JPH10101550A - Film for soft capsule - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a soft capsule filled with a substance highly subject to oxidation such as a lipid containing highly unsaturated fatty acids at a high concentration and prevented from delay of film disintegration time and oxidation of the filler. SOLUTION: This film for soft capsule consists mainly of gelatin and contains tocopherol and is also filled with a lipid containing highly unsaturated fatty acids. In this case, the filler is incorporated with rosemary extract and ascorbic acid or citric acid. Thus, the lipid containing highly unsaturated fatty acids having useful, physiological activities clan be preserved stably for a long period as the soft capsule.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a gelatin film for a soft capsule and a soft capsule in which the film is filled with a lipid containing a highly unsaturated fatty acid. More specifically, the present invention relates to a gelatin capsule film containing gelatin as a main component and containing tocopherol and having excellent disintegration over time, and a soft capsule in which the film is filled with a lipid containing a highly unsaturated fatty acid.

[0002]

2. Description of the Related Art Gelatin films for soft capsules are widely used for formulating oily drugs and oily foods. The characteristics of this film are that (1) the contact between the filler and external oxygen can be blocked to prevent the deterioration of the filler, and (2) the filler can be easily disintegrated in the digestive organs of the human body to release the filler. These two must be met. However, when a substance that is highly oxidized, such as a lipid containing a polyunsaturated fatty acid, is used as a filler, the disintegration time is delayed or the filler deteriorates with the lapse of time with a normal gelatin film. Sometimes.

As a method for suppressing the time-dependent delay of the disintegration time of the gelatin film for soft capsules, the following techniques have been disclosed. (1) A film is prepared by adding a sodium salt of phosphoric acid or a sodium salt of condensed phosphoric acid to gelatin. (JP-A-4-178321) (2) A film is prepared by mixing a hot water extract of microalgae such as chlorella, scenedesmus and spirulina with gelatin.
(JP-A-57-48909) (3) An antioxidant such as tocopherol is added to the filler (cosmetics). (US Patent 5,082,66
1) (4) Tocopherol is added to the filler (therapeutic agent).
(JP-A-58-105913) (5) Tryptophan is added to a filler (not specified). (JP-A-34921) That is, the above (1) and (2) are methods by modifying the coating itself, and (3), (4) and (5) are methods by modifying the filler.

[0004]

It is well known that lipids containing highly unsaturated fatty acids such as docosahexaenoic acid and icosapentaenoic acid, which have effective physiological activities, are easily oxidized by oxygen in the air. Yes, these are formulated as soft capsules by known methods. However, the content of polyunsaturated fatty acids produced by recent advances in purification technology is, for example, 70%.
% Of the lipids are more susceptible to oxidation, and when the above-mentioned conventional technology is used for the production of soft capsules containing these as a filler, the effect of delaying the film disintegration time and suppressing the filler oxidation is not necessarily. It was not satisfactory. The present invention, for example, even when the filler is made of an easily oxidizable substance such as a lipid containing a highly unsaturated fatty acid at a high concentration, the time delay of the film disintegration time is extremely small, and the oxidation of the filler is prevented. It is intended to provide a soft capsule.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, instead of adding tocopherol to a filler as in the prior art, tocopherol together with gelatin was used to form a film. It has been found that the presence of a component makes it possible to minimize the time-dependent delay of the film disintegration time and prevent the filler from being oxidized.
Furthermore, when the filler is a lipid containing a polyunsaturated fatty acid, it was found that adding rosemary extract and citric acid or rosemary extract and ascorbic acid to the filler would provide a greater effect. The invention has been completed.

[0006] That is, the present invention is a film for soft capsules, characterized by containing gelatin as a main component and containing tocopherol. Further, the present invention is a soft capsule in which a lipid containing a polyunsaturated fatty acid is filled in the soft capsule film, and in this case,
A soft capsule in which the lipid containing a polyunsaturated fatty acid contains rosemary extract and citric acid or rosemary extract and ascorbic acid.

