KR960002179B1 - Process for preparing soft capsule containing gingko biloba - Google Patents

Abstract

The soft capsule contg. gingko biloba extract is prepd. by 1) dissolving the extract of gingko biloba leaves 1 wt. part in 800 or less polyethylene glycol, propylene glycol or polyethylene glycol-propylene glycol mixed soln. and leaving it alone at 50-8 deg. C to obtain the gingko biloba extract soln., 2) mixing M.W. 800-20000 polyethylene glycol and 1.0-10.0 wt. parts one or more mixt. selected from M.W. or less polyethylene glycol, propylene glycol and glycerin, heating at 60-90 deg. C, and agitating to obtain the mixt. soln., and 3) adding the gingko biloba extract soln. into the obtd. mixt. soln, and cooling slowly to obtain the final product.

Description

Manufacturing method of soft capsule containing ginkgo leaf extract

The present invention relates to a method for producing a soft capsule containing a ginkgo biloba extract, and more particularly, a ginkgo biloba extract is stirred, dissolved and cooled while maintaining a constant temperature in a mixture of a non-aqueous specific hydrophilic liquid and filled into a gelatinous capsule. The present invention relates to a method for preparing a soft ginkgo biloba extract-containing soft capsule, which increases the preservation stability and efficacy of the ginkgo biloba extract and significantly reduces gastrointestinal disorders.

In general, ginkgo biloba extract is known to significantly increase peripheral blood and cerebral blood volume, increase ATP concentration in tissues, and promote energy metabolism in cells by vasodilation and blood flow promoting activities (Raphin & Le Poncin Lafitte, 1979), it has been found to have excellent prevention and treatment for cerebral ischemia, cerebrovascular and embolism and various hypoxia. (Le Poncin Lafitte et al., 1980: Larsen et al., 1978: Chatterjee & Gabard, 1981). Ginkgo biloba extract is widely used as a medicine because of its efficacy, and its use as a health food is also gradually increasing.

The usual dosage form of ginkgo biloba extract is by tablet or liquid, in which tablets are easy to carry and convenient to take, but side effects such as stomach pain and heartburn have been reported, and because ginkgo biloba extract has low solubility in gastric acid, There is a drawback of poor utilization. In addition, in the case of liquids, the bioavailability is excellent, but above all, there is a big limitation in that it is inconvenient to carry, and the gingoflavone glycoside (abbreviated as GFG), which is an active ingredient of ginkgo biloba extract, is unstable in aqueous solution, resulting in poor storage stability and precipitation. There is a disadvantage that occurs.

The present inventors have studied the above disadvantages of the existing formulation, and as a result, the ginkgo biloba extract was dissolved in a specific non-aqueous hydrophilic liquid at a much higher concentration than water, and then filled with gelatin to produce a soft capsule, which was applied to the stomach. The present invention has been completed by discovering that side effects are significantly reduced, bioavailability can be increased, and stability is excellent even in long-term storage.

Accordingly, an object of the present invention is to provide a soft capsule containing a ginkgo biloba extract, which is a new formulation that has not been prepared in the form of a ginkgo biloba extract.

Hereinafter, the present invention will be described in detail.

The present invention in the preparation of a drug containing a ginkgo leaf extract, 1 part by weight of the ginkgo leaf extract dissolved in 0.1 to 15 parts by weight of polyethylene glycol or propylene glycol or a mixture thereof having a molecular weight of 800 or less and maintained at 50 to 80 ℃, while the molecular weight 800 1.0 ~ 10.0 parts by weight of polystyrene glycol, propylene glycol, glycerin having a molecular weight of 800 or less added to the polyethylene glycol of ~ 20,000, 1.0 to 10.0 parts by weight, warmed to 60-90 ℃, stirred and dissolved, the two solutions are combined and then slowly cooled gelatin It is characterized by filling in a capsule.

Referring to the present invention in more detail as follows.

