Manufacturing method of solid preparations

Abstract

To provide a method for producing a solid preparation that contains riboflavin, has its appearance free of color irregularity, and renders riboflavin less prone to color fading due to light.SOLUTION: Provided is a method for producing a solid preparation that contains riboflavin. The method includes a granulation step for spraying a binding liquid with a riboflavin concentration of 0.03-0.5 wt.% in fluidized bed granulation. Furthermore, the binding liquid has its transmittance controlled under 5%. This structure can provide a method for producing granules with their appearance free of color irregularity and with riboflavin less prone to color fading due to light.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a solid preparation, and more particularly to a solid preparation containing riboflavin, having an even appearance and suppressing fading of the riboflavin due to light. [Background technology]

[0002] Riboflavin, also known as vitamin B2, is a physiologically active substance classified as a water-soluble vitamin. Riboflavin is involved in maintaining normal skin and mucous membrane function, and a deficiency can cause stomatitis, angular cheilitis, glossitis, seborrheic dermatitis, keratitis, etc. However, as a water-soluble vitamin, even if ingested in excess, the excess is excreted in 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.

[0003] Riboflavin is an extremely fine powder consisting of yellow to orange-yellow needle-like crystals, has a slight odor and bitter taste, and its aqueous solution is yellow. In food, when riboflavin is incorporated into solid preparations such as granules or tablets, the uneven appearance of the 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 the 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 appearance of riboflavin.

[0004] 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 consumers tend to avoid it.

[0005] As described above, when riboflavin is incorporated into a solid preparation, uneven color appearance and stability against light become problems. Therefore, there is a demand for a method for producing a solid preparation that contains riboflavin but has no uneven color appearance and is inhibited from fading due to light. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2000-290183 [Non-Patent Document 1] Development and industrial pharmacy,16(1),149-156(1990) Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a method for producing a solid preparation which contains riboflavin, has an even appearance, and is inhibited from fading of the riboflavin due to light. [Means for solving the problem]

[0008] In view of these circumstances, the present inventors have conducted extensive research and have discovered that a method for producing a solid preparation containing riboflavin includes a granulation step in which fluidized bed granulation is performed and a binding solution having a riboflavin concentration of 0.03 to 0.5% by weight is sprayed, and further, by setting the transmittance of the binding solution to 5% or less, it is possible to produce granules that are free from color unevenness in appearance and in which fading of riboflavin due to light is suppressed, thereby completing the present invention.

[0009] The present invention also provides a method for producing granules, wherein pullulan is contained in the binding liquid sprayed in the granulation step.

[0010] The present invention also provides a method for producing tablets using riboflavin-containing granules. [Effects of the Invention]

[0011] The method for producing the solid preparation of the present invention resulted in a solid preparation containing riboflavin, with no color unevenness in appearance, and suppressed fading of riboflavin due to light. BEST MODE FOR CARRYING OUT THE INVENTION

[0012] The riboflavin used in the present invention is a physiologically active substance known as vitamin B2, and is used for a variety of purposes, such as for nutritional enrichment or as a food additive for 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 K.K.) and Riboflavin HF100 (manufactured by BASF Japan Ltd.).

[0013] The "fading" of riboflavin in the present invention refers to a phenomenon in which the riboflavin in a solid preparation containing riboflavin is decomposed and the surface color fades when the solid preparation is exposed to light.

[0014] 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 an active ingredient, excipients, etc. Generally, riboflavin is mixed with the powder components rather than with a binding liquid, but mixing riboflavin with the powder components can cause uneven color appearance.

[0015] The term "binding liquid" as used herein 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 thereof. Disintegrants, sugar alcohols, flavorings, preservatives, and the like can be added to the binding liquid as long as the characteristics of the present invention are not impaired.

[0016] The riboflavin concentration in the binder solution to be sprayed in the present invention is 0.03 to 0.5% by weight, preferably 0.1 to 0.5% by weight. If it is less than 0.03% by weight, sufficient coloring as a coloring agent cannot be obtained, and if it exceeds 0.5% by weight, the riboflavin is not dispersed sufficiently, which may result in uneven color appearance.

[0017] 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.

[0018] The binder used in the present invention is not particularly limited, but examples thereof 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.

[0019] Pullulan is dissolved in water and sprayed to form granules. The concentration of pullulan in the binder solution to be sprayed is not particularly limited, but is preferably 0.5 to 10% by weight, and particularly preferably 1 to 10% by weight.

[0020] The solid preparation of the present invention may contain any ingredients used in conventional solid preparations in addition to the above ingredients, provided that the intended effect is not impaired. Examples of ingredients include active ingredients, excipients, binders, disintegrants, lubricants, colorants, flavorings, coating agents, etc. However, the ingredients are not limited to these examples. [Example]

[0021] The present invention will now be described in more detail with reference to examples, although the present invention is not limited to these examples. The contents are in wt %.

[0022] Example 1 An aqueous solution of pullulan was prepared, and riboflavin was added. 50 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. 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.

[0023] (Examples 2 to 6, Comparative Example 2) Riboflavin-containing tablets were obtained in the same manner as in Example 1.

[0024] (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. 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.

[0025] (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 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. 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.

[0026] 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. 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.

[0027] The tablets obtained in Examples 1 to 6 and Comparative Examples 1 to 4 were evaluated for the following two items: (1) uneven color appearance, and (2) stability against light.

[0028] (1) Uneven color 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 △: One or two tablets have uneven color appearance ×: The number of tablets with uneven color appearance is 3 or more.

[0029] (2) Light stability The tablets were continuously irradiated with 1300 Lux fluorescent light for 2 minutes. The color tone before and after 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. ◯: ΔE value is less than 3 (no fading observed) △: ΔE value is 3 or more and less than 5 (slight fading) ×: ΔE value is 5 or more (obvious fading)

[0030] [Table 1]

[0031] [Table 2]

[0032] In Table 1 above, the riboflavin-containing tablets prepared by the method of the present invention in Examples 1 to 6 had an even color appearance, and fading of riboflavin due to light was suppressed.

[0033] In Table 2 above, when the transmittance exceeded 5% (Comparative Example 1), riboflavin faded due to light. When the riboflavin concentration in the binding solution 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 component rather than with the binding solution to be sprayed (Comparative Example 4), color unevenness occurred in the appearance.

[0034] 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 then 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 Manufacturing 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.

[0035] When the granules shown in Example 7 were evaluated, they were found to have an even appearance and to have inhibited fading of riboflavin due to light. [Industrial Applicability]

[0036] According to the present invention, there can be provided a method for producing a solid preparation which contains riboflavin, has an even appearance, and is inhibited from fading of riboflavin due to light.

Claims

1. 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.

2. A method for manufacturing tablets using granules containing riboflavin as described in claim 1.

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