JPS6187620A - Transparent compounded drug preparation of vitamin b2 butyric acid ester for soft capsule - Google Patents

Abstract

PURPOSE:To prepare a transparent compounded drug of vitamin B2 butyric acid ester for soft capsule, preservable extremely stably for a long period without forming precipitate, and having unparallelled high titer, by dissolving vitamin B2 butyric acid ester in free cholesterol. CONSTITUTION:The titled drug can be prepared by dissolving vitamin B2 butyric acid ester in free cholesterol. Although vitamin B2 butyric acid ester has poor solubility in oils used as a drug component, the solubility can be improved remarkably by the addition of a compound having phenolic hydroxyl group, especially free cholesterol. A soft capsule of vitamin B2 butyric acid ester having unparallelled high titer, e.g. about 30mg/cap can be prepared by this process. It has no irritation to the oral mucosa and digestive tracts, is free from crystallization even at a low temperature, and can be stored extremely stably for a long period.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a drug formulated for soft capsules containing vitamin B2 butyrate.

Specifically, the present invention relates to a compounded drug containing a high-unit vitamin B2 butyrate ester-containing soft capsule.

The content of vitamin B2 butyrate per capsule of conventionally available soft capsules containing vitamin B2 butyrate was 10 Q/cap or less. Recently, demand for soft capsules containing high units of vitamin B2 has increased, and 20% of vitamin B2 in one capsule has increased.
Products containing 119 vitamin B2 butyrate esters have also come to be used on clothing. However, since vitamin B2 butyrate originally has poor solubility in the oil to which it is blended, crystals precipitate and the soft capsule becomes opaque, significantly reducing its commercial value. Therefore, although various efforts have been made to improve the solubility of vitamin B2 butyrate, none have yet been found to be satisfactory as pharmaceuticals for soft capsules.

For example, to prevent precipitation at low temperatures, C8-c1
The use of monoglycerides or diglycerides of O fatty acids gives good results in terms of product stability, but they are extremely irritating to the oral mucosa and the gastrointestinal tract, making them unsuitable for use in long-term health and wellness medicines. Not preferred as a form.

In addition, the invention previously filed by the present inventors (Japanese Patent Application No. 5 (Sho 5) (S-
198392), r-oryzanol and vitamin B
In order to improve the solubility in these oils, it was proposed to add sorbitan fatty acid ester to composite soft capsules of 2-butyric acid ester, but when it comes to high-unit vitamin B2-butyric acid ester, satisfactory stability cannot be obtained.

As a result of various studies on excipients to be added for the purpose of preparing soft capsules containing a high unit of vitamin B2 butyrate, the present inventors found that a compound having a phenolic hydroxyl group in its structure and vitamin B2 butyrate were combined. It has been discovered that the solubility of vitamin B2 butyrate in oils is significantly improved by this method. Furthermore, among the compounds having such a phenolic hydroxyl group, it was discovered that tocopherols exhibit particularly remarkable solubility, and the present invention was achieved.

Therefore, the present invention provides a transparent compounded drug for soft capsules that is stable against precipitation of precipitates, in which vitamin B2 butyrate is dissolved in free tocopherol.

The tocopherol used in the present invention is α-1β-1γ
- and δ-tocopherol homologs may be used alone or in mixtures. Alternatively, natural tocopherols or synthetic tocopherols, which are mixtures thereof, may be used. However, an essential condition is that the phenolic OH group in tocopherol is a free tocopherol that exists in a free state. Using free tocopherol
As a result, the solubility of vitamin B2 butyrate in fats and oils is significantly improved. Although its solubility and structure are not necessarily clear, even if aromatic phenols other than tocopherol, such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA), which are used as food antioxidants, are used, vitamin B2 butyrate ester It is clear that some kind of force is working between the aromatic phenols and vitamin B2 butyrate, as the solubility in fats and oils of the aromatic phenols is considerably improved. It is thought that a weak force such as a van der Waalska force (such as a van der Waalska force) increases mutual affinity and improves solubility between the amine group present in the ring in the structure of vitamin B2 butyrate. It will be done.