Ginkgo biloba extract used in the present invention can be prepared using a known method, for example, Japanese Patent Publication No. 46-28091, No. 49-27323 or Domestic Patent Publication No. 90-5318, 90-5319 The issue describes a method for extracting and purifying bioactive substances from ginkgo biloba leaves.

The ginkgo biloba extract extracted by such a known method is dried under reduced pressure, spray drying, or lyophilization to less than 5% of water to use powder of 100 mesh or less. If the moisture exceeds 5%, there is a risk of damage to the gelatin coating due to moisture over time after filling the gelatin capsule. In addition, when the particle size of the powder is larger than 100 mesh, there is a fear that pinholes may occur during molding of the gelatin capsule.

To 1 part by weight of the ginkgo leaf extract prepared in this way, 1.0-15.0 parts by weight of polyethylene glycol or propylene glycol or a mixture thereof having a molecular weight of 800 or less was added thereto, and the mixture was stirred while maintaining the temperature at 50 ° C to 80 ° C to completely dissolve the ginkgo leaf extract.

Here, the use of less than 1.0 parts by weight of polyethylene glycol, propylene glycol or a mixture thereof of less than 1.0 parts by weight of ginkgo biloba extract is not sufficiently dissolved, when exceeding 15.0 parts by weight of the soft capsules are large, it is inconvenient to take and not commercialized If the temperature is kept below 50 ℃, agitation of the two liquids together will produce a mass of 800-2,000 polyglycol glycol, resulting in a homogeneous mixture, and heating to a temperature higher than 80 ℃ will reduce the content of the ginkgo leaf extract. It is not preferable because there is concern.

Separately, 1.0-10.0 parts by weight of a polyethylene glycol having a molecular weight of 800 to 20,000 is melted by heating to 60 to 90 ° C, or a mixture of one or two or more of polystyrene glycol, propylene glycol, and glycerin having a molecular weight of 800 or less is added to a polyethylene glycol having a molecular weight of 800 to 20,000. 1.0 to 10.0 parts by weight is added, and the mixture is heated and stirred at 60 to 90 ° C to dissolve to prepare a hydrophilic base solution.

When the ginkgo biloba extract prepared in the present invention is dissolved and the water-based base solution having a certain molecular weight is combined and stirred while gradually cooling to room temperature, a semi-fluid soft capsule contents are prepared.

In the hydrophilic liquid used in the present invention, the ginkgo biloba extract was easily dissolved to form a clear liquid, and unlike the aqueous solution, the preservation stability of the GFG was excellent and no breakage of the gelatinous coating occurred. In addition, it showed excellent bioavailability and low gastrointestinal side effects due to excellent dissolution rate and diffusion in gastric juice.

Next, as described above, the soft capsule contents manufactured according to the present invention use a known process such as a rotary die process, a reciprocating die process, or a plate process. By filling the inside of the soft capsule of the gelatine coating, if the soft capsules were prepared using the ginkgo leaf extract as a hydrophilic base is a new formulation that is not known.

On the other hand, according to the present invention, in addition to the fatty acid glyceride component used as the base of the friend, it is expected to be used as a base under certain conditions, such as vegetable fats and oils, lead, braze, pyrapine, and the like.

As described above, the ginkgo biloba extract soft capsule prepared according to the present invention, unlike conventional formulations, is dissolved in a base and is administered in a suspension state, so that the advantages of the solution are excellent in terms of its bioavailability, and thus are preserved compared to the liquid formulation. Excellent safety and homogeneous diffusion in the gastrointestinal tract has fewer side effects.

In addition, while maintaining the above-described improved effect while maintaining the convenience of portability as used conventionally as a tablet.

At this time, the viscosity of the content is too low when using less than 1.0 parts by weight of one or two or more selected from the ethylene glycol having a molecular weight of 800 to 20,000, or the ethylene glycol having a molecular weight of 800 to 20,000, the ethylene glycol having a molecular weight of less than 800, propylene glycol, glycerin. For example, if the amount is used in excess of 10.0 parts by weight, the semi-fluid content may not be actually manufactured.

