JP4573542B2 - Vitamin B1 derivative composition - Google Patents

Description

  The present invention relates to a tablet comprising a vitamin B1 derivative, acetaminophen, and a stearic acid metal salt, and more specifically, a vitamin in a temporal stability test even if it contains a vitamin B1 derivative, acetaminophen, and magnesium stearate. It is a tablet that suppresses a decrease in the residual rate of the B1 derivative.

Various ingredients are blended in cold medicines and antipyretic analgesic preparations marketed as over-the-counter drugs (OTC drugs). One component, acetaminophen, suppresses central prostaglandins and suppresses pain and fever. Other ingredients may include vitamin B1 derivatives that relieve muscle tension and convulsions and reduce pain.
When a tablet containing these components is produced, the component, excipient, binder and the like are formed into granules, then mixed with a lubricant and compressed to form tablets. A widely used lubricant is a metal stearate, particularly magnesium stearate. Patent Documents 1 and 2 describe tablets containing acetaminophen, a vitamin B1 derivative and magnesium stearate.
In the development of pharmaceutical products, in general, when examining the stability of a trial product, a temporal storage test is performed under accelerated test conditions of 40 ° C. relative humidity 75% and severe test conditions of 60 ° C. relative humidity 75%. .
JP-A-5-221857 JP 2000-169367 A

  However, the present inventors have found that when a tablet containing acetaminophen, a vitamin B1 derivative and magnesium stearate is stored over time under conditions of 40 ° C. and a relative humidity of 75%, the residual ratio of the vitamin B1 derivative decreases. It became clear by. In addition, in order to shorten the test period, it is clear that the residual ratio of the vitamin B1 derivative decreases even when stored over time at 60 ° C. and 75% relative humidity, as in the experiment at 40 ° C. and 75% relative humidity. It became. Patent Documents 1 and 2 neither disclose nor suggest a method for preventing the residual rate of the vitamin B1 derivative from decreasing or a method for preventing the residual rate from decreasing.

As a result of the detailed investigation of the stability of vitamin B1 derivative in a preparation containing acetaminophen, vitamin B1 derivative and magnesium stearate, surprisingly, acetaminophen and vitamin B1 derivative or vitamin B1 derivative and magnesium stearate It was found that the vitamin B1 derivative was stable when. Based on the above knowledge, even if it is a solid preparation containing acetaminophen, vitamin B1 derivative and magnesium stearate, 1) add amino acid salt, 2) multilayer with acetaminophen and vitamin B1 derivative as different layers It has been found that a decrease in the residual ratio of vitamin B1 derivative is suppressed by making tablets or 3) tablets with 0.1 (w / w)% or less of metal stearate as a lubricant. Completed the invention.
(1) A solid preparation comprising acetaminophen, a vitamin B1 derivative, a metal stearate and an amino acid salt.
(2) The solid preparation according to the above (1), wherein the amino acid salt is amino acid hydrochloride or amino acid sulfate.
(3) The solid preparation according to the above (1), wherein the amino acid salt is amino acid hydrochloride.
(4) The solid preparation according to the above (1), wherein the amino acid salt is 1 or 2 selected from L-glutamate hydrochloride or glycine hydrochloride.
(5) The solid preparation according to the above (1), wherein the amino acid salt is L-glutamic acid hydrochloride.
(6) A solid preparation, wherein the solid preparation according to any one of (1) to (5) is one preparation selected from tablets, granules and powders.
(7) A solid preparation, wherein the solid preparation according to any one of (1) to (5) is a tablet.
(8) A tablet comprising an acetaminophen, a vitamin B1 derivative and a stearic acid metal salt, wherein the acetaminophen and the vitamin B1 derivative are each a multi-layer tablet blended in different layers.
(9) A tablet comprising acetaminophen, a vitamin B1 derivative and a metal stearate, wherein the blending ratio of the metal stearate per tablet is 0.1% or less.
(10) The tablet according to (9) above, wherein the blending ratio of metal stearate per tablet is 0.01 to 0.1%.
(11) The vitamin B1 derivative is one or more selected from thiamine nitrate, dibenzoyl thiamine, octothiamine, thiamine disulfide, bisbutiamine, bisbenchamine, fursultiamine, benfotiamine, dicetiamine hydrochloride and thiamine hydrochloride A solid preparation or tablet according to any one of (1) to (10) above.
(12) The solid preparation or tablet according to (11) above, wherein the vitamin B1 derivative is dicetiamine hydrochloride.
(13) The solid preparation or tablet according to any one of (1) to (12) above, wherein the metal stearate is magnesium stearate.

