KR20160071833A - Solid dispersion of Angelica gigas Nakai prepared by hot-melting extrusion and preparing method thereof - Google Patents

Abstract

The present invention relates to an Angelica gigas nakai-solid dispersion manufactured by a hot-melt extrusion method, and to a manufacturing method thereof. The manufacturing method comprises the steps of: (a) crushing Angelica gigas nakai and manufacturing Angelica gigas nakai powder; (b) manufacturing fine Angelica gigas nakai powder by finely crushing the Angelica gigas nakai powder using a fine crusher; and (c) manufacturing solid dispersion by hot-melt extruding the fine Angelica gigas nakai powder using a hot-melt extruder with high shear. According to the present invention, the Angelica gigas nakai-solid dispersion exists in a colloid form with a dietary fiber by discharging an effective pharmacological ingredient, contained in Angelica gigas nakai by hot-melt extrusion, to the outside. The Angelica gigas nakai-solid dispersion can reduce the dosage by being solubilized and increasing water solubility of decursin and decursinol angelate, which are poorly water-soluble ingredients, in comparison with the conventional Angelica gigas nakai-crushed powder, and can increase drug compliance.

Description

[0001] The present invention relates to a gelatin-solid dispersion prepared by melt extrusion and a method for producing the same. [0003] Solid dispersion of Angelica gigas Nakai is prepared by hot-

The present invention relates to a method for preparing a gelatin-solid dispersion prepared by melt extrusion and a method for producing the same, and a method for producing a gelatin-solid dispersion having a high bioavailability by increasing solubilization of an effective pharmacological component of Angelica keiskein .

Angelica gigas Nakai, AGN) have been used as traditional herb medicines in East Asian countries including Korea, Japan and China. Also, in Europe and North America, functional foods have been manufactured and commercialized. It is known that Angelica gigas Nakai has various functions such as antibacterial action, anti-cancer action, anti-inflammatory action, neuroprotective action and osteoporosis treatment action.

The compounds identified in the roots and leaves of Angelica gigas include the pyranocoumarins decursin (D), decursinol angelate (DA), decursinol (DOH) prantschimgin, angelinol, agasyllin; Simple coumarins such as scopoletin, umbelliferone; The furocoumarins furocoumarins such as bergapten, xanthotoxin, imperatorin, isoimperatorin, marmesin, marmesinin, nodakenin, Nodakenetin, columbianetin, columbianetin-beta-D-glucoside, demethylsuberosine, and the like. Other forms of coumarins, such as peucedanone, prenyletin, skimmin, apiosylskimmin, isoapiosylskimmine, 6-acetylnodakenine, 7-hydroxy-6- (2R-hydroxy-3-methylphenyl) (2R-hydroxy-3-methylbut-3-ethyl) coumarin); Phthalide derivatives such as ligustilide, Z-butylidenephthalide, butylphthalide; Volatile compounds such as 2,4,6-trimethyl heptane, nonane, undecane, pinene, myrcene, limonene, limonene, beta-phellandrene, elemol, beta-eudesmol, vervenol, spathulenol, camphene; Octadeca-1,9-dien-4,6-diyn-3,8,18-triol, which is a polyacetylenes, 18-acetoxy-octadeca-1,9-diene-4,6-diyne-3,8-diol); Flavonoids such as quercetin, myricetin, catechin, organic acids, ferulic acid, dodecanoic acid, 9,12-octadecanoic acid ( 9,12-octadecanoic acid); Angelan, a polysaccharide, a 25 kDa polysaccharide; And phenolics. The main effective pharmacological component of Angelica gigas is a coumarin derivative which is water-insoluble. The amount of D is 18.7 to 44.8 mg / g, DA is 11.1 to 36.8 mg / g, and DOH is 0.083 to 0.431 mg / g.

Of the active pharmacological components, D and DA were extracted at a concentration of 50 mg / g of D and 42 mg / g of DA and 1 mg / 1.4 mg / g, and the extraction rates of D and DA in water were relatively low.