By the way, the patent application filed earlier by the inventors in 1982-H'
In the invention of No. 8392, acetic acid d-α-
There is an example using tocopherol, but this product shows almost no γ6 decomposition of vitamin B2 acetic acid ester. This is because the 7-enolic hydroxyl group of d-α-tocopherol is esterified with acetic acid. It is clear from these findings that the phenolic hydroxyl group of free tocopherol greatly influences the solubility of vitamin B2 butyrate.

The amount of free tocopherol used in the present invention is not particularly limited as long as vitamin B2 butyrate does not precipitate at temperatures at which vitamin B2 butyrate-containing capsules are normally stored, for example, at temperatures of -5°C to 30°C. Therefore, there are 20 vitamin B2 butyrates in one capsule.
~30179, if more than double the amount of free tocopherol is used, the capsule contents 300
It is sufficient to make capsules of a normal size of about 40,011 g.

Therefore, in the present invention, in addition to vitamin 32 butyrate and free tocopherol, oils and fats, surfactants, other additives in accordance with the purpose of the present invention, and mixtures thereof may be used as the third component. can. However, when these are used as compounding agents, it is necessary that they do not precipitate crystals at low temperatures. In this sense, triglycerides of medium-chain fatty acids of 08 to C10 are preferable as the fats and oils. As the surfactant, nonionic surfactants such as sorbitan fatty acid esters can be used, and sorbitan sesquioleate and sorbitan trioleate are particularly preferred.

However, it is not limited to these, and can be arbitrarily selected as necessary.

According to the present invention, the medicinal liquid content of the vitamin B2 butyrate high unit soft capsule can be prepared arbitrarily, and 1
High content of vitamin B in capsules, for example around 60cm
It is possible to contain dibutyric acid ester (however, the total concentration of the drug solution in the capsule is 600 to 4 oomg/i capsule). This medicinal solution is clear and has no irritation to the eye mucous membranes or gastrointestinal tract when used. In addition, there is no significant change in solubility due to the degree of discolouration (no crystal precipitation occurs even at low temperatures), and it is extremely stable for long-term storage. The effects of the present invention are extremely significant.

The drug of the present invention can be filled into capsules by a conventional method using, for example, gelatin as a film-forming agent. At this time, about 10 to 30 grams of sorbitol may be added to the gelatin to prevent moisture from migrating into the capsule. It goes without saying that it can be done.

EXAMPLES Next, Examples will be shown to further specifically explain the present invention, but the present invention is not limited thereto.

Example 1 As shown in Table 1, natural tocophenol (hereinafter referred to as MTC)
A medicinal solution was prepared by dissolving vitamin B2 butyrate (hereinafter referred to as B2-But) by changing the type and amount of B2-But.
After this chemical solution was left at room temperature for one day, the state of precipitation of B2-But was observed. Furthermore, among these, those in which crystals had precipitated were stored under the following conditions, and their stability against temperature changes was tested.

Storage conditions ■Leave at room temperature (temperature 23℃~36.5℃, humidity 29~92%RH)■
Temperature r51-4 "c ~ 20℃, 12 hour cycle [using constant temperature/humidity chamber made by Satake Chemical Machinery Co., Ltd.] ■Leave at a constant temperature around 2℃ [Matsushita T'+L\'jr production drain (solid refrigerator) HP-261
'I'DR-G type used] The test results are as shown in Shigeru-2 to 4.

Table-1 Prescription (Sho) Reagent ■ Vitamin B2 butyrate (hereinafter referred to as B2-But): (
Tokyo Tanabe) Lot,, A DTO7 ■ Emix 80 (hereinafter referred to as MTC80): (Eisai) natural tocopherol, natural tocopherol homologue content approximately 80% or more, α
- Contains about 15% of tocopherol ■ Emix 40 (hereinafter referred to as MTC40): (Eisai) natural tocopherol, natural tocopherol homologs approximately 87% or more, α-tocopherol content approximately 45% ■ Tocopherol 1008 (hereinafter referred to as MTC100): ( Nisshin Oil) Natural tocopherol, natural tocopherol homologue content approximately 90% or more, α-tocopherol content approximately 26% ■) JTC-F1a (hereinafter referred to as MTcso): (Nippon Seika) natural tocopherol, natural tocopherol homologue 1
- About 57% or more, α-tocopherol content about 4% Lo
t, noF6. TIK-10 Table 2 Stability of chemical solution (Note) ○: No change; ×: B2-But was precipitated.

