Solid Dosage Forms
By incorporating metal silicate salts and magnesium compounds into the formulation, the stability of bisbentiamine, thiamine disulfide, and bisibutiamine in solid dosage forms is enhanced, addressing the issue of lower long-term stability.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- FUJI YAKUHIN CO LTD
- Filing Date
- 2025-12-12
- Publication Date
- 2026-06-25
AI Technical Summary
Bisbentiamine, thiamine disulfide, and bisibutiamine exhibit lower long-term storage stability in solid dosage forms compared to other vitamin B1 derivatives, necessitating a means to stabilize these compounds.
Incorporating metal silicate salts and magnesium compounds into the solid formulation to prevent the decomposition of bisbentiamine, thiamine disulfide, or bisibutiamine.
The addition of metal silicate salts and magnesium compounds stabilizes bisbentiamine, thiamine disulfide, or bisibutiamine, ensuring long-term stability in solid preparations.
Smart Images
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Abstract
Description
Technical Field
[0005] , , ,
[0001] The present invention relates to a solid preparation containing bisbentiamine, thiamine disulfide or bisibutiamine.
Background Art
[0002] Bisbentiamine is a derivative of vitamin B1, a derivative that makes water-soluble vitamin B1 poorly soluble in water and improves absorption from the digestive tract by benzoylation. Thiamine disulfide, bisbentiamine and bisibutiamine have the action as vitamin B1 and are widely used as the main active ingredients of vitamin-containing preparations having efficacy and effects such as a preventive effect on beriberi, a fatigue recovery effect, normalization of nerve function, etc. Note that vitamin-containing preparations include antipyretic analgesics, cold medicines, etc., and have analgesic effects for headache, toothache, pain after tooth extraction, sore throat (throat pain), earache, arthralgia, neuralgia, low back pain, muscle pain, shoulder stiffness pain, contusion pain, fracture pain, sprain pain, menstrual pain / traumatic pain, antipyretic effects for chills (cold feeling due to fever) / fever, and effects such as alleviation of various symptoms of cold (runny nose, nasal congestion, sneezing, throat pain, cough, phlegm, chills (cold feeling due to fever), fever, headache, joint pain, muscle pain) are expected (Non-Patent Documents 1, 2).
[0003] These vitamin-containing preparations are usually widely used in the form of solid preparations, particularly tablets, granules, etc., and long-term storage stability has not been a problem.
Prior Art Documents
Non-Patent Documents
[0004]
Non-Patent Document 1
Non-Patent Document 2
Summary of the Invention
Problems to be Solved by the Invention
[0005] However, when the long-term stability of various solid dosage forms containing vitamin B1 derivatives was examined, it was found that bisbentiamine, thiamine disulfide, and bisibthiamine had lower long-term storage stability compared to other vitamin B1 or its derivatives. Therefore, the object of the present invention is to provide a means for stabilizing solid dosage forms containing bisbentiamine, thiamine disulfide, or bisibthiamine. [Means for solving the problem]
[0006] Therefore, the inventors explored various components in a solid formulation containing bisbentiamine, thiamine disulfide, or bis-ibutiamine to find components that stabilize bisbentiamine, thiamine disulfide, or bis-ibutiamine. As a result, they discovered that by incorporating one or more basic compounds selected from metal silicate salts and magnesium compounds into the solid formulation, the decomposition of bisbentiamine, thiamine disulfide, or bis-ibutiamine can be prevented, thus completing the present invention.
[0007] In other words, the present invention provides the following [1] to
[12] . [1] A solid preparation containing (A) bisbentiamine, thiamine disulfide, or bisibthiamine, and (B) one or more basic compounds selected from metal silicate salts and magnesium compounds. [2] The solid preparation according to [1], wherein the metal silicate salt is one or more selected from calcium silicate, magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium aluminometasilicate, and synthetic aluminum silicate. [3] A solid preparation according to [1] or [2], wherein the magnesium compound is one or more selected from magnesium oxide, magnesium hydroxide, alumina magnesium hydroxide, a coprecipitation product of magnesium hydroxide and aluminum potassium sulfate, a mixed dried gel of aluminum hydroxide and magnesium carbonate, a coprecipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, and magnesium carbonate. [4] A solid preparation according to any one of [1] to [3], wherein component (B) is one or more selected from calcium silicate and magnesium oxide. [5] A solid preparation according to any one of [1] to [4], containing 0.3 parts by mass or more and 10 parts by mass or less of component (B) per 1 part by mass of component (A). [6] A solid preparation according to any one of [1] to [5], containing 1 part by mass or more and 10 parts by mass of calcium silicate per 1 part by mass of component (A). [7] A solid preparation according to any one of [1] to [6], containing 0.3 parts by mass or more and 1 part by mass or less of magnesium oxide per 1 part by mass of component (A). [8] A solid preparation according to any one of the following [1] to [7], further comprising one or more selected from the group consisting of acetaminophen, caffeine, and licorice extract. [9](B) A stabilizer for bisbentiamine, thiamine disulfide, or bisibthiamine, comprising one or more basic compounds selected from metal silicate salts and magnesium compounds as active ingredients.