[0007] The soft capsule referred to in the present invention is a soft capsule obtained by compression-molding a filler between two gelatin plates prepared by adding a plasticizer such as glycerin or sorbitol to gelatin. There are two known rotary die methods. The manufacturing method will be described below by taking a rotary die method, which is the mainstream of the current manufacturing method, as an example. (1) Filling preparation: If the filling is liquid, put it directly into a large medicine tank (100-300 liters). If pretreatment such as emulsion or suspension is required,
After the treatment, it is put in a medicine tank and set in a predetermined position of a filling machine.

(2) Film preparation: gelatin 100-200 k in a gelatin melting tank (about 500 liters)
g plasticizer, colorant, purified water, etc.
After heating and dissolving at ℃, defoaming operation is performed in the same tank to adjust the viscosity (about 25,000 centipoise) to obtain a stock solution of the coating. This undiluted solution is supplied to a subdivision tank (7
(Keeping the temperature at 0 ° C), and set it at a predetermined position of the filling machine. (3) Capsule filling: The formulated film and filling are
An undiluted coating solution is placed at the rear upper portion of the filling machine, and the filling material is suspended at the front upper portion of the tank itself. The soft capsules are formed by the filling machine in which the target die roll is set. The temperature of the filling chamber is 20-26 ° C, and the relative humidity is 45-
Preferably, it is maintained at 60%. The soft capsule immediately after molding is sent to a tumbler dryer connected to a filling machine, and while being rotated, the shape is temporarily fixed and the moisture in the film is temporarily dried in about 1 to 2 hours with the same clean air as indoor conditions. .

(4) Drying: The soft capsules that have been filled and molded and temporarily dried are arranged on a flat surface without overlapping the drying plate, and are dried in dry air at a temperature of 22 to 28 ° C. and a relative humidity of 35 to 45% for 12 to 30 hours. To reduce the water content of about 50% at the time of filling to about 10%. (5) Polishing: After drying, the soft capsule is polished with a tumbler for about 1 hour and finished.

The tocopherol referred to in the present invention includes α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocopherol.
As long as it contains at least one of tocotrienol, γ-tocotrienol and δ-tocotrienol, it may be a synthetic product or a natural product, and is not particularly limited. Dl also specified
-Α-Tocopherol may be used. Tocopherol is used by dissolving it with gelatin in the above-mentioned film preparation step, and the amount of use is not particularly limited. For example, usually, tocopherol having a purity of 100% with respect to 100 parts by weight of gelatin is used. 0.1 to 10 parts by weight, preferably 0.5 to 5 parts by weight, particularly preferably 1 to 2 parts by weight in conversion.

The polyunsaturated fatty acid referred to in the present invention is a fatty acid having 16 or more carbon atoms and 2 or more double bonds, such as linoleic acid, γ-linolenic acid, and the like.
Dihomo-γ-linolenic acid, arachidonic acid, α-linolenic acid, icosapentaenoic acid (hereinafter sometimes abbreviated as EPA), docosahexaenoic acid (hereinafter sometimes abbreviated as DHA) and the like.

The lipid containing a polyunsaturated fatty acid as referred to in the present invention means a lipid containing the above-mentioned polyunsaturated fatty acid as a constituent fatty acid or a polyunsaturated fatty acid free or salted. Examples thereof include dihydric alcohols, monohydric alcohols, phosphoric acids, sugars, and esters with amino acids. Further, as a specific example, EP
Monoglycerides, diglycerides, triglycerides containing high concentrations of A and / or DHA, EPA ethyl esters, DHA ethyl esters, and phospholipids containing EPA and / or DHA can be mentioned.