At present, various methods have been carried out to extract effective pharmacological components contained in Angelica gigas, and alcohol is generally used so far to extract active pharmacological components of Angelica gigas. For example, in the case of alcohol extraction, it can be extracted in an amount of about 50 mg per 1 g of Angelica gigas, so that it can be extracted from about 20 g of dried Angelica gigas.

However, due to the potential toxicity of alcohol, hot water has been used in Korea and China to extract active ingredients from Angelica gigas. However, as described above, D and DA can extract about 50 mg per 1 g of Angelica gigas with ethanol, but since only about 1 mg is extracted under the same conditions as water, hot water extraction is not suitable for extracting effective pharmacological components from herbal medicines Method.

Therefore, in order to develop a method capable of showing the ethanol extraction ratio of D and DA without using an organic solvent, it is necessary to develop a new technique for solubilizing the effective pharmacological ingredient and improving the dissolution rate.

In recent years, various methods such as chemical or physical modification and carrier systems have been attempted to increase the solubility of water-insoluble drugs. As a part of this process, there has been an attempt to improve the bioavailability of the effective pharmacological components of Angelica gigas Nakai by extracting the effective pharmacological components contained in Angelica gigas using an organic solvent. However, There is a concern that environmental pollution may occur due to an organic solvent, and a complicated extraction process is required.

In addition, the ultrasound extraction method using ultrasonic vibration, which has been attempted for extracting effective pharmacological components contained in Angelica gigas, also has disadvantages in that it is inefficient because of its high physiological activity and immune activity, and time and manufacturing cost.

Therefore, in order to develop a method capable of exhibiting extraction efficiency to the extent that ethanol extract of Angelica keiskei does not use an organic solvent, it is necessary to develop a new technique for improving effective pharmacological component extraction and solubilization .

(Prior Patent 0001) Korean Patent Publication No. 10-2013-0020390 (Publication Date: Feb. 23, 2013) (Prior Art Patent No. 0002) Korean Patent Laid-Open No. 10-2007-0084796 (Publication Date: 2008.08.27) (Prior Patent 0003) Korean Patent Laid-Open No. 10-2004-0084936 (Publication Date: October 10, 2004) (Prior Patent 0004) Korean Patent Laid-Open No. 10-2009-0129563 (Publication Date: December 17, 2009)

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made in order to solve the above-mentioned problems, and it is an object of the present invention to provide a method for producing Angelica keiskei koidensis, which is capable of improving solubilization of effective pharmacological components contained in Angelica gigas Nakai .

(B) finely grinding the Angelica powder using a fine grinding machine to produce a granular Angelica powder; and (c) granulating the Angelica powder with a granulator to produce a granular Angelica powder; and ) A method for producing a gelatin-solid dispersion comprising the step of melt-extruding the above-mentioned granular Angelica powder using a high shear melt extruder to prepare a solid dispersion.

Also, the step (b) is performed using a fine grinder including a grinding media having a diameter of 210 mm at a temperature of -15 to -20 ° C and a rotor rotation speed of 10,000 rpm or more.

In addition, the granular Angelica powder has a particle size of 40 to 100 탆.

The step (c) is performed at a temperature of 80 to 100 ° C.

The high-shear melt extruder is characterized by comprising an extrusion die having a diameter of 1 to 3 mm.

In addition, the high-shear melt extruder may include a screw into which a plurality of kneading disk block parts are introduced to produce the solid dispersion by applying a high shear force to the fine-grain alumina powder.

The solid dispersion has a particle size of 10 탆 or less.

The present invention also provides a pharmaceutical composition comprising the Angelica keiskei kagamushi-solid dispersion prepared by the above-mentioned method for producing a gelatin-solid dispersion and a carrier.

In addition, the carrier is characterized by being at least one selected from a surfactant, a water-soluble polymer, or a pharmaceutically acceptable additive.

