JPS627190B2 - - Google Patents
Info
- Publication number
- JPS627190B2 JPS627190B2 JP24087583A JP24087583A JPS627190B2 JP S627190 B2 JPS627190 B2 JP S627190B2 JP 24087583 A JP24087583 A JP 24087583A JP 24087583 A JP24087583 A JP 24087583A JP S627190 B2 JPS627190 B2 JP S627190B2
- Authority
- JP
- Japan
- Prior art keywords
- thiamine disulfide
- acid
- higher fatty
- thiamine
- disulfide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- GFEGEDUIIYDMOX-BMJUYKDLSA-N n-[(4-amino-2-methylpyrimidin-5-yl)methyl]-n-[(z)-3-[[(z)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-hydroxypent-2-en-3-yl]disulfanyl]-5-hydroxypent-2-en-2-yl]formamide Chemical compound C=1N=C(C)N=C(N)C=1CN(C=O)C(\C)=C(CCO)/SSC(/CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N GFEGEDUIIYDMOX-BMJUYKDLSA-N 0.000 claims description 29
- 229960001385 thiamine disulfide Drugs 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 23
- 150000004665 fatty acids Chemical class 0.000 claims description 15
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 14
- 239000000194 fatty acid Substances 0.000 claims description 14
- 229930195729 fatty acid Natural products 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000013078 crystal Substances 0.000 description 11
- 238000002844 melting Methods 0.000 description 8
- JZRWCGZRTZMZEH-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 8
- 235000021355 Stearic acid Nutrition 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 7
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 7
- 235000019157 thiamine Nutrition 0.000 description 7
- 239000011721 thiamine Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 229960003495 thiamine Drugs 0.000 description 6
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- 235000019658 bitter taste Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YAQXGBBDJYBXKL-UHFFFAOYSA-N iron(2+);1,10-phenanthroline;dicyanide Chemical compound [Fe+2].N#[C-].N#[C-].C1=CN=C2C3=NC=CC=C3C=CC2=C1.C1=CN=C2C3=NC=CC=C3C=CC2=C1 YAQXGBBDJYBXKL-UHFFFAOYSA-N 0.000 description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010013911 Dysgeusia Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- RQFLGKYCYMMRMC-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O RQFLGKYCYMMRMC-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 150000003544 thiamines Chemical class 0.000 description 2
- GTQXMAIXVFLYKF-UHFFFAOYSA-N thiochrome Chemical compound CC1=NC=C2CN3C(C)=C(CCO)SC3=NC2=N1 GTQXMAIXVFLYKF-UHFFFAOYSA-N 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明はチアミンジスルフイドと高級脂肪酸か
らの新規な付加化合物及びその製造法に関する。
チアミンジスルフイドはチアミン誘導体の１つ
として、その効力が評価されているものであり、
一般にチアミン塩類に比べて安定性に優れ、広く