  The present invention relates to a solid preparation containing acetaminophen, a vitamin B1 derivative and magnesium stearate, particularly a tablet, in particular 1) an amino acid salt added, and 2) a multilayer in which acetaminophen and vitamin B1 derivative are different layers. 3) Store for 6 months at 40 ° C. and 75% relative humidity by using a tablet or 3) tablet of metal stearate, which is a lubricant, at 0.1 (w / w)% or less, or 60 It has been found that even when stored for 2 weeks at a temperature of 75 ° C. and a relative humidity of 75%, a decrease in the residual ratio of the vitamin B1 derivative is suppressed.

Examples of the drug used in the tablet of the present invention include acetaminophen and vitamin B ₁ which are aniline derivatives and derivatives thereof, and salts thereof, and other drugs may be added. Other drugs include lactylphenetidine, aspirin, aspirin aluminum, etenzamide, sazapyrine, salicylamide, sodium salicylate, lactylphenetidine, isothipentyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, feterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, hydrochloric acid Tonsilamine, phenetazine hydrochloride, methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teoclate, mebhydroline naprodislate, promethazine methylenenisalicylate, maleic tricarbinoxamine maleate, dl-maleic acid d-chlorpheniramine maleate, dipheterophosphate , Allylisopropylacetylurea, bromvalerylurea, aloclamide hydrochloride, cloperastine hydrochloride, pentoxyberine citrate, tibepidin citrate, dibutate sodium, dextromethorphan hydrobromide, dextromethorfen / phenolphthalene salt, hibenzic acid Tipepidine, cloperastine fendizoate, codeine phosphate, dihydrocodeine phosphate, sodium benzoate, caffeine, anhydrous caffeine, nosicapine hydrochloride, noscapine, dl-methylephedrine hydrochloride, dl-methylephedrine saccharine hydrochloride, potassium guaiacolsulfonate, guaifenesin , sodium benzoate caffeine, vitamin B ₂ and its derivatives and their salts, vitamin C and its derivatives and their salts, hesperidin and its derivative And salts thereof, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dry aluminum hydroxide gel, aluminum hydroxide magnesium carbonate Mixed dried gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / potassium aluminum sulfate coprecipitation product, magnesium carbonate, metasilicic acid Examples include magnesium aluminate, ibuprofen, isopropylantipyrine, promethazine methylenedisalicylate, papaverine hydrochloride, phenacetin, and diflofenac sodium. Furthermore, you may mix | blend auxiliary | assistant medicines, such as a mild herbal medicine and Chinese medicine, suitably.
Examples of vitamin B1 derivatives include thiamine nitrate, dibenzoylthiamine, octothiamine, thiamine disulfide, bisibhiamine, bisbenchamine, fursultiamine, benfotiamine, dicetiamine hydrochloride and thiamine hydrochloride. In particular, the present invention is useful when using dicetiamine hydrochloride.

  In the present invention, the solid preparation means a tablet, granule or powder among the preparation general rules listed in the 14th revised Japanese Pharmacopoeia. Of these, granules and powders can be filled in capsules. In the present invention, a particularly preferable solid preparation is a tablet. In addition, although it demonstrates below about a tablet, the additive and manufacturing method well-known in the said field | area can be widely used about a granule and a powder.

In the tablet of the present invention, an excipient, a disintegrant, a binder, a lubricant and / or a stabilizer are blended as additives. A wide variety of excipients known in the art can be used as the excipient. Examples include lactose, corn starch, crystalline cellulose, D-mannitol, calcium hydrogen phosphate, reduced maltose, and erythritol. Preferred are lactose, corn starch, D-mannitol and crystalline cellulose, and more preferred are crystalline cellulose and D-mannitol.
The blending amount of the excipient is 0 to 95 (w / w)%, preferably 5 to 75 (w / w)%, more preferably 7.5 to 50 (w / w)% in one tablet. is there. If the amount is less than this, the granulation process before forming the tablet becomes difficult, and if it is more, the drug content is relatively lowered and the tablet size may be too large.