In addition, at a temperature below 60 ° C., it is not preferable to melt the polyethylene styrene having a molecular weight of 800 to 20,000 sufficiently and to warm it to a temperature exceeding 90 ° C. because it adds an unnecessarily high temperature.

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

Preparation Example: Preparation of Ginkgo Biloba Extract Powder

100 kg of dried ginkgo biloba leaves were extracted under reflux at about 55 ° C. with 380 L of 60% (w / w) acetone aqueous solution according to the method described in Japanese Patent Publication No. 49-27323, which was then cooled and filtered and the layers dissolved in carbon tetrachloride were dissolved. Remove it. 35 kg of ammonium sulphate was added to the filtrate to dissolve. 35 L of methyl ethyl ketone (MEK) was added thereto, stirred well, and the MEK-acetone layer was separated. 26 kg of ammonium sulfate was added to the layer, followed by stirring and standing to remove the solids. The filtrate was concentrated under reduced pressure so that the residue amount was 20 to 60% (w / w).

The concentrate is dissolved in 50% ethanol solution to a final concentration of 10% of the residue and 10 l of lead hydroxide suspension is added dropwise with stirring under nitrogen to remove the pale brown precipitate formed. The filtrate was depressurized and concentrated for about 1/2, and then 10 kg of ammonium sulfate and MEK 8L were added, followed by stirring and standing to separate the organic solvent layer. The water layer was further extracted with MEK, combined with the organic solvent layer, and 0.8 kg of decanter was added to dehydrate. After drying under reduced pressure. The residue was dissolved in 15 L of ethanol and left to stand for 12 hours to remove the resulting precipitate, and the filtrate was dried under reduced pressure at 50 DEG C so that the moisture content was less than 5%. The dried mass is pulverized with a pits mill to obtain 1.2 kg of ginkgo leaf extract powder.

Example 1 Preparation of Soft Capsule Contents

400 g of polyethylene glycol (PEG) # 400 and 1,000 g of propylene glycol were added to 400 g of the ginkgo biloba extract powder obtained in the above preparation, and the mixture was stirred and maintained at 60 ° C. to dissolve transparently. Meanwhile, 300 g of PEG # 4,000 and 300 g of glycerin were added thereto, stirred and dissolved while maintaining at 60 ° C., and the two liquids were combined and left to stir and cooled to room temperature, thereby preparing 5,000 g of a semi-liquid soft capsule.

Example 2 Preparation of Soft Capsule Contents

400 g of PEG # 200 was added to 400 g of the ginkgo biloba extract powder obtained in the above preparation, and the mixture was stirred and maintained at 70 ° C. to dissolve transparently. 1,000 g of PEG # 6,000, 1,000 g of propylene glycol, and 600 g of glycerin were added thereto, stirred and dissolved while maintaining at 70 ° C. The two liquids were combined, left to stir and cooled to room temperature to prepare 5.000 g of a semi-fluid soft capsule.

Example 3 Preparation of Soft Capsule Contents

400 g of PEG # 300 and 500 g of propylene glycol were added to 400 g of the ginkgo biloba extract powder obtained in the above preparation, and the mixture was stirred and maintained at 50 ° C. to dissolve transparently. Meanwhile, 1,000 g of PEG # 20,000 and 600 g of glycerin were added thereto, stirred to dissolve while maintaining at 90 ° C., and the two liquids were combined and left to cool while cooling to room temperature, thereby preparing 5,000 g of a soft capsule contents.

Example 4 Preparation of Soft Capsule Contents

To 400 g of the ginkgo leaf extract powder obtained in the preparation example, 1,000 g of PEG # 600 and 1,000 g of propylene glycol were added, and the mixture was stirred and maintained at 60 ° C. to dissolve transparently. Meanwhile, 1,200 g of PEG # 8,000 and 1,400 g of glycerin were added thereto, stirred and dissolved while maintaining at 60 ° C., the two liquids were combined and left to stir, cooled to room temperature, thereby preparing 5,000 g of a semi-liquid soft capsule.

