JPS625886B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for manufacturing soft capsules,
More specifically, the present invention relates to a method for producing soft capsules using unsaponifiable vegetable oil as a raw material.

Vegetable oil unsaponifiables, such as soybean oil unsaponifiables, are semisolid oils containing plant sterols and natural tocopherols. The former component has a serum cholesterol-lowering effect, and the latter component has various physiological effects and an effect of promoting the absorption of plant sterols, so such unsaponifiable vegetable oils have been used as useful medicines. The first possible dosage form for making such unsaponifiable vegetable oils into medicines is to use soft capsules, but when it comes to unsaponifiable soybean oil, for example, there are various problems with filling operations. For this reason, it was thought that soft capsules of unsaponifiable soybean oil were impossible (see Japanese Patent Publication No. 49-46899, column 2, lines 1 to 11). For this reason, in the prior art, hard capsules are obtained by adsorbing unsaponifiable soybean oil to a different formulation base and granulating it. However, such a method not only requires a large amount of base material, resulting in a large dosage form, but also suffers from secondary drawbacks such as poor storage stability.

The present inventors have conducted various studies on the physicochemical behavior of such unsaponifiable vegetable oils for the purpose of soft encapsulation of unsaponifiable vegetable oils, and found that unsaponifiable vegetable oils can be stirred under non-heating conditions to have a viscosity of 10,000 centipoise or less. By coating the product with gelatin after the preparation, the unsaponifiable vegetable oil was successfully encapsulated into soft capsules without the above-mentioned problems. The present invention will be explained in more detail below regarding the case of unsaponifiable soybean oil.

As is clear to those skilled in the art, unsaponifiable soybean oil is a semi-solid oil with very poor flowability;
It has been found that excellent fluidity is irreversibly ensured during the soft encapsulation operation when this material is stirred under non-heated conditions to a concentration of less than 10,000 centipoise. When the stirring is carried out under heating, the fluidity increases more rapidly, but the fluidity thus obtained is lost again as the unsaponifiable soybean oil cools. Therefore, it is necessary that a viscosity of at least 10,000 centipoise or less be finally achieved by stirring under non-heated conditions. The prior art literature does not indicate that unsaponifiables of this type can be reduced in viscosity simply by stirring. The non-fluidity of unsaponifiable soybean oil is probably due to the non-uniform large crystals of the plant sterols contained therein, but since these are cut into pieces below a certain size during the stirring process, they become homogenized and the viscosity increases. This is thought to cause a decrease in On the other hand, when heated, the viscosity temporarily decreases due to the dissolution of the plant sterols, but as the temperature decreases, crystal growth may be promoted, so stirring that involves heating should be avoided. Although it is acceptable in the middle of the process, it is not desirable in the final stage. Stirring is sufficient to bring the viscosity of the unsaponifiable soybean oil to 10,000 centipoise or less, and soft encapsulation can be achieved without any problem at a viscosity below this limit.

The "unsaponifiables of soybean oil" as used herein refers to sterins, tocopherols, and high-grade substances distilled by steam distillation during the deodorizing process that is carried out after soybean oil has been extracted, degummed, deoxidized, etc. It is refined using raw materials such as alcohol, terpenes, fatty acids, and neutral fats. That is, this raw material is purified through esterification and distillation steps. In this case, esterification may be carried out after saponification, or direct transesterification may be carried out. As a result of this esterification, free fatty acids and neutral fats are esterified and have a significantly lower boiling point than unsaponifiable substances, making them extremely easy to separate in the subsequent distillation step. As the ester, lower fatty acid esters, particularly methyl esters, are advantageous in terms of boiling point and economy. Distillation may be carried out by ordinary vacuum distillation or molecular distillation. As for operation, it is 150-200 at about 2-1 Torr.
The fatty acid fraction that distills out at about ℃ is first removed, and then heated at a vacuum level of about 5×10 ^-2 to 5×10 ^-3 Torr at 150 to
By separating the fraction at about 200°C, it is possible to obtain the desired unsaponifiable soybean oil. The yield of the esterified product is approximately 90% based on the raw material, and the yield of the soybean oil unsaponifiables is approximately 30 to 50% based on the ester compound.