A wide variety of disintegrants known in the art can be used. For example, carmellose calcium (carboxymethylcellulose calcium), croscarmellose calcium, low-substituted hydroxypropylcellulose, carboxymethylcellulose, corn starch, hydroxypropyl starch, crystalline cellulose, carboxymethylcellulose sodium, crospovidone, and the like. Carmellose calcium and croscarmellose calcium are preferable, and carmellose calcium is more preferable.
As a compounding quantity of a disintegrating agent, it is 0-20 (w / w)% in 1 tablet, Preferably it is 1-10 (w / w)%, More preferably, it is 2-6 (w / w)%. If the blending amount is less than this, the disintegration time of the tablet when the tablet is put in water becomes extremely slow, and if it is large, there is a possibility that a tablet having sufficient hardness cannot be formed.

At the time of tablet manufacture, once the aqueous solution of the binder is added to the mixed powder containing the drug, wet granulation granules are formed by wet granulation methods (extrusion granulation method, fluidized bed granulation method, stirring granulation method, etc.). This is made into granules for tableting. As the binder for wet granulation, a wide variety of binders known in the art can be used. As the binder for wet granulation, a wide variety of binders known in the art can be used. For example, there are hydroxypropylcellulose, corn starch, pregelatinized starch, partially pregelatinized starch, dextrin, polyvinylpyrrolidone, hydroxypropylmethylcellulose, methylcellulose, gum arabic and the like. Preferred is hydroxypropylcellulose.
As a compounding quantity of a binder, it is 0.25-10 (w / w)% in 1 tablet, Preferably it is 0.5-5 (w / w)%, More preferably, it is 1-3 (w / w). %. If it is less than this blending amount, it is difficult to obtain a granulated product that has grown during wet granulation, and there are many fine powders, so fluidity is poor, and weight fluctuation during tableting tends to be large. Collapse time may be extremely slow. As the wet granulation method, a wide variety of methods well known in the art can be used.

A wide variety of lubricants known in the art can be used. For example, metal stearate, preferably magnesium stearate, calcium stearate, sodium stearyl fumarate, more preferably magnesium stearate.
As the blending amount of the lubricant, in the case of the tablet by the internal lubrication method containing the lubricant inside the tablet, 0.25 to 6 (w / w)% in one tablet, preferably 0.5 to 3 (W / w)%, more preferably 1-2 (w / w)%. If the amount is less than this amount, sticking may occur at the time of tablet formation, and if it is large, the tablet hardness may be lowered and the disintegration time of the tablet in water may be delayed.

A wide variety of stabilizers known in the art can be used. In particular, as described above, when a aging stability test is performed on a tablet in which acetaminophen, a vitamin B1 derivative, and magnesium stearate are mixed, the residual rate of the vitamin B1 derivative is reduced, so that the residual rate of the vitamin B1 derivative is reduced. Any substance that can be prevented is acceptable. For example, an amino acid salt, preferably amino acid hydrochloride or amino acid sulfate, more preferably L-glutamate hydrochloride, L-cysteine hydrochloride and glycine hydrochloride, particularly preferably L-glutamate hydrochloride.
As a compounding quantity of a stabilizer, what is necessary is just a compounding quantity that the pH of a stabilizer becomes acidic (pH 1-3). Specifically, 0.001 to 5 (w / w)% in one tablet, preferably 0.005 to 2.5 (w / w)%, more preferably 0.01 to 1.5 (w / w). w)%. In particular, in the case of L-glutamate hydrochloride, 0.05 to 5 (w / w)%, preferably 0.2 to 2.5 (w / w)%, more preferably 0.5 to 1 in one tablet. .5 (w / w)%. If the amount is less than this amount, the vitamin B1 derivative may not be stabilized, and if it is more, the pH will be increased and the decomposition of the drug may be accelerated. In addition, you may add an amino acid and an acid separately like an amino acid and hydrochloric acid.

  In designing a tablet, if the tablet is divided into multiple layers, the so-called multilayer tablet contains acetaminophen in one layer, vitamin B1 derivative in the other layer, and magnesium stearate as a lubricant. Even if it is tableted and contains no stabilizer, it is possible to suppress a decrease in the residual ratio of vitamin B1 derivative. Dividing into multiple layers means that the tablet is divided into two or more layers. Depending on the drug, a stabilizer may be added. Of course, the above-mentioned excipients, disintegrants, binders, lubricants and stabilizers can be used.