The present invention also provides a functional food comprising the Angelica keiskei kagamushi-solid dispersion prepared by the above-mentioned method for producing a gelatin-solid dispersion as an active ingredient.

The method for preparing a gelatin-solid dispersion using the melt extrusion method according to the present invention is a low-cost simple process for producing a solid dispersion by pulverizing Angelicae gruelina into fine powder and melt-extruding the gelatin with high shear force, It is an eco-friendly and economical method.

The present invention also relates to a method for producing a gelatin-solid dispersion according to the present invention, which comprises melt-extruding a fine powder with a high shear force to disperse an insoluble active ingredient in the gelatin and disperse it into a colloid in a dietary fiber, When dissolved, the dissolution rate is very high and the bioavailability is improved.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a conceptual diagram schematically showing a melt extruder for use in the production of a gelatin-solid dispersion according to the present invention. FIG.
FIG. 2 is a view showing a screw included in a melt extruder used for the production of an Angelica keiskei kerosene solid dispersion according to the present invention.
Fig. 3 is an SEM image of particle surfaces of the rough-cut Angelica powder, the granular Angelica powder and the high shear force solid dispersion.
4 is an image obtained by further enlarging the particle surface morphology of the crude crushed Angelica powder, the granular Angelica powder and the high shear force solid dispersion by SEM.
FIG. 5 is a graph showing changes in the concentration of DOH detected in the plasma of each rat administered with the ethanol extract, the granular Angelica powder, and the high shear force solid dispersion.

Hereinafter, the present invention will be described in detail.

In the present invention, in order to increase the solubilization of the insoluble active ingredient contained in Angelica gigas Nakai, the Angelica keisuke is crushed with the granulated Angelica keiskei Powder to increase the surface area per unit volume of Angelica keiskei grains and melt extruded to prepare a solid dispersion, Solubilization of the active ingredient is increased to produce a gelatin-solid dispersion having a high bioavailability.

To this end, the present invention provides a method for preparing a gelatin-solid dispersion according to the present invention, comprising the steps of: (a) preparing angelica powder by crushing Angelica gigas Nakai; (b) finely pulverizing the Angelica keratin powder using a fine- (c) melt-extruding the granular Angelica powder using a high-shear melt extruder to produce a solid dispersion.

The step (a) is a step of pulverizing Angelica gigas to prepare Angelica keiskei Powder. The dried Angelica keiskei strain and the roots of the Angelica keiskei koidz. Are treated with a known grinder such as a jaw crusher or a gyratory crusher, Followed by pulverization to produce Angelica gigas Nakai powder.

In the step (b), ultra fine crushing of the Angelica powder is performed using a fine grinder to produce a granular Angelica powder.

The granular powder for grinding the Angelica powder may be any of various well-known products, and may be manufactured by grinding media having a diameter of 210 mm at a rotor rotation speed of 10,000 rpm or more at a temperature of 5 to -20 캜 ). It is preferable to use the above-mentioned finely pulverized granular Angelica powder having a particle size of 40 to 100 mu m.

In the step (c), the granular Angelica powder is melt-extruded using a high-shear melt extruder to produce a solid dispersion.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a conceptual diagram schematically showing a melt extruder for use in the production of a gelatin-solid dispersion according to the present invention. FIG.

Referring to FIG. 1, the melt extruder according to the present invention includes a raw material supply part, a screw, a barrel part and an extrusion die.

In order to mold the gelatin-solid dispersion by melt extrusion, various factors such as temperature control of the melt extruder, shear force according to the arrangement of the screw, the rotation speed of the screw, and the diameter of the extrusion die are controlled, The physical and chemical properties of the dispersion can be controlled.

The high-shear melt extruder may include a screw into which a plurality of kneading disk blocks are introduced, and the solid dispersion may be produced by applying a high shear force to the granular Angelica powder during the melt extrusion process.