[10] The stabilizer according to [9], wherein component (B) is one or more selected from calcium silicate and magnesium oxide.
[11] A method for stabilizing bisbentiamine, thiamine disulfide, or bisibthiamine in a solid preparation, characterized by containing (B) one or more basic compounds selected from metal silicate salts and magnesium compounds in the solid preparation containing bisbentiamine, thiamine disulfide, or bisibthiamine.
[12] The stabilization method according to
[11] , wherein component (B) is one or more selected from calcium silicate and magnesium oxide. [Effects of the Invention]
[0008] According to the present invention, a bisbentiamine-containing solid preparation containing bisbentiamine, thiamine disulfide, or bisibthiamine stably for a long period of time can be obtained. [Modes for carrying out the invention]
[0009] Terms used herein shall be used in the sense commonly used in the art unless otherwise specified.
[0010] One embodiment of the present invention is a solid preparation containing (A) bisbentiamine, thiamine disulfide, or bisibthiamine, and (B) one or more basic compounds selected from metal silicate salts and magnesium compounds. The component (A) contained in the solid formulation of the present invention is bisbentiamine, thiamine disulfide, or bis-ibutiamine. As described above, bisbentiamine, thiamine disulfide, and bis-ibutiamine are vitamin B1 derivatives and are active ingredients of the solid formulation of the present invention. Therefore, the solid formulation of the present invention is a vitamin-containing formulation, and more preferably a vitamin B1-containing formulation. The content of bisbentiamine, thiamine disulfide, or bisibthiamine in the solid formulation of the present invention is preferably 0.04% by mass or more and 4.4% by mass or less, more preferably 0.4% by mass or more and 2.2% by mass or less, and even more preferably 0.6% by mass or more and 1.6% by mass or less. Furthermore, the content of bisbentiamine, thiamine disulfide, or bisibthiamine is preferably such that the daily dose for adults is 1 mg to 100 mg, and is preferably 1 mg to 25 mg.
[0011] Component (B) contained in the solid dosage form of the present invention is one or more basic compounds selected from metal silicate salts and magnesium compounds. In the solid dosage form of the present invention, component (B) functions as a stabilizer for bisbentiamine, thiamine disulfide, or bisibthiamine. The metal silicate salt is preferably one or more selected from calcium silicate, magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium aluminometasilicate, and synthetic aluminum silicate. From the viewpoint of stabilizing bisbentiamine, thiamine disulfide, or bis-ibuthiamine, one or more selected from calcium silicate and magnesium silicate are more preferable, and calcium silicate is even more preferable. Preferably, the magnesium compound is one or more selected from magnesium oxide, magnesium hydroxide, alumina magnesium hydroxide, coprecipitation product of magnesium hydroxide and aluminum potassium sulfate, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, and magnesium carbonate. More preferably, from the viewpoint of stabilizing effect of bisbentiamine, thiamine disulfide, or bisibthiamine, one or more selected from magnesium oxide and magnesium hydroxide is preferred, and magnesium oxide is even more preferred.
[0012] In the solid formulation of the present invention, from the viewpoint of stabilizing component (A), it is preferable to contain 0.3 parts by mass to 10 parts by mass of component (B) per 1 part by mass of component (A), and more preferably 0.3 parts by mass to 5 parts by mass. Furthermore, it is preferable to contain 1 part by mass to 10 parts by mass of calcium silicate per 1 part by mass of component (A), and more preferably 1 part by mass to 5 parts by mass. It is preferable to contain 0.3 parts by mass to 2 parts by mass of magnesium oxide per 1 part by mass of component (A).