The rosemary extract used in the present invention is:
After extraction from rosemary, a Labiatae herb, with an organic solvent such as ethanol or hexane, the solvent may be removed, but a commercially available product may be used more simply. The citric acid and ascorbic acid used together with the rosemary extract may be added separately from the rosemary extract, or a commercially available product preformulated with the rosemary extract may be used. As a rosemary extract preparation to which citric acid is added, KAL
DURALOX OXIDATION M manufactured by SEC
As ANAGEMENT BLEND NC-1 as a rosemary extract preparation containing ascorbic acid,
DURALOX OXIDA, also made by KALSEC
TIONMANAGEMENT AN-1 can be exemplified. The amount of the rosemary extract or the rosemary extract preparation is not particularly limited.For example, although the purpose can be achieved without using at all, usually, the lipid containing a polyunsaturated fatty acid is used. On the other hand, it is at least 0.1%, preferably at least 0.2%.

The soft capsule produced by the above method has a very small delay in the film disintegration time even when stored under severe conditions for a long period of time, and prevents the filling material from being oxidized. Therefore, even when the filler is made of a substance that is easily oxidized, such as a lipid having a high content of highly saturated fatty acids, a soft capsule that can maintain its physiological effectiveness and safety for a long time can be provided.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

[0016]

【Example】

(Example 1) dl-α-
Tocopherol was added at 0, 0.1, 0.5, 1.
0 and 1.5 parts by weight, and 28 parts by weight of concentrated glycerin and 200 parts by weight of purified water were added.
And dissolved on a water bath. The mixture was spread on a tray coated with liquid paraffin to a thickness of about 2 mm, dried at room temperature for 24 hours, and then the solidified gelatin film was cut into about 1 cm squares and dried at room temperature for further 24 hours. DHA oil 1 (DHA7) whose composition is shown in Table 1 was placed in a glass sample bottle.
1.07%, containing 5.11% EPA), immerse the cut and dried gelatin film in DHA oil, cover and cover at 20 ° C (50-70% relative humidity) and 40 ° C (75% relative humidity). ). After the gelatin film was taken out for a storage period of 1 month and 2.5 months and the oil was wiped off, the disintegration time of the gelatin film in distilled water was measured according to the Japanese Pharmacopoeia General Test Disintegration Test Method. The disintegration time was defined as the time for the gelatin film to dissolve without using an auxiliary plate for the measurement. The criterion for the determination was that when no residue of the sample was observed in the glass tube of the tester, or even if it was recognized, it was smaller than the mesh. The delay rate of the film disintegration time of the gelatin film was calculated by the following equation. Delay rate = 100 * (T−T0) / T0 (%) where T0: film disintegration time (min) before starting storage T: film disintegration time after storage (min)

The average value of 6 samples was determined, and the results are shown in Table 2. According to this, at a storage temperature of 20 ° C.,
The retardation did not increase even after 2.5 months, but under the severe conditions of 40 ° C. and 75% relative humidity, the retardation was 80% in the gelatin film to which no tocopherol was added. But,
In the gelatin film to which tocopherol was added, an increase in the delay rate was suppressed with an increase in the tocopherol addition rate.

[0018]

[Table 1]

[0019]

[Table 2]

Comparative Example 1 A gelatin film cut and dried in the same manner as in Example 1 except that tocopherol was not added during the preparation of the gelatin film. In a glass sample bottle, 10 ml of DHA oil 1 having the composition shown in Table 1 was taken, and when no antioxidant was added, when dl-α-tocopherol was added at 0.2%, mixed tocopherol (60%) was added.
%) Was added, and four conditions were set when 0.2% of antioxidant A was added.

The antioxidant A is obtained by adding 0.5 parts by weight of trisodium citrate (special grade reagent) to 1 part by weight of rosemary extract (provided by Kaneka Sun Spice Co., Ltd.). A storage test was carried out in the same manner as in Example 1 by immersing a gelatin film to which no tocopherol was added in these DHA oils. Table 3 shows the results. According to this,
It was found that when tocopherol was not present in the gelatin film itself, an increase in the delay rate could not be suppressed even when an antioxidant was added to the oil.

