JP7799313B2 - Manufacturing method of solid preparations - Google Patents

Description

The present invention relates to a method for producing a solid preparation, and more specifically to a solid preparation containing riboflavin, which has a uniform appearance and is inhibited from fading due to light.

Riboflavin, also known as vitamin B2, is a physiologically active substance classified as a water-soluble vitamin. Riboflavin is involved in maintaining the normal function of the skin and mucous membranes, so a deficiency can cause stomatitis, angular cheilitis, glossitis, seborrheic dermatitis, keratitis, etc. On the other hand, riboflavin is a water-soluble vitamin, so even if excessive amounts are ingested, the excess is excreted in the urine and does not accumulate in the body, so no tolerable upper intake level has been set. Riboflavin is used for a variety of purposes, such as for nutritional enrichment and as a food additive for coloring.

Riboflavin is an extremely fine powder consisting of yellow to orange-yellow needle-shaped crystals. It has a slight odor and bitter taste, and its aqueous solution is yellow. When riboflavin is incorporated into food products such as solid preparations like granules or tablets, the uneven color appearance caused by riboflavin can be a problem. This is due to the poor flowability caused by the fine powder-like crystals, which have a large volume and strong cohesiveness. To improve this poor flowability, methods for producing riboflavin granules or riboflavin microgranules have been proposed (Patent Document 1). However, these methods require the addition of auxiliary agents such as alkali metals, and furthermore, there is no mention of the uneven color appearance of riboflavin.

One method for improving the color unevenness of the appearance of solid dosage forms is to use riboflavin 5'-phosphate sodium, a derivative of riboflavin. Riboflavin 5'-phosphate sodium is highly soluble in water and has almost no odor, so it is commonly used in liquids such as beverages. However, riboflavin 5'-phosphate sodium is highly hygroscopic and easily decomposed by light, making its stability to light an issue when incorporated into solid dosage forms.
In order to improve stability against light, a method of adding disodium ethylenediamine (EDTA) to a riboflavin solution has been proposed (Non-Patent Document 1), but this compound is a chemically synthesized product and therefore tends to be avoided by consumers.

As mentioned above, when riboflavin is incorporated into solid preparations, uneven color appearance and stability against light become problems. Therefore, there is a need for a method for producing a solid preparation that contains riboflavin but has an even color appearance and suppresses fading of riboflavin due to light.

Japanese Patent Application Laid-Open No. 2000-290183 Development and industrial Pharmacy, 16(1), 149-156 (1990)

The objective of the present invention is to provide a method for producing a solid preparation that contains riboflavin, has a uniform color appearance, and is inhibited from fading due to light.

In light of these circumstances, the present inventors conducted extensive research and discovered that a method for producing a solid formulation containing riboflavin involves fluidized bed granulation, a granulation step in which a binding solution with a riboflavin concentration of 0.03 to 0.5% by weight is sprayed, and by setting the transmittance of the binding solution to 5% or less, it is possible to produce granules with a uniform appearance and in which fading of riboflavin due to light is suppressed, thereby completing the present invention.

The present invention also provides a method for producing granules, characterized in that the binding liquid sprayed in the granulation process contains pullulan.

The present invention also provides a method for producing tablets using granules containing riboflavin.

The manufacturing method of the solid preparation of the present invention resulted in a solid preparation containing riboflavin, with no uneven color appearance and suppressed fading of riboflavin due to light.

The riboflavin used in this invention is a physiologically active substance known as vitamin B2, and is used for a variety of purposes, including as a food additive for nutritional enrichment or coloring. Furthermore, there are no limitations on the production method, and natural extracts, microbial fermentation products, and chemically synthesized products can all be used. Examples include Riboflavin (manufactured by DSM Corporation) and Riboflavin HF100 (manufactured by BASF Japan Ltd.).

In the present invention, "fading" of riboflavin refers to the phenomenon in which a solid preparation containing riboflavin is exposed to light, causing the riboflavin in the solid preparation to decompose and the surface color to fade.