FIG. 2 is a view showing a screw included in a melt extruder used for the production of an Angelica keiskei kerosene solid dispersion according to the present invention.

Referring to FIG. 2 (c), the high shear melt extruder according to the present invention includes a high shear force screw designed to introduce a plurality of kneading disk blocks in a known full flight screw, A melt extruder having a shape characteristic as shown in FIG. 2 (c) and including a high shear screw having such an arrangement is referred to as a high shear force melt extruder.

In comparison, in the present invention, a low shear force screw is used together. The low-shear force screw shown in FIG. 2 (a) includes a kneading disk block portion having a blade angle of 50 to 70 ° and capable of increasing a shear force, the screw having a lower shear force than a high shear force screw flight And the shear force of the screw is lower than that of the high shear force screw.

2 (b) is a screw in which the number of kneading disk blocks is smaller than that of the high shear force screw, and the shear force is lower than that of the high shear force screw.

In order to prepare the solid dispersion, the granular Angelica powder containing about 25% moisture is introduced into a melt extruder and melt-extruded at a temperature of 80 to 100 ° C.

It is also preferable to rotate the high shear force screw at a speed of 150 rpm to melt extrud the granular Angelica powder. Through the extrusion die having a diameter of 1 to 3 mm, a solid dispersion can be obtained. The diameter of the extrusion die is 1 mm Is more preferable.

The solid dispersion prepared as described above has a particle size of 10 μm or less and is melt-extruded to further improve the water solubility of the insoluble active ingredient by forming more pores in the microparticulate powder of the microparticle.

In addition, chemical changes of the insoluble active ingredient in the inner part of the Angelica keiskei radix are induced. Particularly, D and DA, which are insoluble and effective components, are dispersed after exiting from the molecular level and fused in the colloid form with outer dietary fiber, And it is expected that the bioavailability increase effect of D and DA, which are active ingredients of Angelicae gigantis, can be expected due to the change of physico-chemical properties.

The present invention also provides a pharmaceutical composition comprising the Angelica keiskei koidowoides-solid dispersion prepared by the above-mentioned method for preparing a gelatin-solid dispersion and a carrier.

The carrier comprises at least one of a surfactant, a water-soluble polymer, or a pharmaceutically acceptable additive. More specifically, the surfactant is selected from the group consisting of fatty acid esters, natural vegetable oils, ethylene glycol- Etc., so that the stability of the physical properties of the active ingredient contained in the Angelica keiskei koidz.-Solid dispersion can be improved and the shelf life thereof can be improved by eliminating instability due to dehydration of the gelatin-solid dispersion.

In addition, the water-soluble polymer is composed of a polysaccharide, a cellulose-based polymer, a polysaccharide, or an oxide copolymer, and may be added in the preparation of a pharmaceutical composition to improve the flowability and physical properties of the Angelica giganta-solid dispersion. In order to prepare the angelic-solid dispersion for oral administration, a pharmaceutical additive such as an excipient or a lubricant is further added to prepare a gelatin-solid dispersion pharmaceutical composition for oral administration in which the apparent solubility is increased under physiological equivalent conditions .

The present invention also provides a functional food containing the Angelica gigas Nakai-solid dispersion as an active ingredient.

The ginseng-solid dispersion according to the present invention can be produced as a functional beverage by liquid-phase extraction so as to contain it as a solid content, or as a functional food having a form of a leach tea which can be easily taken by putting the ginseng-solid dispersion in a storage container such as a tea bag Can be manufactured.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

<Examples>

(1) Preparation of raw materials and materials

We obtained standard samples of D, DA, and DOH from Korea Promotion Institute for Traditional Medicine Industry, Gyeongsan, Korea in Gyeongsan. All solvents used in the experiments were HPLC grade. All other chemicals were used without additional purification steps, using analytical grade.

