JPH0154328B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to hard capsules containing a high content of tocopherol nicotinate. The present inventor previously filed Japanese Patent Application No. 54-141187
No. 4524), we filed a patent application for an invention relating to hard capsules containing a high content of tocopherol nicotinate. That is, the description in the specification attached to the request for the patent application is as follows. Regarding tocopherol nicotinate, it is desired to provide a hard capsule containing a high content of the same, and the hard capsule can be manufactured by directly filling tocopherol nicotinate into a hard capsule. However, I learned that the liquid leakage phenomenon was so severe that it could not be used as a commercial product. As a result of various studies, we found that the above problem could be solved by blending (1) tocopherol nicotinate, (2) oils and fats that are liquid at room temperature, and (3) oils and fats that are waxy at room temperature in an appropriate weight ratio. We have found a solution to this problem.
For example, they succeeded in obtaining a hard capsule containing a high content of tocopherol nicotinate, which does not exhibit any leakage phenomenon even after being left at 45°C for one month. In other words, the patent application No. 141187/1987 is a uniform liquid at 60°C, passes through the filling nozzle without difficulty during filling, and solidifies or gels uniformly at room temperature after filling, without leaking into the capsule. It is an attempt to disclose that, as a requirement for the content composition to be stored, liquid fat and waxy fat that are compatible with tocopherol nicotinate should be selected in an appropriate weight ratio. In addition, the same application states that if silicic acids are added as necessary,
It is also mentioned that the prevention of liquid leakage is further strengthened and that the addition of a nonionic surfactant promotes the disintegration and dispersion of the content composition. After that, the present inventor conducted further improvement studies and found that in order to more reliably prevent liquid leakage and improve dispersibility, it is necessary to select even more limited materials and a limited blending ratio. I learned what was desirable. Namely, (1) tocopherol nicotinate, (2) oil or fat-based substance alone with a melting point of 40°C or higher, and (3) silicic acids.
(4) When the four hydrophilic nonionic surfactants are blended in an appropriate weight ratio, the liquid leakage phenomenon can be even more reliably prevented. For example, the liquid leakage phenomenon can be prevented even after being left at 45℃ for two months. The present invention has been completed based on the discovery that hard capsules containing a high content of tocopherol nicotinate can be obtained without causing a large amount of tocopherol nicotinate and having good dispersion. The present invention is characterized in that a hard capsule containing a high content of tocopherol nicotinate is obtained, and the high content is, for example, 150 to
200mg, or 200-250mg for No. 2 capsules
This means that it contains tocopherol nicotinate. Therefore, if 1 part by weight of this high content of tocopherol nicotinate is used, oils and fats or oil-based substances alone with a melting point of 47°C or higher are
Small amounts of 0.1 to 1 part by weight, 0.025 to 0.3 parts by weight for silicic acids, and 0.025 to 0.5 parts by weight for hydrophilic nonionic surfactants are sufficient. That is, when the content composition of the above weight ratio is filled into a No. 3 capsule or a No. 2 capsule, the content of tocopherol nicotinate per capsule is 150 to 200 mg and 200 to 200 mg, respectively.
It has a high content of 250mg. Specifically, the fats and oils according to the present invention include beeswax, carnauba wax, beef tallow, and hydrogenated oils, all of which have a melting point of 40°C or higher. Further, in the present invention, a substance that is not an oil or fat but has oil-like properties, that is, an oil-based substance can be used in place of the oil or fat. Higher fatty acids, higher fatty alcohols, and lipophilic surfactants are substances that belong to the concept of oily substances, specifically stearic acid,
myristic acid, valmitic acid, stearyl alcohol, cetyl alcohol, sorbitan monostearate, sorbitan sesquistearate, sorbitan tristearate, glyceryl monostearate, acetylated glyceryl monostearate,
Propylene glycol monostearate, etc., all of which have melting points of 40°C or higher.
In the present invention, these fats and oils or oil-based substances may be used alone or in combination. The essential requirement is that the melting point of the individual substance be 40°C or higher. The silicic acids according to the present invention include Japanese Pharmacopoeia light anhydrous silicic acid, synthetic aluminum silicate, bentonite, Aerosil 200, Carplex, Thyroid 244 (manufactured by Fuji Davidion Co., Ltd.), and the like. When silicic acids are added to the fat or oil-based substance according to the present invention, the liquid leakage phenomenon is reliably prevented and the effects of the present invention are achieved. However, since the composition obtained here is extremely oily, it does not mix with the water in the gastrointestinal tract, and the composition itself has poor dispersion, impairing the absorption of tocopherol nicotinate. In order to improve this defect, it is necessary to incorporate a hydrophilic nonionic surfactant into the content composition according to the present invention. Since the hydrophilic nonionic surfactant added here only needs to be added in a small amount, it will not significantly affect the melting point of the entire composition, but it is preferable that the melting point is 40°C or higher. . Therefore, specifically, JP Polyoxyl 40 stearate, which is a polyoxyethylene fatty acid ester, and Nikkor HCO-, which is a polyoxyethylene castor oil derivative.
60, Pluronic F-68, a polypropylene glycol/polyethylene glycol polymer, is used. The blending weight ratio of each component in the content composition according to the present invention has an optimum range, and the amount of the oil or oil-based substance alone is 0.1 to 1 part by weight per 1 part by weight of tocopherol nicotinate, and the amount of silicic acid teeth
0.025-0.3 parts by weight, hydrophilic nonionic surfactant
0.025 to 0.5 part by weight is preferable. Next, the content composition according to the present invention is heated to 60° C. to become a liquid, and then filled into a hard capsule through a nozzle. Therefore, if air bubbles are mixed in the heating liquid, it is desirable to remove them as much as possible. In order to fill the content composition according to the present invention into hard capsules, a conventional capsule filling machine, such as a capsule filling machine manufactured by Hefliger or a capsule filling machine manufactured by Zanashi, can be used. That is, a method is adopted in which the filling device part is replaced with a filling device for liquid filling, and the content composition according to the present invention is filled through a nozzle while being heated and stirred in a tank. The heating temperature is 50 to 70°C, preferably 60°C. Next, it will be explained with the following effect examples that the hard capsule of the present invention has excellent safety with respect to liquid leakage phenomenon and exhibits good dispersibility. Effect Example 1 Sample Content: 8 types, No. 1 to No. 8, whose weight ratios of (1) tocopherol nicotinate (2) fats and oils or oil-based substances (3) silicas are as shown in the table below. The sample was a hard capsule. Each composition contains 0.025 parts by weight of JP Polyoxyl Stearate 40 per 1 part by weight of tocopherol nicotinate.