ビタミンB1含有製剤の製造に使用されている。
しかしチアミンジスルフイドは苦味が強く、錠剤
特に糖衣錠、フイルムコーテイング錠、カプセル
剤などの剤形で投与する場合には問題ないが、散
剤又はチユアブルな剤形、口中で溶解するような
崩壊性の優れた顆粒剤、細粒剤などの剤形で投与
することは困難である。
本発明者らは、このようなチアミンジスルフイ
ドの苦味の少ない製剤を得るため、研究を行つた
結果、チアミンジスルフイドと高級脂肪酸とが一
定組成の苦味のほとんどない付加化合物を生成す
ることを見出した。
本発明は、チアミンジスルフイドと炭素数12〜
18の高級脂肪酸とのモル比が１：６であるチアミ
ンジスルフイドと高級脂肪酸の付加化合物であ
る。
本発明に用いられる炭素数12〜18の高級脂肪酸
としては例えばオクタデカン酸（ステアリン
酸）、ペンタデカン酸、ドデカン酸（ラウリン
酸）などがあげられる。高級脂肪酸は高純度のも
のが好ましいが、オクタデカン酸等の日本薬局方
収載品では、日本薬局方の純度のものであれば、
融点にやや幅がみられても用いることができる。
チアミンジスルフイドとしては、医薬品として
の規格に適合するものを用いることが好ましい。
市販のチアミンジスルフイドは融点120〜140℃の
低融点型と呼ばれるもので、吸湿性が強く、通常
５〜６％の水分を含むものが多いが、これをその
まま用いることができる。また融点170℃以上の
高融点型を用いても、付加化合物を得ることがで
きる。
本発明の付加化合物の製造は、チアミンジスル
フイドと炭素数12〜18の高級脂肪酸とを溶媒中で
反応させることにより行われる。高級脂肪酸の使
用量は、チアミンジスルフイド１モルに対し６モ
ル程度が好ましい。
溶媒としてはチアミンジスルフイド及び高級脂
肪酸が溶解するものであればよく、例えば１・２
−ジクロルエタン、クロロホルムなどが用いられ
る。溶解温度は30〜90℃が好ましい。この溶液を
０℃ないし室温に放置すると、白色の結晶が析出
する。これを取し、溶媒で洗浄したのち乾燥す
ると、目的物質が得られる。
本発明の付加化合物は、次式で表わされる。式
中のｎは10ないし16の数である。
本発明の付加化合物は、チアミンジスルフイド
に比べて著しく苦味が減少しているので、散剤、
顆粒剤、細粒剤などの剤形でも容易に内服するこ
とができる。また高湿度下の保存では、チアミン
ジスルフイドより臨界湿度が高く、保存性にも優
れている。
実施例 １
チアミンジスルフイド11.3ｇ（0.02モル）及び
オクタデカン酸（ステアリン酸）34.2ｇ（0.12モ
ル）を１・２−ジクロルエタン1200mlに加温溶解
した。この溶液を30℃で48時間放置したのち、析
出した結晶を取し、少量の１・２−ジクロルエ
タンで洗浄したのち乾燥すると、融点80〜81℃の
チアミンジスルフイド−オクタデカン酸付加化合
物の白色結晶42.3ｇ（計算値45.5ｇに対する収量
93％）が得られた。
この結晶はろう様の感触を呈し、苦味を感じな
い。またこの結晶をエタノールに溶解し、含有さ
れるオクタデカン酸の量を水酸化カリウム・エタ
ノール液で定量し、一方、この結晶からチアミン
ジスルフイドを塩酸試液で抽出し、塩酸システイ
ンで処理したのちチオクロム法で定量したとこ
ろ、チアミンジスルフイドとオクタデカン酸の含
量比率はモル比で１：6.04であつた。
本発明のチアミンジスルフイド−オクタデカン
酸付加化合物(b)及びチアミンジスルフイド１モル
とオクタデカン酸６モルの混合物(a)の赤外吸収ス
ペクトル（臭化カリウム錠剤法）を図面に示す。
両者は波数3200cm-1及び1600〜1800cm-1付近に相
違がみられ、本発明の付加化合物が単なる混合物
でないことが知られる。
実施例 ２
チアミンジスルフイド2.8ｇ（0.005モル）及び
ベンダデカン酸7.3ｇ（0.03モル）を１・２−ジ
クロルエタン45mlに加温溶解した。この溶液を室
温で12時間放置したのち、実施例１と同様に処理
すると、融点67〜69℃のチアミンジスルフイド−
ペンタデカン酸付加化合物の白色結晶9.8ｇ（計
算値10.1ｇに対する収量97％）が得られた。
このチアミンジスルフイド−ペンタデカン酸付
加化合物の結晶も、実施例１に示したチアミンジ
スルフイド−オクタデカン酸付加化合物の結晶と
同様にろう様の感触を呈し、苦味を感じない。ま
たチアミンジスルフイド及びペンタデカン酸をそ
れぞれ定量した結果から得られた両者の全量比率
はモル比で１：6.05であつた。
実施例 ３
チアミンジスルフイド16.9ｇ（0.03モル）及び
ドデカン酸（ラウリン酸）36.1ｇ（0.18モル）を
１・２−ジクロルエタン300mlに加温溶解し、こ
の溶液を０〜５℃の低温で12時間放置したのち、
実施例１と同様に処理すると、融点53〜55℃のチ
アミンジスルフイド−ドデカン酸付加物の白色結
晶52.0ｇ（計算値530ｇに対する収量98％）が得
られた。
この結晶も、ろう様の感触を呈し、苦味を感じ
ない。またチアミンジスルフイド及びドデカン酸
をそれぞれ定量した結果から得られた両者の含量
比率はモル比で１：5.93であつた。
同様にして得られられチアミンジスルフイド−
高級脂肪酸（１：６）付加化合物の融点を第１表
に示す。また付加化合物の元素分析値を第２表に
示す。
The present invention relates to a novel addition compound from thiamine disulfide and higher fatty acids and a method for producing the same. Thiamine disulfide is one of the thiamine derivatives that has been evaluated for its efficacy.
It generally has better stability than thiamine salts and is widely used in the production of vitamin B1- containing preparations.