(2) Preparation of Angelicae solid dispersion

The Angelicae were dried in an oven at 55 ° C for 24 hours and cooled at room temperature. Angelicae samples were stored at 4 ° C until they were milled. The turmeric powder was pulverized with a coarse powder using a pin crusher (Myungsung Machine, Seoul, Korea), and the crude powder was subjected to low temperature turbo milling (HKP-05; Korea Energy Technology Co., Ltd. , Seoul, Korea). Powder of granular Angelica gigas Nakai was passed through an impeller at a high rotation speed and then pulverized into fine particles. In a stator classifier system composed of three stages, centrifugal force and drag force were used to classify the granular powder. In the process of producing ultra fine powder, the rotor speed was set at 10,500 rpm, and the diameter of the pulverizing medium was 210 mm. The temperature of the milling chamber was maintained at -18 ° C.

In order to prepare the solid dispersion, the granular Angelica powder was extruded with a shear force using a twin-screw extruder (STS-25HS). Each of the other screws in the array was used to achieve low shear, high shear and high shear. Water was added together as a solvent.

The screw speed of the hot melt extruder was 150 rpm and the temperature of the barrel portion was adjusted as shown in Table 1 below. The prepared solid dispersion was dried in an oven at 40 ° C.

<Experimental Example>

(1) Particle size analysis of the prepared Angelica xanthan gum-solid dispersion

The mean size of the Angelica gigas was determined using a particle size analyzer (Mastersizer-2000; Malvern Ins., Ltd., Worcestershire, UK). For particle size measurement, the prepared Angelica granules were dispersed in 10 mL of distilled water at a ratio of 1: 400 (w / v) to make a suspension. The suspension was continuously stirred at room temperature for 3 minutes and measured at 25 ° C with a scattering angle of 90 °. Nine times were measured for all samples and the average particle size is shown in Table 1 below.

[Table 1] Average particle size of the prepared Angelica xerup powder and solid dispersion

However, each value is expressed by including the standard deviation (mean ± SD).

As shown in Table 1 and FIG. 2, it can be seen that the particle size of the Angelica powder or the granular Angelica powder before the melt extrusion method is larger than that of the high shear force solid dispersion. The decrease in particle diameter leads to an increase in the particle surface area per unit volume, and has the effect of increasing the solubility (or water extraction rate) of the water-insoluble active active ingredient in water. Particularly, in order to put the sample into the hot melt extruder in this experiment, it is necessary to grind the powder into the granular flour.

As the shear strength increases, the average particle diameter decreases. Particularly, in the case of the high shear force solid dispersion, it was confirmed that the average particle size was about 42 탆 and had a very small particle size.

(2) Measurement of particle size in supernatant of solid dispersion suspension

0.3 g of each solid dispersion thus prepared was suspended in 30 mL of distilled water and the resulting suspension was centrifuged at 3,000 rpm for 20 minutes to obtain a supernatant. The particle size and polydispersity index of the solid dispersion contained in the supernatant were measured using a light-scattering spectrophotometer (ELS-Z; Otsuka Electronics, Tokyo, Japan)

[Table 2] Particle size and polydispersity index (n = 3) in the solid dispersion suspension [

As shown in Table 2, in the suspension, the particle diameter of the granular Angelica gigas Nakai was smaller than that of Angelica gigas, and the high shear force Angelica-zirconia solid dispersion formed particles having a diameter of 500 nm or less, It was confirmed that the particle diameter was decreased.

The polydispersity index is an index indicating the degree of dispersion of the particles, whereby the narrowness of the particle size distribution can be evaluated. As a result of the measurement, the polydispersity index values of all the formulations were measured to be about 0.2 to 0.3, indicating that the particles were uniformly formed.

It is presumed that the cellulosic components of Angelica gigas cells acted as matrix during the hot melt extrusion process by injecting water and Angelica gigas powder, and nanoparticles were formed by dispersing the insoluble active ingredient in the matrix.