Example 5 Preparation of Soft Capsule Contents

To 400 g of the ginkgo leaf extract powder obtained in the above preparation, 1,000 g of PEG # 200, 800 g of PEG # 400, and 1,500 g of propylene glycol were added thereto, and the mixture was stirred and maintained at 70 ° C. to dissolve transparently. Meanwhile, 700 g of PEG # 6,000 was heated to 70 ° C., melted, and the two liquids were left together with stirring to cool to room temperature, thereby preparing 5,000 soft capsule contents.

Example 6 Preparation of Soft Capsule Contents

To 400 g of the ginkgo biloba extract powder obtained in the preparation example, 1,500 g of PEG # 400, 600 g of PEG # 600 and 1,000 g of propylene glycol were added thereto, and the mixture was stirred and maintained at 65 ° C. to dissolve transparently. Meanwhile, 500 g of PEG # 4,000, 700 g of PEG # 20,000, and 300 g of glycerin were added thereto, stirred and maintained at 90 ° C., the two liquids were combined, left to stir and cooled to room temperature, thereby preparing 5,000 g of a semi-fluid soft capsule contents.

Comparative Example 1 Preparation of Ginkgo Leaf Extract-Containing Tablet for Comparative Test

400 g of the ginkgo leaf extract powder obtained in the above preparation, 2,000 g of microcrystalline cellulose, 800 g of hydrous lactose, 400 g of corn starch, hard silicic anhydride, and 360 g were mixed in an Eweka Ribbon Mixer for 20 minutes, and then 40 g of magnesium stearate was mixed. A circular punch with a diameter of 9 mm was placed on an Erweka single tablet press and tableted at a speed of 40 tablets per minute to produce 10,000 tablets weighing 400 mg.

Dissolve 10,000 g tablets containing ginkgo leaf extract prepared by dissolving 120 g of hydroxy propyl methylcellulose (HPMC), 15 g of PEC # 6,000, and 10 g of titanium oxide in 1,500 g of ethanol and 300 g of purified water. Erweka Coating Pan) was used for film coating to obtain 10,000 tablets of 415 mg weight coated film.

Comparative Example 2 Preparation of Ginkgo Biloba Extract-Containing Liquid Preparation for Comparative Test

100L of purified water was heated to 80 ° C, 40g of ginkgo leaf extract powder, 10,000g per bag, 80g of citric acid and 10g of sodium benzoate were added and stirred to dissolve completely. 5 Filter through a cartridge filter and fill into a 100 ml brown bottle to obtain 1,000 bottles of liquid.

Test Example 1: Storage stability test of each formulation

To 1 part by weight of gelatin, 1 part by weight of water, 0.3 part by weight of glycerin, and 0.3 part by weight of a solitol solution were added and stirred and dissolved while maintaining at 80 ° C. to prepare a soft capsule film preparation solution using the plate process described above. And the contents of Comparative Example 1 was prepared by the soft capsules and each product prepared according to the Examples and Comparative Examples were stored in an incubator at 40 ℃ relative humidity 75% and stored for 2 months, 4 months, 6 months and 8 months The% content of GFG was then analyzed by HPLC. Analysis conditions are as follows, and the results are shown in Table 1 below.

Column: Novapak C ₁₈

Mobile phase; Water: Methanol: Acetic Acid = 60: 40: 3

Sensitivity: 0.2Aufs

Wavelength: 365nm

Time: 30 minutes

TABLE 1

Long-term preservation test results (%)

The soft capsule prepared according to the Example and the tablet prepared according to Comparative Example 1 maintained a content of 90% or more for 6 months at 40 ° C. and 75% relative humidity, but the liquid prepared according to Comparative Example 2 was relatively unstable. Only 58% of the content was maintained.