[Table] In the table, ODO is octyldecyl triglyceride (manufactured by Nisshin Oil Co., Ltd.), cacao butter is Japan Pharmacopoeia cacao butter (melting point 31-35°C), and Mybaset 5-07T is acetylated monoglyceride SS- manufactured by Eastman Co., Ltd.
10 is Nitsuko-Nitsuko (melting point 41-46℃), Sorbitan fatty acid ester manufactured by Chemicals (melting point 56-60℃)
℃), Nitsukor A-1070 is an acetylated monoglyceride manufactured by Nitsuko Chemicals (melting point 51-56℃),
NITSUKOL MGS-F means fatty acid monoglyceride (melting point 58 to 62°C) manufactured by NITSKO CHEMICALS. Test method: Place 10 sample capsules in a plastic container.
The capsules were stored at room temperature (25°C) and heated (45°C) for two months, and the number of capsules that adhered to the bottom of the container due to liquid leakage was determined. Test results The test results are shown in Table 1. As is clear from the comparison between samples No. 3 and No. 7 in Table 1, in order to improve the stability during storage at 45°C for 2 months, it is necessary to include the content composition according to the present invention, which is represented by Aerosil. 3) It turns out that silicic acids need to be added. Furthermore, regarding the relationship between the melting point of fats and oils or oil-based substances and their stability during storage at 45°C for two months, a significant difference in effect is observed at the melting point of 40°C. In other words, if fats or oil-based substances with a melting point of 40°C or lower are added, liquid leakage will occur; conversely, if oils or fat-based substances with a melting point of 40°C or higher are added, liquid leakage will occur. No leakage phenomenon is observed.