[0022]

[Table 3]

(Example 2) 28 parts by weight of concentrated glycerin, 200 parts by weight of water and a small amount of a coloring agent were added to 100 parts by weight of gelatin, and dl-α-tocopherol was not added thereto. The film was prepared under the two conditions in which was added. As the filler, D having the composition shown in Table 1 was used.
HA Oil 2 (containing 75.78% DHA, 4.75% EPA) was used without the addition of antioxidants. Using these as raw materials, OV under a nitrogen stream is carried out by a usual rotary die method.
AL NO4 type soft capsules were prepared. The average capsule weight without adding tocopherol to the film is 3
14 mg / capsule, average filling weight 196 mg / capsule
Capsules, average film weight was 118 mg / capsule. When tocopherol is added to the film, the average capsule weight is 318 mg / capsule, the average filling weight is 196 mg / capsule, and the average film weight is 122 mg.
/ Capsule. The obtained soft capsule was stored in a polypropylene bottle under the following three conditions with a lid in the presence of air.

Storage condition 1: temperature 4 ° C., relative humidity 80
９５95% refrigerator Storage condition 2: Temperature 20 ° C., relative humidity 50 to 70% constant temperature room Storage condition 3: Temperature 40 ° C., relative humidity 75% constant temperature and humidity Storage days 0 days, 60 days, 90 days, 120 days, 150 days,
180 days, 210 days, 150 days, 180 days, 210 days,
Samples were taken at 240 days and 270 days, and subjected to a capsule disintegration test and measurement of POV (peroxide value) of the filling oil.

The capsule disintegration test conformed to the Japanese Pharmacopoeia General Test Disintegration Test Method. As the test liquid, distilled water was used, and the disintegration time was defined as the time when the film was dissolved using the auxiliary plate. The criterion for the determination was that when no residue of the sample was observed in the glass tube of the tester, or even if it was recognized, it was smaller than the mesh. The average of 6 samples was determined, and the results are shown in Table 4. The POV of the filling oil was measured by extracting the filling oil from the soft capsule with a syringe and collecting the oil by an iodometric titration method in accordance with the Japanese Agricultural Standards Measurement Method. Table 5 shows the results. According to this, it can be seen that when tocopherol was added to the soft capsule film, the delay of the film disintegration time and the increase in the POV of the filling oil were suppressed as compared with the case where no tocopherol was added.

[0026]

[Table 4]

[0027]

[Table 5]

(Example 3) DHA oil 2 in Example 2
0.2% antioxidant A (1 part by weight of rosemary extract plus 0.5 part by weight of trisodium citrate)
Soft capsules were prepared in the same manner as in Example 2 except that they were added, under the two conditions where no tocopherol was added to the film. When tocopherol was not added to the film, the average capsule weight was 319 mg / capsule, the average filling weight was 198 mg / capsule, and the average film weight was 121 mg / capsule. The average capsule weight when adding tocopherol to the film was 320 mg.
/ Capsule, the average filling weight was 197 mg / capsule, and the average coating weight was 123 mg / capsule.

The obtained soft capsules were subjected to a storage test under the same conditions as in Example 2 to determine the film disintegration test and the PO of the filled oil.
The V measurement results are shown in Tables 6 and 7, respectively. According to this, it can be seen that when tocopherol was added to the soft capsule film, the delay of the film disintegration time and the increase in the POV of the filling oil were suppressed as compared with the case where no tocopherol was added.
In addition, as compared with Example 2, by adding rosemary extract and citric acid to the filling oil, the above-mentioned suppression effect was further increased.