However, thiamine disulfide has a strong bitter taste, and while it poses no problem when administered in the form of tablets, especially sugar-coated tablets, film-coated tablets, capsules, etc. It is difficult to administer the drug in suitable dosage forms such as granules and fine granules. The present inventors conducted research in order to obtain a preparation of thiamine disulfide with little bitterness, and as a result, they found that thiamine disulfide and higher fatty acids form an adduct compound with a certain composition that has almost no bitterness. I found out. The present invention uses thiamine disulfide and carbon atoms of 12 to 12.
It is an addition compound of thiamine disulfide and higher fatty acid with a molar ratio of 1:6 to 18 higher fatty acids. Examples of higher fatty acids having 12 to 18 carbon atoms used in the present invention include octadecanoic acid (stearic acid), pentadecanoic acid, and dodecanoic acid (lauric acid). Higher fatty acids are preferably of high purity, but for products listed in the Japanese Pharmacopoeia, such as octadecanoic acid, if they are of the purity of the Japanese Pharmacopoeia,
It can be used even if the melting point varies slightly. As the thiamine disulfide, it is preferable to use one that meets the standards as a pharmaceutical product.
Commercially available thiamine disulfide is a so-called low-melting type with a melting point of 120 to 140°C, and has strong hygroscopicity and usually contains 5 to 6% water, but it can be used as is. Further, the addition compound can also be obtained by using a high melting point type having a melting point of 170°C or higher. The addition compound of the present invention is produced by reacting thiamine disulfide and a higher fatty acid having 12 to 18 carbon atoms in a solvent. The amount of higher fatty acid used is preferably about 6 moles per mole of thiamine disulfide. The solvent may be any solvent that can dissolve thiamine disulfide and higher fatty acids, for example 1.2
-Dichloroethane, chloroform, etc. are used. The melting temperature is preferably 30 to 90°C. When this solution is left at 0°C to room temperature, white crystals precipitate. When this is taken, washed with a solvent, and then dried, the target substance is obtained. The addition compound of the present invention is represented by the following formula. n in the formula is a number from 10 to 16. The addition compound of the present invention has significantly reduced bitterness compared to thiamine disulfide, so it can be used as a powder,
It can also be easily taken internally in dosage forms such as granules and fine granules. In addition, when stored under high humidity, it has a higher critical humidity than thiamine disulfide, and has excellent storage stability. Example 1 11.3 g (0.02 mol) of thiamine disulfide and 34.2 g (0.12 mol) of octadecanoic acid (stearic acid) were dissolved in 1,200 ml of 1,2-dichloroethane under heating. After this solution was left at 30°C for 48 hours, the precipitated crystals were collected, washed with a small amount of 1,2-dichloroethane, and dried. 42.3g of crystals (yield for calculated value of 45.5g)
93%) was obtained. The crystals have a waxy feel and do not taste bitter. In addition, this crystal was dissolved in ethanol, and the amount of octadecanoic acid contained was determined using a potassium hydroxide/ethanol solution. On the other hand, thiamin disulfide was extracted from this crystal with a hydrochloric acid test solution, treated with cysteine hydrochloride, and then thiochrome As determined by a method, the molar ratio of thiamine disulfide to octadecanoic acid was 1:6.04. The drawings show infrared absorption spectra (potassium bromide tablet method) of the thiamine disulfide-octadecanoic acid addition compound (b) of the present invention and the mixture (a) of 1 mole of thiamine disulfide and 6 moles of octadecanoic acid.
Differences are seen between the two in the wave number of 3200 cm -1 and in the vicinity of 1600 to 1800 cm -1 , indicating that the addition compound of the present invention is not a simple mixture. Example 2 2.8 g (0.005 mol) of thiamine disulfide and 7.3 g (0.03 mol) of bendadecanoic acid were dissolved in 45 ml of 1,2-dichloroethane under heating. This solution was allowed to stand at room temperature for 12 hours, and then treated in the same manner as in Example 1.