[Table] Effect example 2 Sample No. 1 to No. 5 filled with a composition consisting of the components listed in the table below, whose component weight ratios are respectively indicated by the numerical values in the table. A hard capsule was used as a sample.

[Table] Nikkor MGS-F and Nikkor A in the table
-1070 is the same as that described in the section of Effect Example 1 Sample. Ryoto Sugar Ester P-1570
Sucrose fatty acid ester manufactured by Ryoto Co., Ltd. (monoester content approximately 70%), and polyoxyl stearate 40
respectively mean JP Polyoxyl Stearate 40. Test method 1 The test method regarding liquid leakage phenomenon is the same as the method described in the section of Effect example 1 test method. 2. Regarding dispersibility, 6 capsules of each sample were taken immediately after manufacture, and a disintegration test was conducted using water as the test liquid according to the disintegration test method described in the Japanese Bureau, and the state of dispersion in the test liquid was observed after 20 minutes. Test results The test results are shown in Table 2.

[Table] The dispersibility was expressed in the following three levels. 1. The test solution is not cloudy...- 2. The test solution is slightly cloudy...+ 3. The test solution is noticeably cloudy...++ Table 2 shows that the content composition according to the present invention is stable with respect to the liquid leakage phenomenon. Furthermore, it has been found that it is necessary to add a hydrophilic nonionic surfactant to improve the dispersibility of the composition. Next, the present invention will be explained in more detail with reference to Examples. Example 1 Tocopherol nicotinate 1.0Kg, acetylated glyceryl monostearate (Nitsukol A-
1070) 500g was heated and melted at 80°C and mixed with stirring.
In addition, 100g of sucrose fatty acid ester (Ryotosugar ester P-1570), Aerosil 200 75
g was gradually added and stirred to make the mixture uniform throughout, and the mixture was depressurized and degassed. While keeping this prepared liquid at 70℃, fill it with a capsule filling machine GKF330-L manufactured by Heffliger.
Using this, 335 mg per capsule was filled into No. 2 capsules, and the mixture was allowed to cool at room temperature. The resulting capsules contain tocopherol nicotinate per capsule.
Contains 200mg. Example 2 1.0 kg of tocopherol nicotinate and 200 g of fatty acid monoglyceride (Nitsukor MGS-F) were heated at 80°C.
The mixture was heated to melt and mixed by stirring. Furthermore, sucrose fatty acid ester (lyotosugar ester P-
1570) and 100 g of Aerosil 200 were gradually added and stirred to make the mixture uniform throughout, and the mixture was depressurized and degassed. This prepared liquid was filled into No. 2 capsules at a rate of 320 mg per capsule using a capsule filling machine GKF330-L manufactured by Hoefliger while keeping the temperature at 70° C., and allowed to cool at room temperature. Each capsule contains 200 mg of tocopherol nicotinate.

Claims (1)

[Scope of Claims] 1. In a hard capsule containing a high content of tocopherol nicotinate, in the content composition of the hard capsule, based on 1 part by weight of tocopherol nicotinate, fats and oils, higher fatty acids, higher fatty alcohols, 0.1 to 1 part by weight of lipophilic surfactants with a melting point of 40°C or higher, 0.025 to 0.3 parts by weight of silicic acids, and 0.025 to 0.5 parts of hydrophilic nonionic surfactants. A hard capsule containing a high content of tocopherol nicotinate, characterized in that it contains part by weight. 2. The hard capsule containing a high content of tocopherol nicotinate according to claim 1, wherein the oil or fat is beeswax, carnauba wax, or hydrogenated oil. 3 Higher fatty acids include stearic acid, myristic acid,
The hard capsule containing a high content of tocopherol nicotinate according to claim 1 or 2, which is palmitic acid. 4 Claim 1 in which the higher fatty alcohol is stearyl alcohol or cetyl alcohol
The hard capsule containing a high content of tocopherol nicotinate according to item 1, 2 or 3. 5. Claim 1, wherein the lipophilic surfactant is sorbitan monostearate, sorbitan sesquistearate, sorbitan tristearate, glyceryl monostearate, acetylated glyceryl monostearate, propylene glycol monostearate, The hard capsule containing a high content of tocopherol nicotinate according to item 2, 3, or 4.