[0030]

[Table 6]

[0031]

[Table 7]

Example 4 DHA oil 2 in Example 2
To antioxidant B (a preparation obtained by adding ascorbic acid to rosemary extract, DURALOX O manufactured by KALSEC)
Soft capsules were prepared in the same manner as in Example 2, except that tocopherol was not added to the film, except that 0.2% of XIDATION MANAGEMENT AN-1) was added. The average capsule weight without adding tocopherol to the coating was 319 mg / capsule, the average filling weight was 197 mg / capsule, and the average coating weight was 122 mg / capsule. The average capsule weight when adding tocopherol to the film was 3%.
24 mg / capsule, average filling weight 196 mg / capsule
Capsules, average film weight was 128 mg / capsule. The obtained soft capsule was subjected to a storage test under the same conditions as in Example 2, and the results of the film collapse test and the POV measurement of the filled oil are shown in Tables 8 and 9, respectively. According to this, when tocopherol is added to the soft capsule film,
It can be seen that the delay of the film disintegration time and the increase in the POV of the filling oil are suppressed as compared with the case where no coating was performed. In addition, by adding rosemary extract and ascorbic acid to the filling oil in comparison with Example 2, the above-mentioned inhibitory effect was increased, and in comparison with Example 3, the effect of rosemary extract and citric acid was increased. It can be seen that the addition of the rosemary extract and the ascorbic acid preparation is superior to the addition.

[0033]

[Table 8]

[0034]

[Table 9]

Example 5 28 parts by weight of concentrated glycerin, 200 parts by weight of water and a small amount of a coloring agent were added to 100 parts by weight of gelatin, and dl-α-tocopherol was not added thereto. The film was prepared under the two conditions in which was added. As a filler, 90% EPA ethyl ester was used without adding an antioxidant. Using these as raw materials, soft capsules were prepared under a nitrogen stream by a usual rotary die method. The average capsule weight was 528 mg / capsule, and the average filling weight was 345 m, both with and without tocopherol added to the skin.
g / capsule, average film weight was 183 mg / capsule. The obtained soft capsule was covered with a glass brown wide-mouth bottle in the presence of air, and the temperature was 20 ° C. * relative humidity 50.
It was stored for 6 months under the conditions of ７０70% and temperature of 40 ° C. * relative humidity of 75%.

The capsules before the start of storage and after the end of storage were subjected to a capsule disintegration test according to the general disintegration test method of the Japanese Pharmacopoeia. The test liquid is distilled water, and the test is carried out using an auxiliary plate.The time when the contents start to be released is defined as the content release start time, and no film residue is observed in the glass tube of the tester. Even when it was smaller than the mesh, the film collapse completion time was taken as the time. Table 10 shows the results. According to this, temperature 40 ° C. * relative humidity 7
When stored under severe conditions of 5%, soft capsules without tocopherol added to the film had a test time of 12%.
Even after 0 minutes, the film only swelled and did not collapse, and the contents were not released. On the other hand, in the soft capsule in which tocopherol was added to the film, the disintegration time was not delayed as compared to before the start of storage.

[0037]

[Table 10]

[0038]

By using the soft capsule film according to the present invention, even if the soft capsule filled with a substance which is extremely susceptible to oxidation is stored for a long time, the delay of the disintegration time is extremely small, and the oxidation of the filled substance is prevented. A highly safe soft capsule can be provided. This makes it possible to stably store lipids containing high concentrations of highly unsaturated fatty acids having useful physiological activities as soft capsules for a long period of time.

Continued on the front page (72) Inventor Masato Takahashi 560 Nakazato Higashicho, Fujinomiya City, Shizuoka Prefecture Toyo Capsule Co., Ltd.

Claims (4)

[Claims] 1. A film for soft capsules comprising gelatin as a main component and tocopherol. 2. A soft capsule comprising the capsule for a soft capsule according to claim 1 filled with a lipid containing a highly unsaturated fatty acid. 3. The soft capsule according to claim 2, wherein the lipid containing the polyunsaturated fatty acid contains rosemary extract and citric acid. 4. A soft capsule according to claim 2, wherein the lipid containing the polyunsaturated fatty acid contains rosemary extract and ascorbic acid.