As can be seen from the above results, as the particle size of the solid dispersion decreases, the surface area increases accordingly. As a result, it can be seen that the decrease of the particle size will contribute to the improvement of the solubility of the insoluble component in water.

(3) SEM analysis

SEM (scanning electron microscopy, JEOL, JSM-6380, Japan) with an acceleration voltage of 5 kV was used to investigate the shape of the surface of the sample. Each sample was placed on a SuS plate using carbon tape and platinum coated for 90 seconds under air injection. SEM photographs are shown in Figs. 3 and 4.

As shown in FIG. 3 and FIG. 4, although the overall shape of the particles was irregular, it was confirmed that the particle size of the granular Angelica powder was significantly reduced compared to that of Angelica gigas.

In particular, in the case of a high shear force solid dispersion, it was confirmed that numerous pores were formed on the surface of the particles. This is considered to be because the physical and chemical properties of the Angelica keiskei keo at the time of hot melt extrusion are considered to change if they are formed by melt extrusion by high shear force after grinding. In particular, numerous pores present on the surface of high shear solid dispersion particles may be associated with the enhancement of water absorption capacity of Angelica gigas.

(4) Measurement of water absorption index (WAI), water solubility (WS) and swelling power (SP)

In order to evaluate the water absorption index of the solid dispersion of Angelica gigas and to provide a basic basis for extracting the active ingredient of the solid dispersion, the water absorption index was evaluated. WSI was measured three times repeatedly. Each sample was suspended in 30 mL of distilled water for 1 hour at room temperature, stirred slowly, and centrifuged at 3000 rpm for 20 minutes. The supernatant was poured into an evaporation dish whose weight was known. WAI, WS, and SP were calculated using the following equations, and the results are shown in Table 3 below. WAI represents the ratio of the wet bulk precipitate to the dry sample weight, and WS represents the weight ratio of the sample extracted in the supernatant.

[Mathematical Expression]

[Table 3] WSI, WS and SP (mean 占 standard deviation) of Angelica gigas Nakai

As shown in Table 3, the particle size of the granular Angelica gigas powder was smaller than that of Angelica gigas, so the solubility of the particles in water was increased and WAI was decreased and WS was increased. From low shear force to high shear force sample, WAI decreased and WS increased by the same principle.

Particularly, in the case of the high shear force solid dispersion, the WAI was 4.18, the water absorption index was remarkably decreased, WS was 48.10, the water solubility index was significantly increased, SP was 7.08, and the swelling power And it was confirmed that it decreased remarkably.

(5) Measurement of extraction rate of water of Angelica gigas Nakai powder and solid dispersion

0.3 g of the prepared Angelica gigas powder or 0.2 g of the solid dispersion was added to 30 mL of distilled water and mixed. The mixture was put in a stirrer and stirred at 40 DEG C for 2 hours. The mixture was filtered to separate the supernatant and the precipitate. The supernatant was dried in a vacuum-evaporator. For the quantitative analysis of D and DA of each of the prepared samples, it was analyzed by high-performance liquid chromatography (HPLC) (LC-20AT, Shimadzu Scientific Instruments, Tokyo, Japan). The experimental conditions are shown in Table 4 below. (10, 20, 40, 60 and 80 μg / mL of D and DA) containing D and DA were prepared and calibration curves were prepared.

[Table 4] HPLC analysis conditions of D and DA

The extractability (solubility) of the active pharmacological components D and DA in water was measured by the above method and is shown in Table 5.

[Table 5] Amount of D and DA extracted from each sample

As shown in Table 5, the extraction rate of D and DA in water was increased in the case of the granular Angelica powder compared to that of Angelica gigas Nakai. As the shear force was increased during the preparation of the solid dispersion, the extraction rate of D and DA in water also increased remarkably. Particularly, in the case of the high shear force solid dispersion, the extraction amount of D was 5.43 mg / g and the extraction amount of DA was 4.72 mg / g, which showed a remarkably improved water extraction amount as compared with the low shear force solid dispersion and heavy shear force solid dispersion. Enhancement of D and DA extraction rates in water can lead to improved dissolution rate in the gastrointestinal tract after oral administration.