  As a method for producing tablets, a wide variety of methods well known in the art can be used. For example, 1) a direct powder compression method in which a drug and an additive to be mixed into a tablet are directly compressed; Tablet granule), dry granule compression method for tableting this granule, 3) wet granulation of drug and additives to produce granule (tablet granule), then wet granulation for tableting this granule There is a compression method. Of these, the wet granulation tableting method is preferred. Examples of the wet granulation method include an extrusion granulation method, a tumbling granulation method, a wet crushing granulation method, a stirring granulation method, and a fluidized bed granulation method, and a fluidized bed granulation method is preferable. The multilayer tablet described above can be produced in the same manner.

  As a machine for tableting, there are a single tableting machine and a rotary tableting machine, and a rotary tableting machine is preferred.

In addition, conventional tablets are prepared by mixing excipients, disintegrants, binders and / or stabilizers, once producing granules, mixing the granules and lubricant, and then compressing the tablets. Tablets were manufactured by the Lusawa method. However, as described above, when the acetaminophen, vitamin B1 derivative and magnesium stearate are mixed and the tablet produced by the internal lubrication method for producing the tablet is subjected to the stability test over time, the residual ratio of the vitamin B1 derivative Decreases. On the other hand, if the blending amount of the magnesium stearate, which is a lubricant, is reduced, the decrease in the residual ratio of the vitamin B1 derivative can be suppressed, but if the blending amount of the lubricant is decreased, a tableting failure occurs in the tablet. .
Therefore, when tablets are produced by an external lubrication method in which a small amount of lubricant can be directly attached to the surface of the pestle and mortar, tableting can be prevented and a decrease in the residual rate of vitamin B1 derivative can be suppressed. Became clear.
In tablets produced by the external lubrication method, the blending amount of the lubricant is 0.2 (w / w)% or less per tablet, preferably 0.01 to 0.15 (w / w)%, more preferably Is 0.02 to 0.1 (w / w)%. If the amount is less than this amount, sticking may occur at the time of tablet formation, and if it is large, decomposition of the vitamin B1 derivative may be accelerated.

  In the case of producing a tablet by the external lubrication method, the tablet can be produced by using a device in which an external lubrication spray device is incorporated in a general rotary tableting machine. As an external lubrication spray device, for example, there is ELS-P1-Type III sold by Kikusui Seisakusho.

  The antipyretic analgesic formulation of the present invention is effective for headache, toothache, extraction pain, menstrual pain headache and chills, and antipyretic during fever. The maximum daily dose for adults is 1500 mg for acetaminophen, 25 mg for vitamin B1 and its derivatives and their salts, and the method of administration is oral administration.

Ａｔ：試料溶液の内標準物質に対する有効成分のピーク面積比
Ａｓ：標準溶液の内標準物質に対する有効成分のピーク面積比
Ｗｓ：標準溶液を調製した時の薬物の秤取量（ｍｇ）

(1)ＨＰＬＣ条件
検出器：紫外吸光光度計（測定波長：２１０ｎｍ及び２５４ｎｍ ）
カラム：Symmetry Shield^TM RP₁₈（3.5μm）, 4.6mmφ×100mm（Waters製）
カラム温度：４５℃付近の一定温度
移動相：下記のタイムテーブルに従った０．０１Ｍジブチルアミンリン酸緩衝液 ／メタノールの混液

(2)流量：０．９ｍＬ／分
(3)保持時間：
アセトアミノフェン：約３．０分
塩酸ジセチアミン：約７．７分
内標準物質（フェナセチン）：約１１．６分
(4)含量計算

２．実験結果
経時保存後の供試した試料中の塩酸ジセチアミンの残存率を表２に示す。

以上の結果から、塩酸ジセチアミン、アセトアミノフェンおよびステアリン酸マグネシウムを混合した場合、塩酸ジセチアミンは顕著に含量低下し、アセトアミノフェンと塩酸ジセチアミンあるいは塩酸ジセチアミンとステアリン酸マグネシウムを混合した系において、塩酸ジセチアミンは比較的安定であることが明らかとなった。
The present invention will be described more specifically with reference to the following examples. However, the examples are merely illustrative and do not limit the present invention.
A. Residual rate of vitamin B1 derivative when vitamin B1 derivative, acetaminophen, and magnesium stearate are mixed (preliminary test)
1. Raw materials and experimental method 1) Raw materials Discetamine amine hydrochloride and acetaminophen which are vitamin B1 derivatives were used as drugs, and magnesium stearate was used as a lubricant.
2) Sample preparation method Dicetiamine hydrochloride, acetaminophen and magnesium stearate were mixed at a weight ratio of 1: 1: 1 to prepare a sample.
3) Stability test method over time It was stored at 60 ° C. and 75% relative humidity for 2 weeks. After storage, the content of dicetiamine hydrochloride was measured.