Table-6 Stability of chemical solution (Note) There was no change in O, and × indicates that B2-But was precipitated.

Table-4 Stability of chemical solution (Note) ◯ indicates no change, × indicates that B2-But was precipitated.

From the above results, the solution obtained by dissolving approximately 25% of B2-But in MTCK is highly stable against temperature changes.

Regarding the solubility of B2-But, if the added MTC contains tocopherol in an amount of 2.5 to 3 times that of B2-But in terms of weight ratio, a clear and stable oil solution can be obtained.

In addition, as a result of investigating the difference in solubility due to the content ratio of α-1β-1γ- and δ-tocopherol homologs in MTC, we found that the solubility of 82-Put is There is no correlation between traps and traps.

Example 2 A drug solution' was prepared in the proportions shown in Table-6. The preparation method is MT
C and B2-But were mixed and stirred while heating to about 80°C. When B2-Put was completely dissolved, medium chain fatty acid triglyceride (hereinafter referred to as MCT) was added, and further heated and stirred at the same temperature to dissolve it. It was made into a medicinal solution. B2-
Table 6 shows the solubility of But.

(Note) Reagent ■ Vitamin B2 butyrate ester (hereinafter referred to as B2-Put): Same as in Table 1 ■ Tokotsuyuroll 100S (hereinafter referred to as MT
C100): Same as Table 1 ■ Coconut MT (hereinafter referred to as MCT): (chemical soap) medium chain fatty acid triglyceride
Fatty acid composition Caprylic acid dicabanoic acid (approximately 80:20) Further, in Table 6, the stability against temperature changes was tested in the same manner as in Example 1 for the chemical solution without B2-But precipitation. The results are shown in Table-7.

(Note) There was no change in O, and B2-But was precipitated in X.

Example 3 A drug solution was prepared in the proportions shown in Table-8. The preparation method is MTC
(MTC100) and B2-But are mixed and stirred while heating, and when B2-But is dissolved, sorbitan sesquioleate (hereinafter referred to as 5o-15) or sorbitan trioleate (hereinafter referred to as 80-50) or both are added. Alternatively, MCT (same as shown in Table 6) was added and dissolved with stirring while heating to about 80°C to obtain a drug solution. Table showing the solubility of B2-Put for each chemical solution.
8.

In addition, 1c, 74-8 is stored at a low temperature within 0 (-4℃ to 2℃)
0° C., 12-hour cycle) Chemical solutions in which B2-Put did not precipitate after 24 hours were tested for stability against rapid temperature changes in the same manner as in Example 1. The results are shown in Table-9.

Example 4 A drug solution was prepared according to the formulation shown in Table-10. Preparation method C. Synthetic tocopherol (dl!-α-tocopherol) and B2
-But (same as Table 6) was mixed and stirred while heating to about 80°C to dissolve B2-But. Furthermore, M
When adding CT (similar to Table 6), use B2-
After dissolving But, this was added and dissolved in a heating bath to obtain a drug solution. Table 10 shows the solubility of B2-Put for each chemical solution.

Furthermore, in Table 10, the chemical solutions in which B2-But did not precipitate were stored under the same storage conditions as in Example 1 [■ Standing at room temperature, ■
Stability was tested under temperature change cycles: (1) storage at low temperature (approximately 2° C.); The results are shown in Table-11.

Table-11 Stability of chemical solution using dl-α-tocopherol (Note) ◯ indicates no change, × indicates that B2-But was precipitated.

Claims (1)

[Claims] A transparent combination drug for vitamin B_2 butyrate soft capsules, in which vitamin B_2 butyrate is dissolved in free tocopherol.