[Test Example 2]: Stimulation test for the stomach

Twenty healthy men and women and 15 patients with gastrointestinal diseases such as gastric ulcer and gastritis were administered three times, respectively, and tested for gastrointestinal irritation such as stomach pain and heartburn. Table 2 summarizes the results.

TABLE 2

Gastrointestinal irritation test of each formulation

In the soft capsules prepared according to the above example, gastrointestinal stimulation occurred in an average of about 3% in healthy adults and 6% in gastrointestinal patients. In the tablet of Comparative Example 1, 12.5% of healthy adults and 43% of gastrointestinal diseases showed gastrointestinal stimulation, and in the liquid of Comparative Example 2, 7% of healthy adults and 13% of gastrointestinal patients showed gastrointestinal stimulation. .

It can be seen that the soft capsule prepared according to the embodiment has a low gastrointestinal stimulation in the ginkgo biloba extract-containing preparation compared to the tablet and the liquid preparation.

Test Example 3: Comparative Dissolution Test between Soft Capsule and Tablet

As a preliminary test for predicting the bioavailability of each prescription in vivo, prepared according to Examples 1 to 6 and Comparative Example 1 was carried out six times each dissolution test and the results are shown in Table 3 below. Dissolution test conditions are as follows.

Test method: 100rpm of the first law of the Korean Pharmacopoeia

Test liquid: 900 ml of the first liquid (artificial gastric fluid)

Test time: 30 minutes

Analytical method: Take 225 ml of elution test solution, filter with a 0.22 μm filter, concentrate the filtrate under reduced pressure, add 6 ml of methanol and 4 ml of 1.5N hydrochloric acid to the residue, hydrolyze for 25 minutes under boiling water, and filter again. Analysis was carried out by HPLC under the conditions of.

TABLE 3

Comparative dissolution test result (%)

The soft capsules prepared according to Examples 1 to 6 exhibited a dissolution rate of 90% or more, but a relatively low dissolution rate of 66.7% in the case of tablets.

[Test Example 4]: Test for measuring blood pressure strengthening effect in rats of soft capsules and tablets

Table 4 shows the results of measuring blood pressure lowering effects by administering the products prepared according to Examples 1 to 6 and Comparative Example 1 (control) to experimental rats. Ginkgo biloba leaf extract was administered once per day for 5 days, and the number of animals was 7 each.

The rats used in this test were SD rats (average body weight 144 ± 14g: 5 weeks of age), and the method of administration was orally administered at once and measured the changes in arterial pressure three times a day considering the absorption time in the body. It was. At this time, the arterial pressure was measured using the indirect arterial blood pressure measurement.

TABLE 4

Changes in Arterial Pressure in Rats

Herein, the soft capsule prepared according to the embodiment showed an excellent blood pressure lowering effect as compared to the tablet (control), which means that the soft capsule is an agent having excellent bioavailability.

[Review of Test Results]

From the above experimental results, it can be seen that the soft capsule of the present invention is the formulation having the most excellent effect having the advantages of each of the following Table 5 and each formulation compared to the conventional tablets or liquid formulations.

TABLE 5

A: Very good, B: Excellent, C: Normal, D: Poor, E: Extremely poor.

Claims (2)

In preparing a pharmaceutical containing a ginkgo biloba extract, 1 part by weight of ginkgo biloba extract is dissolved in 0.1-15 parts by weight of ethylene glycol or propylene glycol or a mixture thereof of 800 or less, and maintained at 50-80 ° C., while the molecular weight is 800-20,000. 1.0 to 10.0 parts by weight of one or more mixtures selected from polyethylene glycol, propylene glycol, and glycerin having a molecular weight of 800 or less are added to the glycol, heated to 60 to 90 ° C, dissolved by stirring, and then slowly cooled. Production method of soft capsule. The method of claim 1, wherein the ginkgo biloba extract has a water content of 5% or less and a powder of 100 mesh or less.