4) Content measuring method The test sample is placed in a 100 mL volumetric flask. About 30 mL of distilled water was added thereto, and the mixture was shaken vigorously at 37 ° C. for about 30 minutes. About 50 mL of methanol was added thereto, and the volumetric flask was occasionally mixed by inversion until the liquid temperature reached room temperature so that the contents did not stick to the bottom. Add methanol to make exactly 100 mL, accurately measure 1 mL of this solution, add exactly 1 mL of internal standard solution, and add methanol / 0.01 M dibutylamine phosphate buffer (18/82) to make exactly 25 mL. . About 5 mL of this liquid was filtered with a membrane filter (HLC-DISK 13 aqueous system, Kanto Chemical) having a pore diameter of 0.45 μm, about 2 mL of the initial flow was discarded, and the next filtrate was used as a sample solution. Separately, a standard solution was prepared using a standard as follows. About 0.04 g of dicetiamine hydrochloride was accurately weighed and transferred to a 100 mL volumetric flask, and a methanol / distilled water mixture (70/30) was added to make exactly 100 mL. This solution was designated as solution (A). Further, about 0.08 g of acetaminophen was accurately weighed and transferred to a 100 mL volumetric flask, 10 mL of the solution (A) was accurately added, and a methanol / distilled water mixture (70/30) was added to make exactly 100 mL. 1 mL of this solution was accurately weighed, 1 mL of the internal standard solution was accurately added, and a methanol / 0.01 M dibutylamine phosphate buffer mixed solution (18/82) was added to make exactly 25 mL to obtain a standard solution. A sample solution and 40 μL of a standard solution were injected, and each peak area was measured by a liquid chromatograph method under the following conditions.
The amount of drug contained in the sample is determined by the following formula.

At: Peak area ratio of active ingredient to internal standard substance of sample solution As: Peak area ratio of active ingredient to internal standard substance of standard solution Ws: Weighed amount of drug (mg) when preparing standard solution

(1) HPLC condition detector: ultraviolet absorptiometer (measurement wavelength: 210 nm and 254 nm)
Column: Symmetry Shield ^TM RP ₁₈ (3.5μm), 4.6mmφ × 100mm (Waters)
Column temperature: constant temperature around 45 ° C. Mobile phase: 0.01M dibutylamine phosphate buffer / methanol mixture according to the following timetable

(2) Flow rate: 0.9mL / min
(3) Retention time:
Acetaminophen: about 3.0 minutes Discetamine hydrochloride: about 7.7 minutes Internal standard substance (phenacetin): about 11.6 minutes
(4) Content calculation

2. Experimental Results Table 2 shows the residual ratio of dicetiamine hydrochloride in the tested samples after storage over time.

From the above results, when dicetiamine hydrochloride, acetaminophen and magnesium stearate are mixed, the content of dicetiamine hydrochloride is significantly reduced. Was found to be relatively stable.

以上の結果から、塩酸ジセチアミン、アセトアミノフェンおよびステアリン酸マグネシウムおよびアミノ酸塩酸塩であるグリシン塩酸塩を混合した場合、塩酸ジセチアミンの残存率は９０％以上あり、他の安定化剤を添加した場合に比べ、塩酸ジセチアミンの残存率が高まった。
B. Stability of dicetiamine hydrochloride when amino acid salt is added (1)
1. Raw material and experimental method 1) Raw material Acetaminophen and dicetiamine hydrochloride which is a vitamin B1 derivative were used as drugs. As stabilizers, glycine, glycine hydrochloride, L-cysteine, L-cysteine hydrochloride, citric acid, ammonium chloride, and L-glutamate hydrochloride were used.

2) Sample preparation method Dicetiamine hydrochloride, acetaminophen, magnesium stearate and stabilizer were mixed at a weight ratio of 1: 1: 1: 1 to prepare a sample.

3) Stability test method over time It was stored at 60 ° C. and 75% relative humidity for 2 weeks. After storage, the content of dicetiamine hydrochloride was measured.