The method for producing riboflavin-containing granules of the present invention is characterized by spraying a binding liquid, which is a mixture of riboflavin and a binder in an aqueous solvent, onto a powder mixture of active ingredients, excipients, etc., to form granules. Generally, riboflavin is mixed with the powdered ingredients rather than with a binding liquid, but mixing riboflavin with the powdered ingredients can result in uneven color appearance.

In the present invention, the term "binding liquid" refers to a mixture of riboflavin and a binder in an aqueous solvent, which is sprayed onto a powder mixture during fluidized bed granulation. Examples of aqueous solvents include water, alcohols such as ethanol, and mixtures of these. Disintegrants, sugar alcohols, flavorings, preservatives, and other additives can be added to the binding liquid as long as they do not impair the characteristics of the present invention.

The riboflavin concentration in the sprayed binding solution of the present invention is 0.03 to 0.5% by weight, and preferably 0.1 to 0.5% by weight. If it is less than 0.03% by weight, sufficient coloring as a coloring agent will not be obtained, and if it exceeds 0.5% by weight, the riboflavin will not be sufficiently dispersed, which may result in uneven color appearance.

The transmittance of the binding solution containing riboflavin of the present invention at a wavelength of 655 nm is 5% or less, preferably 2% or less. If the transmittance exceeds 5%, the riboflavin will fade due to light.

Binders used in the present invention are not particularly limited, but examples include pullulan, carrageenan, guar gum, sodium carboxymethylcellulose, xanthan gum, etc. Among these, pullulan is preferred in terms of stability over time. These binders can be used alone or in combination of two or more.

Pullulan is dissolved in water and sprayed to form granules. There are no particular restrictions on the pullulan concentration in the sprayed binding solution, but it is preferably 0.5 to 10% by weight, and particularly preferably 1 to 10% by weight.

The solid formulation of the present invention may contain any ingredients used in conventional solid formulations in addition to the ingredients listed above, provided that the intended effect is not impaired. Examples include, but are not limited to, active ingredients, excipients, binders, disintegrants, lubricants, colorants, flavorings, and coating agents.

The present invention will now be described in more detail using examples. However, the present invention is not limited to these examples. Contents are in weight percent.

Example 1
An aqueous solution of pullulan was prepared, and riboflavin was added. 50 g of this solution was used as a binding solution, and 500 g of maltitol was spray-granulated using a fluidized bed granulation coating device FLO-1 (manufactured by Okawara Manufacturing Co., Ltd.). The resulting granules were dried at an inlet air temperature of 80°C and then sieved through a 30 mesh sieve. 98 g of the resulting granules were mixed with 2 g of calcium stearate (lubricant), and then tableted to obtain the riboflavin-containing tablets of Example 1.

(Examples 2 to 6, Comparative Example 2)
Riboflavin-containing tablets were obtained in the same manner as in Example 1.

(Comparative Example 1)
An aqueous solution of pullulan was prepared, and riboflavin was added. 150 g of this solution was used as a binding liquid, and 500 g of maltitol was spray-granulated using a fluidized bed granulation coating device FLO-1 (manufactured by Okawara Manufacturing Co., Ltd.). The resulting granules were dried at an inlet air temperature of 80°C and then sieved through a 30 mesh sieve. 98 g of the resulting granules were mixed with 2 g of calcium stearate (lubricant), and then tableted to obtain riboflavin-containing tablets of Comparative Example 1.

(Comparative Example 3)
An aqueous solution of pullulan was prepared, and riboflavin 5'-phosphate sodium was added. 50 g of this solution was used as a binding solution, and 500 g of maltitol was spray-granulated using a fluidized bed granulation coating device FLO-1 (manufactured by Okawara Manufacturing Co., Ltd.). The resulting granules were dried at an inlet air temperature of 80°C and then sieved through a 30 mesh sieve. 98 g of the resulting granules were mixed with 2 g of calcium stearate (lubricant) and then tableted to obtain riboflavin-containing tablets of Comparative Example 3.

