6%, and Comparative Example 1 showed a dissolution rate of almost 0% at pH 6.8 buffer for 45 minutes (Fig. 4A). In Example 3, the dissolution rate was about 40% and the dissolution rate was about 65% in Comparative Example 1, and about 22% in Comparative Example 1, (Fig. 4B). These results indicate that the self-emulsifying drug delivery system composition of the present invention is significantly more eluted than the simple composition of Comparative Example 1.

Based on the results of FIGS. 2 to 4 above, Comparative Example 1 did not elute in all solutions without sodium lauryl sulfate, whereas the dissolution rate of the mono acetyl diacyl glycerol compound in the compositions of Examples 3 and 24 was increased .

Therefore, as a result of the experiment, it was determined that the mono acetyl diacyl glycerol compound oral oral microemulsifying drug delivery system composition of the present invention greatly improved the dissolution rate of the mono acetyl diacyl glycerol compound, and the solid micro emulsion drug delivery system composition It is believed that this self-emulsifying drug delivery system improves the dissolution rate more than soft capsules.

[Experimental Example 5] Stability test at room temperature

The contents of the mono acetyl diacyl glycerol compounds were measured while the compositions prepared in Examples 3 and 24 were stored for 12 months under the temperature conditions of 25 캜 and 45 캜. Approximately 50 mg of the mono acetyl diacyl glycerol compound of Examples 3 and 24 was added to 100 ml of the mobile phase, stirred for 5 minutes, filtered through a millipore filter, and quantified using high performance liquid chromatography (HPLC).

division Example 3 Example 24 25 ℃ 45 ° C 25 ℃ 45 ° C 0 months Appearance No change No change No change No change content (%) 98.9 ± 2.2 99.1 + 1.7 98.6 ± 2.3 97.9 ± 1.5 2 months Appearance No change No change No change No change content (%) 97.8 ± 2.1 99.2 ± 1.5 97.9 ± 1.6 98.6 ± 1.9 4 months Appearance No change No change No change No change content (%) 98.3 ± 2.6 98.1 ± 2.1 98.3 ± 2.4 96.9 ± 1.8 6 months Appearance No change No change No change No change content (%) 97.5 ± 2.3 98.6 ± 1.8 97.3 ± 2.3 97.3 ± 2.4 12 months Appearance No change No change No change No change content (%) 98.1 ± 1.9 97.6 ± 2.1 98.1 ± 3.1 98.1 ± 1.5

As shown in Table 7, as a result, the composition of the compositions of Examples 3 and 24 and the content of mono acetyl diacyl glycerol compound were not significantly different for 12 months, and the content of mono acetyl diacyl glycerol compound was 25 ° C and 45 ° C , The formulation is stable for at least one year at a temperature of 45 < 0 > C. This result shows that both the soft capsule preparation, the general tablet and the film coating are stable.

[Experimental Example 6] Evaluation of dynamics in the body

The compositions of Examples 3 and 24 and the composition of Comparative Example 1 (200 mg / kg of monoacetyl diacyl glycerol compound administered) were orally administered to SD male mice together with 0.8 ml of water. After the blood was collected from the femoral artery, 20 μl of 1% formic acid and 5 μl of 2% EDTA were added, and the plasma was separated by centrifugation. 100 μl of isopropyl alcohol was added to the separated plasma 1 ml of Hexane: Ethyl acetate = 1: 2 solution containing the internal standard solution (PLAG d3) was added. After centrifugation, the supernatant was volatilized and the mobile phase was added thereto. LC / MS / MS And the results are shown in Table 9 below. In Table 8 below, Solvent A is a solvent in which 10% distilled water and 10 mM ammonium formate are mixed in acetonitrile, and solvent B is 10% distilled water (isopropyl alcohol) in isopropyl alcohol distilled water and 10 mM ammonium formate, wherein the formic acid is 0.1 mol% in the 10 mM ammonium formate.

division Condition column Phenomenex kinetex ㄾ 2.6 탆 C18 Dose 5 μl Flow rate 0.3 ml / min mode MS (TSQ), ESI, Positive mode, MRM mode Mobile phase Solvent A: Solvent B = 60: 40

Parameter Example 3 Example 24 Comparative Example 1 AUC (h · ng / ml) 16.71 ± 12.79 28.25 + - 24.25 8.79 ± 5.32 C _max (ng / ml) 5.99 ± 3.84 10.65 ± 10.41 4.25 + 2.63 T _max (h) 1.00 ± 0 1.05 + - 0.69 0.62 ± 1.01

FIG. 5 is a graph showing the results of measuring the blood concentration of a drug after oral administration of Example 24 (composition), Example 3 (soft capsule) and Comparative Example 1 (soft capsule) according to the present invention to rats. As shown in Figure 5 and Table 9, when comparing the compositions of Examples 3 and 24 with those of Comparative Example 1, the compositions of Examples 3 and 24 showed a significant increase in AUC and Cmax In particular, AUC is about 1.9 times higher than that of Comparative Example 1, and 3.2 times higher than that of Example 24. Therefore, it was confirmed that the composition of the present invention shows excellent bioavailability.

Claims (10)

delete delete delete delete delete delete 1-palmitoyl-2-linoleoyl-3-acetylglycerol compound, a surfactant and an adsorbent,
The surfactant may be selected from the group consisting of docusate sodium, emulsifying wax, self-emulsifying glyceryl monooleate, sodium lauryl sulfate, cetrimide, glyceryl monooleate, polyoxyethylene alkyl ether, polyoxyethylene- Polyoxyethylene stearate, polysorbate 80, sorbic acid, sorbitan ester, sorbitan laurate, triethyl citrate, polyglycerol fatty acid ester, and mixtures thereof,
The adsorbent may be selected from the group consisting of silicon dioxide, magnesium aluminas metasilicate, calcium silicate, amberlite, hydroxypropylcellulose, hydroxypropylmethylcellulose or methylcellulose, derivative carbomer, kaolin, bentonite, gelatin, mannitol, maltodextrin, dicalcium phosphate, Mixtures thereof, and mixtures thereof.
Wherein the solid preparation is dissolved in water and emulsified in vivo. The solid preparation according to claim 7, wherein the weight ratio of the 1-palmitoyl-2-linoleoyl-3-acetylglycerol compound: surfactant: adsorbent is 1: 0.1 to 10: 0.01 to 10. delete The pharmaceutical composition according to claim 7, which is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, propylene glycol alginate, polyvinylalcohol, povidone, carbohydrate, cellulose acetate phthalate, Phthalate, hydroxypropylmethylcellulose trimellidate, hydroxypropylmethylcellulose maliate, xanthan gum, xanthan gum, eudragit, methacrylic acid copolymer, methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl methacrylate Acrylate copolymer, acrylate-acrylate copolymer, acrylate-acrylate copolymer, and a mixture thereof.

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