(6) Determination of solubility of D and DA at various pH conditions

Each of the prepared solid dispersions was mixed with 30 mL of a buffer solution of pH 1.2 or pH 6.8. The mixture was stirred in a stirrer at 40 占 폚 for 2 hours. The mixture was filtered to separate the supernatant and the precipitate. The supernatant was dried in a vacuum dryer. The contents of D and DA in each formulation of the prepared solid dispersion were quantitatively analyzed by HPLC. The HPLC (HPLC; LC-20AT, Shimadzu Scientific Instruments, Tokyo, Japan) assay conditions used for the quantitative analysis are shown in Table 6 above.

The dissolution rates of D and DA, which are poorly soluble components of Angelicae giganta, were evaluated from the respective solid dispersions in artificial gastric juice (pH 1.2) and artificial intestinal juice (pH 6.8), and are shown in Table 6 below.

The dissolution rate (mg / g, w / w) of D and DA in gastric juice (pH 1.2) and intestinal juice (pH 6.8)

As shown in Table 6, the dissolution rates of D and DA were higher than those of Angelica gigas Nakai and Ganoderma lucidum powder by shear force application by thermal melt extrusion method.

As described above, according to the results of the elution of the effective components D and DA in the pH environment of the artificial gastric juice and the artificial intestinal fluid, when the solid dispersion is administered when oral administration of Angelica gigantis is administered, the insoluble active ingredients D and DA Could be more effectively eluted in the gastric juice.

(7) Analysis of pharmacokinetic characteristics in rats

In vivo pharmacokinetics studies were performed in male SD rats (Sprague-Dawley rats, weight 250 ± 5 g, Orient Bio, Sungnam, Korea). A polyethylene tube (PE-50, Becton Dickinson Diagnostics, MD, USA) was inserted into the left femoral artery under anesthesia for blood sampling.

Each of the solid dispersion formulations prepared in the Examples was orally administered at a dose corresponding to 100 mg / kg ethanol extract. After injection, 200 μL of blood samples were collected from the femoral artery at 5, 15, 30, 60, 90, 120, 240 and 480 min. Blood samples were centrifuged at 16,000 rpm at 4 ° C for 2.5 minutes and stored at -70 ° C until a portion of the plasma sample (70 μL) was analyzed.

The concentration of DOH in rat plasma was measured by a liquid chromatography-tandem mass spectrometer (LC-MS / MS) system. 5 μL of losartan (LST, internal standard) solution (10 μg / mL) and acetonitrile were added to 50 μL of the plasma sample and vortex-mixed for 5 minutes. Then, after centrifugation at 16,000 rpm for 5 minutes, the supernatant (5 μL) was injected into a liquid chromatography tandem mass spectrometer equipped with a HPLC (Agilent Technologies 1260 Infinity HPLC system, Agilent Technologies, Wilmington, Del., USA) . Chromatography was performed using a Synergi ™ 4 μ Hydro-RP 80 Å column (75 × 2.0 mm; Phenomenex, CA, USA) and a C18 guard column (4 × 2.0 mm; Phenomenex, CA, USA) . The mobile phase was acetonitrile and 5 mM ammonium formate buffer (70:30, v / v) and the flow rate was 0.4 mL / min. ESI source settings were manually optimized: gas temperature, gas flow rate, sprayer pressure and capillary voltage were 300 ° C, 11 L / min, 15 psi and 4000 V, respectively.