4) Content measuring method The content was measured in the same manner as in Example 1.

2. Experimental Results Table 3 shows the residual ratio of dicetiamine hydrochloride in the tested samples after the aging stability test (storage conditions: 60 ° C., relative humidity 75%, storage for 2 weeks).

From the above results, when mixing dicetiamine hydrochloride, acetaminophen, magnesium stearate and amino acid hydrochloride glycine hydrochloride, the residual ratio of dicetiamine hydrochloride is 90% or more, and when other stabilizers are added In comparison, the residual rate of dicetiamine hydrochloride increased.

２）錠剤製造法
エテンザミド、アセトアミノフェン、アリルイソプロピルアセチル尿素、無水カフェイン、カルメロースカルシウムおよび結晶セルロースを混合し、これに塩酸ジセチアミン、安定化剤、ＨＰＣ−ＳＬを溶解した水溶液を流動層造粒機内で噴霧して造粒、乾燥した後、調粒して造粒顆粒を得た（造粒条件は表５）。
前記造粒顆粒、カルメロースカルシウムおよびステアリン酸マグネシウムを混合し、表６の条件で打錠操作をおこなった。

３）経時安定性試験法
４０℃、相対湿度７５％下において、6ヶ月間保存した。保存後、塩酸ジセチアミンの含量を測定した。

４）含量測定法
本品１錠を１００ｍＬのメスフラスコに入れる。これに蒸留水約３０ｍＬを加えて３７℃で約３０分間激しく振とうした。これにメタノール約５０ｍＬを加え、液温が室温になるまで、底に内容物が固着しないようメスフラスコを時々転倒混和した。さらにメタノールを加え正確に１００ｍＬとし、この液１ｍＬを正確に量り、内標準溶液１ｍＬを正確に加え、メタノール／０．０１Ｍ ジブチルアミンリン酸緩衝混液（１８／８２）を加えて正確に２５ｍＬとした。この液約５ｍＬを孔径０．４５μｍのメンブランフィルター（HLC-DISK 13水系、関東化学）でろ過し、初流約２ｍＬを捨て、次のろ液を試料溶液とした。別に以下のように標準品を用いて標準溶液を調製した。塩酸ジセチアミン約０．０４ｇを精密に量り、１００ｍＬのメスフラスコに移し、メタノール／蒸留水混液（７０／３０）を加えて正確に１００ｍＬとし、この液を（Ａ）液とした。また、エテンザミドを約０．２０ｇ、アセトアミノフェンを約０．０８ｇ、アリルイソプロピルアセチル尿素を約０．０３ｇ、無水カフェインを約０．０４ｇ精密に量り、１００ｍＬのメスフラスコに移し、（Ａ）液１０ｍＬを正確に加え、メタノール／蒸留水混液（７０／３０）を加えて正確に１００ｍＬとした。この液１ｍＬを正確に量り、内標準溶液１ｍＬを正確に加え、メタノール／０．０１Ｍジブチルアミンリン酸緩衝混液（１８／８２）を加えて正確に２５ｍＬとし、標準溶液とした。試料溶液及び標準溶液４０μＬを注入して、以下に示した条件の液体クロマトグラフ法により、それぞれのピーク面積を測定した。

１錠中に含まれる薬物量は以下の式により求める。

Ａｔ：試料溶液の内標準物質に対する有効成分のピーク面積比
Ａｓ：標準溶液の内標準物質に対する有効成分のピーク面積比
Ｗｓ：標準品の秤取量（ｍｇ）
(1)ＨＰＬＣ条件
検出器：紫外吸光光度計（測定波長：２１０ｎｍ及び２５４ｎｍ ）
カラム：Symmetry Shield^TM RP₁₈（3.5μm）, 4.6mmφ×100mm（Waters製）
カラム温度：４５℃付近の一定温度
移動相：下記表７のタイムテーブルに従った０．０１Ｍ Ｄ／メタノールの混液

(2)流量：アリルイソプロピルアセチル尿素の保持時間が約１７．８分になるように調整した。（通常０．９ｍＬ／分）
(3)保持時間：
アセトアミノフェン：約３．０分
無水カフェイン：約４．６分
塩酸ジセチアミン：約７．７分
エテンザミド：約９．７分
内標準物質（フェナセチン）：約１１．６分
アリルイソプロピルアセチル尿素：約１７．８分
(4)含量計算