For stirring in the method of the present invention, a homogenizer,
Any known equipment may be used, such as a mixer. Operating conditions during stirring vary depending on the device, and conditions are selected depending on each device. For example, when using a vacuum homo mixer (manufactured by Nippon Seiki Seisakusho), the rotation speed is 1000~
15000rpm, time 1-10 minutes and pressure 15-760mm
Hg is used. When performing ultrasonic treatment, a frequency of about 20 KHz is used, for example. Regarding the temperature conditions during stirring, it is preferable to stir at room temperature to avoid deterioration of the ingredients, but if stirring is difficult,
There is no hindrance to heating the soybean oil to about 100°C and once dissolving the soybean oil unsaponifiables, and then cooling it with stirring. However, in this case it is important to continue stirring until the temperature drops to 30°C and the viscosity reaches the desired level.

The unsaponifiable soybean oil treated in this way not only becomes highly fluid, but also becomes uniform because the plant sterol crystals are destroyed and fragmented by the shearing during stirring, and it can be filled into soft capsules and used as a pharmaceutical product. Therefore, the dosage form does not become large and is favorable for absorption in the body.

For example, unsaponifiable soybean oil usually has a viscosity of about 15,000 to 18,000 centipoise, but if it is subjected to a soft encapsulation operation as it is, in the case of the punching method, the raw material will not be sufficiently accommodated between the gelatin sheets and sealing will not be possible. This causes a punk phenomenon. Furthermore, when the dropping method is used, pressure is required to extrude the drug, so that uniform gelatin coating is not achieved, resulting in irregular shapes and insufficient capsule hardness. On the other hand, the unsaponifiable soybean oil treated by the method of the present invention can be easily carried out industrially by any of the punching method, dropping method, dipping method, etc. It is also not precluded to add to the raw material small amounts of diluents such as triglycerides, surfactants such as sorbitan monooleate.

Examples are provided to illustrate the present invention in further detail. The viscosity referred to in this specification, including the examples, was measured using a B-type viscometer (manufactured by Solomon Electronics Co., Ltd.).
Measured at 30°C.

Example 1 16 kg of soybean oil deodorized scum was dissolved in 50 g of benzene, 2.8 kg of potassium hydroxide and 100 g of pyrogallol were dissolved in 19 g of methanol, and this was added to the benzene layer and refluxed for 5 hours. After cooling, add about 1.5% sulfuric acid to make it slightly acidic, and make isopropyl ether about 150%
After liquid-liquid extraction by adding about 100% of water and water, the isopropyl ether layer was further washed with about 100% of water, then with about 80% of saturated saline, and about 1% of anhydrous sodium sulfate was added.
Kg and leave it for a day and night, then separate. Concentrate the isopropyl ether layer to obtain 15.8Kg.

Dissolve this in methanol 19 and sulfuric acid
Add 500 ml and reflux for 3 hours. Approximately 150 after cooling
of isopropyl ether and about 100% water were added for liquid-liquid extraction, and the isopropyl ether layer was sequentially washed with 100% water and then with 80% saturated saline,
Approximately 1 kg of anhydrous sodium sulfate was added, left overnight, and then separated. Isopropyl ether is distilled off to obtain 14 kg of esterified product. The obtained esterified product was vacuum distilled and the fatty acid methyl ester fraction was divided into 4 kg (5 to 5 kg).
1Torr, 100~160℃) and removed soybean oil unsaponifiables 5.1Kg (viscosity 15000cps, natural tocopherol 21
%, plant sterols 43%, fatty acids etc. 36%) (1×
10 ^-2 to 1×10 ^-3 Torr, 170 to 200°C).

This unsaponifiable soybean oil was put into a baguyou homomixer [manufactured by Nippon Seiki Seisakusho Co., Ltd.], and the pressure was 15 mm.
Hg, 10 under the conditions of temperature 30℃ and rotation speed 1500rpm
After stirring for a minute, the viscosity decreases to 6500 cps.

Next, 26 kg of a soft capsule shell-forming composition containing 5 parts by weight of gelatin, 2 parts by weight of glycerin, and 6 parts by weight of pure water was formed into a uniform liquid film with a thickness of 0.9 mm. Punching method continuous automatic capsule manufacturing machine equipped with capsule type Oval 5 (Leiner & Sons)
24,000 soft capsules containing about 200 mg of contents were manufactured by supplying the oily substance with reduced viscosity and the composition for forming a liquid film shell to a soft capsule (manufactured by KK). The properties of the obtained soft capsules were as follows.