The fragmentor voltage was 247.1 to 229.1 at m / z for DOH and 207.3 at m / z 423.4 for LST. The fragmentation voltage and impact energy were 96 V and 16 V for DOH and 115 V and 20 V for LST, respectively. The retention times of DOH and LST were 0.71 min and 0.47 min, respectively. Data collection and processing was performed with quantitative analysis software (MassHunter Workstation Software Quantitative Analysis, Version B.05.00; Agilent Technologies). The pharmacokinetic parameters (parameters) of DOH were calculated by the WinNonlin program (Version 3.1; Pharsight, Mountain View, CA, USA).

In this pharmacokinetic experiment, blood levels of DOH, not D and DA, were measured. This is because D and DA, which are poorly soluble components of Angelicae gigas, are metabolized to DOH in the liver after being absorbed in the small intestine when orally administered. Therefore, the absorption rate of each solid dispersion is evaluated by measuring DOH after orally administering the solid dispersion Respectively. OH was plotted in FIG. 5, and the calculated pharmacokinetic parameters are shown in Table 7.

[Table 7] Pharmacokinetic parameters of body DOH (n ≥ 3)

#p <0.05, compared with the ethanol extract group

* p <0.05, compared with the granulated Angelica powder group

+ p < 0.05, high shear force Comparison with Angelicae solid dispersion

As shown in Table 7, the relative bioavailability (F _rel ) was 6.43 times higher than the ethanol extract in the high shear force Angelicae solid dispersion after oral administration.

In addition, the highest blood concentration ( _Cmax ) was also found to be higher in the blood serum concentration of the ethanol extracts than that of the ethanol extracts of the granulated Angelica gigantis powder and the high shear force Angelica sp.

As shown in FIG. 5, it can be seen that the concentration of DOH detected in the plasma of rats administered orally in the high shear force Angelica giganti-solid dispersion was significantly higher than that of the ethanol extract.

Therefore, it can be expected that the bioavailability of the high shear force Angelicae solid dispersion is high when the concentration of DOH detected in plasma is high.

As described above, the reason why the relative bioavailability of DOH increases in the high shear force angelic-solid dispersion is that the formation of the suspension of nanoparticles of 500 nm or less having a narrow particle size distribution and the formation of the effective pharmacological component at pH 6.8 It can be assumed that the dissolution rate is increased. When the relative bioavailability is increased as in the case of high shear force Angelicae solid dispersion, it is possible to reduce a dose for manifesting pharmacological effect upon administration of the dosage form, thereby improving the relative therapeutic effect.

Claims (10)

(a) crushing Angelicae gruel to produce angelica powder;
(b) finely pulverizing the Angelica powder using a fine grinder to prepare a fine angelic-red powder; And
(c) melt-extruding the granular Angelica powder using a high shear melt extruder to produce a solid dispersion. The method according to claim 1,
Wherein step (b) is carried out using a fine grinder containing a grinding media of 210 mm in diameter at a temperature of -15 to -20 占 폚 and a rotor rotation speed of 10,000 rpm or more. &Lt; / RTI &gt; The method according to claim 1,
Characterized in that the particle size of the granular Angelica powder is 40 to 100 mu m. The method according to claim 1,
Wherein the step (c) is performed at a temperature of 80 to 100 ° C. The method according to claim 1,
The high-shear melt extruder may comprise:
And an extrusion die having a diameter of 1 to 3 mm. The method according to claim 1,
The high-shear melt extruder may comprise:
A method for manufacturing a gelatin-solid dispersion, comprising the step of applying a high shear force to the fine-grain alumina powder containing a screw into which a plurality of kneading disk block parts are introduced. The method according to claim 1,
Wherein the solid dispersion has a particle size of 10 占 퐉 or less. A pharmaceutical composition comprising a Angelica gigas-solids dispersion and a carrier prepared by the method according to any one of claims 1 to 7. 9. The method of claim 8,
Wherein the carrier is at least one selected from a surfactant, a water-soluble polymer, or a pharmaceutically acceptable additive. A functional food comprising an Angelica keiskei kagamushi-solid dispersion prepared by the method according to any one of claims 1 to 7 as an active ingredient.

Images