[0013] Examples of solid formulations of the present invention include oral solid formulations such as tablets (including orally disintegrating tablets), lozenges, hard capsules, granules, powders, and fine granules, with tablets being more preferred. Furthermore, as described above, the solid preparations of the present invention contain bisbentiamine, thiamine disulfide, or bis-ibutiamine as active ingredients, and are preferably vitamin-containing preparations, and particularly preferably vitamin B1-containing preparations. The efficacy and effects of these vitamin-containing preparations include relief of headaches, toothaches, post-extraction pain, sore throats, earaches, joint pain, neuralgia, lower back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain, and traumatic pain; relief of chills (shivering due to fever) and fever; relief of various cold symptoms (runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills (shivering due to fever), fever, headache, joint pain, muscle pain); fatigue recovery; and normalization of nerve function. Therefore, in addition to bisbentiamine, thiamine disulfide, or bis-ibutiamine, the solid preparation of the present invention may also contain vitamin B6, vitamin B12, vitamin B2, etc. Furthermore, it may contain anti-inflammatory and analgesic drugs such as acetaminophen, aspirin, aluminum aspirin, ibuprofen, isopropylantipyrine, ethenzamide, ibuprofen, sazapyrine, salicylamide, sodium salicylate, lactylphenedine, and loxoprofen; sedatives such as allyl isopropylacetylurea, tranexamic acid, and bromovalerylurea; vitamins such as vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin C and its derivatives and their salts, hesperidin and its derivatives and their salts; licorice such as valerian, licorice powder, licorice extract, and licorice dry extract; cinnamon, and Japanese pepper. The solid preparation of the present invention may contain crude drugs such as peony, ginger, zheng lily, citrus peel, and peony peel, glycine, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitate, aluminum hydroxide / magnesium carbonate mixed dried gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitate, magnesium hydroxide / potassium aluminum sulfate coprecipitate product, magnesium carbonate, antacids such as magnesium aluminometasilicate, sodium benzoate caffeine, caffeine, and anhydrous caffeine. The solid preparation of the present invention preferably contains one or more selected from the group consisting of acetaminophen, ethenzamide, allyl isopropylacetylurea, licorice dry extract, and caffeine, and more preferably contains one or more selected from the group consisting of acetaminophen, caffeine, and licorice dry extract.
[0014] The solid preparations of the present invention may contain various formulation additives, such as excipients, binders, disintegrants, lubricants, and the like. Examples of excipients include lactose, starches, crystalline cellulose, sucrose, mannitol, and the like. Examples of binders include hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, pregelatinized starch, polyvinylpyrrolidone, pullulan, and the like. Examples of disintegrants include carmellose, carmellose calcium, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, and the like. Examples of lubricants include sucrose fatty acid esters, hydrogenated oils, stearic acid, magnesium stearate, talc, and the like.
[0015] As shown in the following examples, if a silicate or a magnesium compound is added to a solid preparation containing bisbentiamine, thiamine disulfide or bisibuthiamine, the decomposition of bisbentiamine, thiamine disulfide or bisibuthiamine during long-term storage is prevented, and bisbentiamine, thiamine disulfide or bisibuthiamine is stabilized. Therefore, another aspect of the present invention is a stabilizer for bisbentiamine, thiamine disulfide or bisibuthiamine, which contains at least one basic compound selected from metal silicate salts and magnesium compounds as an active ingredient. Another aspect of the present invention is a method for stabilizing bisbentiamine, thiamine disulfide or bisibuthiamine in a solid preparation, which is characterized by containing (B) at least one basic compound selected from metal silicate salts and magnesium compounds in the solid preparation containing bisbentiamine, thiamine disulfide or bisibuthiamine. Here, as the stabilizer for bisbentiamine, thiamine disulfide or bisibuthiamine, it is particularly preferable that it is at least one selected from calcium silicate and magnesium oxide.
Examples
[0016] Hereinafter, the present invention will be specifically described by way of examples. However, the scope of the present invention is not limited by the following examples.
[0017] Example 1 After mixing the components described in Table 1 below, they were filled into brown test tubes and stored at 50 °C / 75% relative humidity under open conditions for 0, 8, 15, 20, 30, 44, and 61 days. After storage, the residual rate of bisbentiamine was measured by HPLC. The results are shown in Table 2.
[0018] [Table 1]
[0019] From the results in Table 2, by comparing the residual rates of bisbentiamine in Example 1-1 and Example 1-2, it was found that in Example 1-2 containing calcium silicate and magnesium oxide, the stability of bisbentiamine was improved.
[0020] [Table 2]
[0021] Example 2 After mixing the components described in Table 3 below, they were filled into brown test tubes and stored at 50 °C / 75% relative humidity under open conditions for 0, 2, 5, 8, 12, 15, and 20 days. After storage, the residual rate of bisbentiamine was measured by HPLC. The results are shown in Table 4.
[0022] [Table 3]
[0023] From the results in Table 4, by comparing the residual rates of bisbentiamine in Example 2-1 and Example 2-2, it was found that in Example 2-2 containing calcium silicate and magnesium oxide, the stability of bisbentiamine was improved.