Content weight 202.47mg Shell weight 140.25mg Capsule hardness (using Monsanto type hardness tester)
17.5Kg/ ^cm2 Disintegration time (Japanese Pharmacopoeia No. 1 liquid) 4 to 7 minutes If the unsaponifiable soybean oil, which is the raw material in the above, is subjected to soft encapsulation in the same way as it is, the contents will ooze out and complete capsules will be formed. No structure was obtained.

Furthermore, when seamless capsules were manufactured from the same raw materials using a double cylindrical capsule manufacturing machine (manufactured by Globex International), the hardness of the seamless capsules obtained was only 2.8 Kg/cm ² .

Example 2 Unsaponifiable soybean oil obtained according to the method of Example 1 (viscosity 17000 cps, 45% plant sterols, 20% natural tocopherols, 35% unsaturated fatty acids, etc.) 10
Kg and 1 Kg of Miglyol 812 (manufactured by Dynamit Nobel) are placed in a closed reactor equipped with a turbine-type stirring blade and the pressure is reduced to 20 mmHg. 80~
Heat to 90 °C and stir at 800 rpm for 20 minutes, then 30
Cool to 0.degree. C. and continue stirring for a further 30 minutes after reaching 30.degree. The obtained oily substance with a viscosity of 8000 cps is transferred to a double cylindrical capsule making machine (dropping method).
(manufactured by Globex International), while 20 parts by weight of gelatin, 5 parts by weight of glycerin,
- A composition for forming a soft capsule shell in the ratio of 3 parts by weight of sorbitol and 25 parts by weight of pure water is supplied to the outer cylinder so that the shell thickness is about 1.0 mm and the content is about 210 mg. seamless capsule
52,000 balls were produced. The properties of the obtained soft capsules were as follows. Note that the measurement method and measurement conditions were based on the method of Example 1.

Contents weight 210.35mg Shell weight 145.18mg Capsule hardness 19.7Kg/cm ² Disintegration time 3-7 minutes Example 3 Soybean oil unsaponifiables (viscosity 17500cps, plant sterols 44.6%, natural tocopherols 21.0%, unsaturated fatty acids, etc. 34.4%) ) 200g using ultrasonic generator UR-
Processed for 10 minutes while cooling with 200P (manufactured by Tomy Seiko) at room temperature, fluidity (viscosity 10,000 cps)
An excellent unsaponifiable product of soybean oil was obtained. This product was filled into soft capsules in the same manner as in Example 1.

Example 4 Unsaponifiable soybean oil obtained according to the method of Example 1 (viscosity 17000 cps, 45% plant sterols, 20% natural tocopherols, 35% unsaturated fatty acids, etc.)10
Kg and 4 Kg of Miglyol 812 (manufactured by Dynamit Nobel) are placed in a closed reactor equipped with a turbine type stirring blade and the pressure is reduced to 20 mmHg. 80~
Heat to 90 °C and stir at 800 rpm for 20 minutes, then 30
Cool to 0.degree. C. and continue stirring for an additional 30 minutes after reaching 30.degree. C. to obtain an oil with a viscosity of 7000 cps.

Next, 26 kg of a soft capsule shell-forming composition containing 5 parts by weight of gelatin, 2 parts by weight of glycerin, and 6 parts by weight of pure water was formed into a uniform liquid film with a thickness of 0.9 mm. Punching method continuous automatic manufacturing machine for soft capsules equipped with capsule type Oval 15 (Leiner & Sons
About 47,000 soft capsules containing about 280 mg of contents were manufactured by supplying the oily substance with reduced viscosity and the composition for forming a liquid film shell to a soft capsule (manufactured by Seiko Co., Ltd.) containing about 280 mg of contents. The properties of the obtained soft capsules were as follows.

Note that the measurement method and measurement conditions were based on the method of Example 1.

Content weight 281.78mg Shell weight 140.53mg Capsule hardness 7.1Kg/ ^cm2 Disintegration time 3-7 minutes

Claims (1)

[Claims] 1. A method for producing soft capsules of unsaponifiable vegetable oils, which comprises stirring the unsaponifiable vegetable oils under non-heating conditions until the viscosity reaches 10,000 centipoise or less, and then soft encapsulating the unsaponifiables. 2. A method for producing soft capsules of unsaponifiable vegetable oils, which comprises stirring unsaponifiable vegetable oils and medium-chain fatty acid triglycerides under non-heating conditions until the viscosity reaches 10,000 centipoise or less, and then forming the mixture into soft capsules.