(Comparative Example 4)
An aqueous solution of pullulan was prepared, and 50 g of this solution was used as a binding solution to spray-granulate 500 g of maltitol and 0.1 g of riboflavin using a fluidized bed granulation coating device FLO-1 (manufactured by Okawara Manufacturing Co., Ltd.). The resulting granules were dried at an inlet air temperature of 80°C and then sieved through a 30 mesh sieve. 98 g of the resulting granules were mixed with 2 g of calcium stearate (lubricant) and then tableted to obtain riboflavin-containing tablets of Comparative Example 4.

The tablets obtained in Examples 1 to 6 and Comparative Examples 1 to 4 were evaluated for two items: (1) color unevenness in appearance, and (2) stability against light, as follows.

(1) Color Unevenness in Appearance The appearance of 20 tablets was observed and evaluated according to the following evaluation criteria.
(Evaluation criteria)
○: The number of tablets with uneven color appearance is 0. △: The number of tablets with uneven color appearance is 1 or 2. ×: The number of tablets with uneven color appearance is 3 or more.

(2) Stability against Light The tablets were continuously irradiated with 1,300 Lux fluorescent light for 2 minutes. The color tone before and after the irradiation was measured using a color difference meter, Spectrophotometer SE7700 (manufactured by Nippon Denshoku Industries Co., Ltd.), and the degree of change in color tone (ΔE value) was calculated (n=3) and evaluated according to the following evaluation criteria.
Good: ΔE value is less than 3 (no fading is observed)
△: ΔE value is 3 or more and less than 5 (slight fading)
×: ΔE value is 5 or more (obvious fading)

In Table 1 above, the riboflavin-containing tablets prepared by the method of the present invention in Examples 1 to 6 had a consistent color appearance and suppressed fading of riboflavin due to light.

In Table 2 above, when the transmittance exceeded 5% (Comparative Example 1), riboflavin faded due to light. When the riboflavin concentration in the binding liquid to be sprayed was higher than 0.5% by weight (Comparative Example 2), color unevenness occurred in the appearance. When riboflavin 5'-phosphate sodium ester was used (Comparative Example 3), riboflavin clearly faded due to light. When riboflavin was mixed with the powder components rather than being mixed with the binding liquid to be sprayed (Comparative Example 4), color unevenness occurred in the appearance.

Example 7
(Ingredients) (Weight%)
1. Reduced palatinose 83.85
2. Citric acid 1.4
3. Rice germ extract 0.1
4. GABA-containing lactic acid bacteria fermented extract 1.1
5. Dextrin 10.0
6. Lemon juice powder 2.0
7. Pyridoxine hydrochloride 0.01
8. Stevia extract 0.02
9. Pullulan 1.0
10. Riboflavin 0.02
11. Fragrance 0.5
(Preparation method)
An aqueous solution was prepared by adding 5 g of component 9 to 50 g of purified water, and 0.1 g of component 10 was further added. Using this solution as a binding liquid, 492.4 g of powders of components 1 to 8 were spray-granulated using a fluidized bed granulation coating device FLO-1 (manufactured by Okawara Seisakusho Co., Ltd.). The resulting granules were dried at an inlet air temperature of 80°C and then sieved through a 30 mesh sieve. 0.5 g of component 11 was mixed with 99.5 g of the resulting granules to obtain riboflavin-containing granules.

When the granules shown in Example 7 were evaluated, they were found to have a uniform color appearance and to have inhibited fading of riboflavin due to light.

The present invention provides a method for producing a solid formulation that contains riboflavin, has a uniform appearance, and is inhibited from fading due to light.

Claims (2)

A method for producing a solid preparation containing riboflavin, which is characterized by comprising a granulation step of spraying a binder solution containing pullulan, the riboflavin concentration being 0.03 to 0.5% by weight, which is produced by fluidized bed granulation, and the binder solution having a transmittance of 5% or less. A method for producing tablets using the riboflavin-containing granules according to claim 1.