[0024] [Table 4]
[0025] Example 3 The components listed in Table 5 were mixed, packed into brown test tubes, and stored for 15 days under open conditions at 50°C / 75% relative humidity. After storage, the remaining bisbentiamine content was measured by HPLC. The results are shown in Table 6.
[0026] [Table 5]
[0027] The results in Table 6 show that, comparing the remaining bisbentiamine content in Example 3-1 with that in Examples 3-2 through 3-8, the inclusion of calcium silicate improved the stability of bisbentiamine.
[0028] [Table 6]
[0029] Example 4 The components listed in Table 7 were mixed, packed into brown test tubes, and stored for 15 days under open conditions at 50°C / 75% relative humidity. After storage, the remaining bisbentiamine content was measured by HPLC. The results are shown in Table 8.
[0030] [Table 7]
[0031] The results in Table 8 show that, comparing the remaining bisbentiamine content in Example 4-1 with that in Examples 4-2 through 4-5, the inclusion of magnesium oxide improved the stability of bisbentiamine.
[0032] [Table 8]
[0033] Test Example 1 The components listed in Table 9 were mixed, packed into brown test tubes, and stored for 30 days under open conditions at 50°C / 75% relative humidity. After storage, the remaining bisbentiamine content was measured by HPLC. The results are shown in Table 10.
[0034] [Table 9]
[0035] As shown in Table 10, Test Example 1-8 showed higher stability compared to Test Example 1-1 in terms of bisbentiamine retention. This result indicates that acetaminophen, anhydrous caffeine, and licorice extract destabilized bisbentiamine.
[0036] [Table 10]
[0037] Example 5 The components listed in Table 11 were mixed, packed into brown test tubes, and stored for 0, 8, 15, and 32 days under open conditions at 50°C / 75% relative humidity. After storage, the remaining percentages of thiamine disulfide and bis-ibthiamine were measured by HPLC. The results are shown in Table 12.
[0038] [Table 11]
[0039] [Table 12]
[0040] From the results in Table 12, comparing the residual rates of thiamine disulfide or bis-ibutiamine in Example 5-1 or Example 5-3, it was found that the addition of calcium silicate and magnesium oxide improved the stability of thiamine disulfide or bis-ibutiamine. [Industrial applicability]
[0041] The present invention is useful for stabilizing solid dosage forms containing bisbentiamine, thiamine disulfide, or bisibthiamine.
Claims
1. A solid preparation containing (A) bisbentiamine, thiamine disulfide, or bisibthiamine, and (B) one or more basic compounds selected from metal silicate salts and magnesium compounds.
2. The solid preparation according to claim 1, wherein the metal silicate salt is one or more selected from calcium silicate, magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium aluminometasilicate, and synthetic aluminum silicate.
3. The solid preparation according to claim 1 or 2, wherein the magnesium compound is one or more selected from magnesium oxide, magnesium hydroxide, alumina magnesium hydroxide, a coprecipitation product of magnesium hydroxide and aluminum potassium sulfate, a mixed dried gel of aluminum hydroxide and magnesium carbonate, a coprecipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, and magnesium carbonate.
4. The solid preparation according to claim 1 or 2, wherein component (B) is one or more selected from calcium silicate and magnesium oxide.
5. A solid preparation according to claim 1 or 2, containing 0.3 parts by mass or more and 10 parts by mass or less of component (B) per 1 part by mass of component (A).
6. The solid preparation according to claim 1 or 2, containing 1 to 10 parts by mass of calcium silicate per 1 part by mass of component (A).
7. The solid preparation according to claim 1 or 2, wherein it contains 0.3 parts by mass or more and 1 part by mass of magnesium oxide per 1 part by mass of component (A).
8. Furthermore, the solid preparation according to claim 1 or 2 contains one or more selected from the group consisting of acetaminophen, caffeine, and licorice extract.
9. (B) A stabilizer for bisbentiamine, thiamine disulfide, or bisibthiamine, comprising one or more basic compounds selected from metal silicate salts and magnesium compounds as active ingredients.
10. The stabilizer according to claim 9, wherein component (B) is one or more selected from calcium silicate and magnesium oxide.
11. A method for stabilizing bisbentiamine, thiamine disulfide, or bisibthiamine in a solid preparation, characterized by containing (B) one or more basic compounds selected from metal silicate salts and magnesium compounds in the solid preparation containing bisbentiamine, thiamine disulfide, or bisibthiamine.
12. The stabilization method according to claim 11, wherein component (B) is one or more selected from calcium silicate and magnesium oxide.