9.8 g (97% yield based on calculated value of 10.1 g) of white crystals of the pentadecanoic acid addition compound were obtained. Similar to the crystals of the thiamine disulfide-octadecanoic acid addition compound shown in Example 1, the crystals of the thiamine disulfide-pentadecanoic acid addition compound also have a waxy feel and do not taste bitter. Further, the total ratio of thiamine disulfide and pentadecanoic acid obtained from the results of quantitative determination of both was 1:6.05 in terms of molar ratio. Example 3 16.9 g (0.03 mol) of thiamine disulfide and 36.1 g (0.18 mol) of dodecanoic acid (lauric acid) were heated and dissolved in 300 ml of 1,2-dichloroethane, and this solution was dissolved at a low temperature of 0 to 5°C for 12 After leaving it for some time,
When treated in the same manner as in Example 1, 52.0 g of white crystals of a thiamine disulfide-dodecanoic acid adduct having a melting point of 53 to 55° C. (yield 98% based on the calculated value of 530 g) was obtained. This crystal also has a waxy feel and no bitter taste. Furthermore, the molar ratio of thiamine disulfide and dodecanoic acid was 1:5.93, as determined by the quantitative determination of both. Thiamine disulfide obtained in the same manner
Table 1 shows the melting points of the higher fatty acid (1:6) addition compounds. Table 2 also shows the elemental analysis values of the additional compounds.
【表】【table】
【表】【table】
【表】【table】
【表】
本発明の付加化合物の吸湿性を調べるため、チ
アミンジスルフイド−オクタデカン酸付加化合物
（試料１）、チアミンジスルフイド−ヘキサデカン
酸付加化合物（試料２）及び対照として市販のチ
アミンジスルフイド〔融点135〜136℃（発泡分
解）、水分5.3％〕を用い、この３種の試料を約２
ｇずつ精密に秤量し、40℃で相対湿度70％、80％
及び90％の条件下に解放のまま放置して10日間に
わたり重量の変化を調べた。その結果を第３〜５
表に示す。この結果から本発明の付加化合物は、
かなりの高湿度においても吸湿がみられず、防湿
性が優れていることが知られる。[Table] In order to investigate the hygroscopicity of the adduct compounds of the present invention, thiamine disulfide-octadecanoic acid adduct compound (sample 1), thiamine disulfide-hexadecanoic acid adduct compound (sample 2), and a commercially available thiamine disulfide adduct compound (sample 2) were used as a control. These three types of samples were heated to about 20% by
Weigh accurately in grams and store at 40℃ and relative humidity 70% and 80%.
Changes in weight were examined over a period of 10 days after being left open under conditions of 90% and 90%. The results are 3rd to 5th
Shown in the table. From this result, the addition compound of the present invention is
It is known to have excellent moisture resistance, with no moisture absorption observed even in extremely high humidity.
【表】【table】
【表】【table】
図面は本発明の付加化合物と対応する混合物の
赤外吸収スペクトルを比較して示すものであつ
て、曲線ａはチアミンジスルフイド１モルとオク
タデカン酸６モルの混合物、曲線ｂはチアミンジ
スルフイド−オクタデカン酸付加化合物の場合で
ある。
The drawing shows a comparison of infrared absorption spectra of the addition compound of the present invention and the corresponding mixture, where curve a is a mixture of 1 mole of thiamine disulfide and 6 moles of octadecanoic acid, and curve b is a mixture of thiamine disulfide and 6 moles of octadecanoic acid. - This is the case for octadecanoic acid addition compounds.
Claims (1)
脂肪酸とのモル比が１：６であるチアミンジスル
フイドと高級脂肪酸の付加化合物。 ２ チアミンジスルフイドと炭素数12〜18の高級
脂肪酸とを溶媒中で反応させることを特徴とす
る、チアミンジスルフイドと前記高級脂肪酸との
モル比が１：６であるチアミンジスルフイドと高
級脂肪酸の付加化合物の製法。[Scope of Claims] 1. An addition compound of thiamine disulfide and higher fatty acid in which the molar ratio of thiamine disulfide to higher fatty acid having 12 to 18 carbon atoms is 1:6. 2 Thiamine disulfide and a higher fatty acid having 12 to 18 carbon atoms are reacted in a solvent, and the molar ratio of thiamine disulfide and the higher fatty acid is 1:6. A method for producing addition compounds of higher fatty acids.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24087583A JPS60132964A (en) | 1983-12-22 | 1983-12-22 | Thiamine disulfide addition compound and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24087583A JPS60132964A (en) | 1983-12-22 | 1983-12-22 | Thiamine disulfide addition compound and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60132964A JPS60132964A (en) | 1985-07-16 |
| JPS627190B2 true JPS627190B2 (en) | 1987-02-16 |
Family
ID=17065991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP24087583A Granted JPS60132964A (en) | 1983-12-22 | 1983-12-22 | Thiamine disulfide addition compound and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60132964A (en) |
-
1983
- 1983-12-22 JP JP24087583A patent/JPS60132964A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60132964A (en) | 1985-07-16 |
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