２．実験結果
添加剤をL−グルタミン酸塩酸塩とし、４０℃、相対湿度７５％、６ヶ月で保存した経時安定性試験において、供試した試料中の塩酸ジセチアミンの残存率を表８に示す。

実施例２と実施例3の結果、グリシン塩酸塩、Ｌ−システイン塩酸塩またはＬ−グルタミン酸塩酸塩を錠剤中に添加した場合、塩酸ジセチアミンの残存率低下は抑制された。
C. Stability of dicetiamine hydrochloride when amino acid salt is added (2)
1. Raw materials and experimental method 1) Raw materials Raw materials having the formulations shown in Table 4 were used. As drugs, etenzamide, acetaminophen, allylisopropylacetylurea, anhydrous caffeine, and vitamin B1 derivative dicetiamine hydrochloride were used. As additives, crystalline cellulose, carboxymethylcellulose calcium (hereinafter abbreviated as “carmellose calcium”), hydroxypropylcellulose (hereinafter abbreviated as “HPC-SL”), crystalline cellulose, and magnesium stearate were used. Glycine, glycine hydrochloride, L-cysteine, L-cysteine hydrochloride, citric acid, ammonium chloride, and L-glutamate hydrochloride were used as stabilizers.

2) Tablet manufacturing method Fluidized bed construction of an aqueous solution in which etenzamide, acetaminophen, allylisopropylacetylurea, anhydrous caffeine, carmellose calcium and crystalline cellulose are mixed and dissolved in this solution, dicetiamine hydrochloride, stabilizer and HPC-SL. After granulating and drying by spraying in a granulator, granulation was performed to obtain granulated granules (granulation conditions are Table 5).
The granulated granules, carmellose calcium and magnesium stearate were mixed, and tableting was performed under the conditions shown in Table 6.

3) Stability test method over time The sample was stored for 6 months at 40 ° C. and 75% relative humidity. After storage, the content of dicetiamine hydrochloride was measured.

4) Content measuring method 1 tablet of this product is put into a 100 mL volumetric flask. About 30 mL of distilled water was added thereto, and the mixture was shaken vigorously at 37 ° C. for about 30 minutes. About 50 mL of methanol was added thereto, and the volumetric flask was occasionally mixed by inversion until the liquid temperature reached room temperature so that the contents did not stick to the bottom. Add methanol to make exactly 100 mL, accurately measure 1 mL of this solution, add exactly 1 mL of internal standard solution, and add methanol / 0.01 M dibutylamine phosphate buffer (18/82) to make exactly 25 mL. . About 5 mL of this liquid was filtered with a membrane filter (HLC-DISK 13 aqueous system, Kanto Chemical) having a pore diameter of 0.45 μm, about 2 mL of the initial flow was discarded, and the next filtrate was used as a sample solution. Separately, a standard solution was prepared using a standard as follows. About 0.04 g of dicetiamine hydrochloride was accurately weighed and transferred to a 100 mL volumetric flask, and a methanol / distilled water mixture (70/30) was added to make exactly 100 mL. This solution was designated as solution (A). Further, about 0.20 g of etenzamide, about 0.08 g of acetaminophen, about 0.03 g of allylisopropylacetylurea and about 0.04 g of anhydrous caffeine are precisely weighed and transferred to a 100 mL volumetric flask. 10 mL of the liquid was accurately added, and a methanol / distilled water mixture (70/30) was added to make exactly 100 mL. 1 mL of this solution was accurately weighed, 1 mL of the internal standard solution was accurately added, and a methanol / 0.01 M dibutylamine phosphate buffer mixed solution (18/82) was added to make exactly 25 mL to obtain a standard solution. A sample solution and 40 μL of a standard solution were injected, and each peak area was measured by a liquid chromatograph method under the following conditions.

The amount of drug contained in one tablet is determined by the following formula.

At: Peak area ratio of active ingredient to internal standard substance of sample solution As: Peak area ratio of active ingredient to internal standard substance of standard solution Ws: Weighed amount of standard product (mg)
(1) HPLC condition detector: ultraviolet absorptiometer (measurement wavelength: 210 nm and 254 nm)
Column: Symmetry Shield ^TM RP ₁₈ (3.5μm), 4.6mmφ × 100mm (Waters)
Column temperature: constant temperature around 45 ° C. Mobile phase: 0.01 M D / methanol mixture according to the timetable in Table 7 below

(2) Flow rate: The flow rate was adjusted so that the retention time of allylisopropylacetylurea was about 17.8 minutes. (Usually 0.9 mL / min)
(3) Retention time:
Acetaminophen: about 3.0 minutes Anhydrous caffeine: about 4.6 minutes Dicetiamine hydrochloride: about 7.7 minutes Etenzamide: about 9.7 minutes Internal standard substance (phenacetin): about 11.6 minutes Allylisopropylacetylurea: 17.8 minutes
(4) Content calculation

2. Experimental Results Table 8 shows the residual ratio of dicetiamine hydrochloride in the samples tested in a temporal stability test in which the additive was L-glutamic acid hydrochloride and stored at 40 ° C. and 75% relative humidity at 6 months.

As a result of Example 2 and Example 3, when glycine hydrochloride, L-cysteine hydrochloride or L-glutamate hydrochloride was added to the tablet, a decrease in the residual rate of dicetiamine hydrochloride was suppressed.

２）錠剤製造法
エテンザミドおよびＤ−マンニトールを混合し、これに塩酸ジセチアミン、ＨＰＣ−ＳＬを溶解した水溶液を流動層造粒機内で噴霧して造粒、乾燥した後、調粒して造粒顆粒を得た（造粒条件は表３と同様）。この造粒顆粒にカルメロースカルシウムおよびステアリン酸マグネシウムを添加、混合して打錠用顆粒を製造した（以下「Ｅ顆粒」と略す）。
一方、アセトアミノフェン、アリルイソプロピルアセチル尿素、無水カフェイン、結晶セルロースおよびカルメロースカルシウムを混合し、これにＨＰＣ−ＳＬを溶解した水溶液を流動層造粒機内で噴霧して造粒、乾燥した後、調粒して造粒顆粒を得た（造粒条件は表５と同様）。この造粒顆粒にカルメロースカルシウムおよびステアリン酸マグネシウムを添加、混合して打錠用顆粒を製造した（以下「Ａ顆粒」と略す）。
まず、下層としてＥ顆粒を臼に充填し、打錠圧約２０ｋｇで成型し、この上にＡ顆粒を上層として積層した後、打錠圧４１０ｋｇで圧縮打錠することにより、二層錠剤を製造した。なお、錠剤は、１０．５ｍｍダブルR面の杵を用い、静的圧縮機で簡易的に圧縮成型して製造した。

３）経時安定性試験法（保存条件：４０℃、相対湿度７５％、６ヶ月保存）、含量測定法は、実施例１、２と同様である。

２．実験結果
経時安定性試験後の塩酸ジセチアミンの残存率を表１０に示す。

以上の結果から、二層錠剤にした場合、塩酸ジセチアミンの残存率の低下が抑制されることが明らかとなった。 D. Stability of dicetiamine hydrochloride in bilayer tablet Raw materials and experimental method 1) Raw materials Raw materials having the formulations shown in Table 9 were used. As drugs, etenzamide, acetaminophen, allylisopropylacetylurea, anhydrous caffeine, and vitamin B1 derivative dicethiamine were used. Moreover, crystalline cellulose, D-mannitol, carmellose calcium, HPC-SL, crystalline cellulose, and magnesium stearate were used as additives.

2) Tablet manufacturing method Ethenzamide and D-mannitol are mixed, and an aqueous solution in which dicetiamine hydrochloride and HPC-SL are dissolved is sprayed in a fluid bed granulator, granulated and dried, and then granulated to granulate granules. (Granulation conditions are the same as in Table 3). To this granulated granule, carmellose calcium and magnesium stearate were added and mixed to produce a tableting granule (hereinafter abbreviated as “E granule”).
On the other hand, after acetaminophen, allyl isopropyl acetyl urea, anhydrous caffeine, crystalline cellulose and carmellose calcium are mixed and sprayed with an aqueous solution in which HPC-SL is dissolved in the fluidized bed granulator, the granulated and dried To obtain granulated granules (granulation conditions are the same as in Table 5). To this granulated granule, carmellose calcium and magnesium stearate were added and mixed to produce a tableting tablet (hereinafter abbreviated as “A granule”).
First, E granules as a lower layer were filled in a mortar, molded with a tableting pressure of about 20 kg, and A granules were laminated as an upper layer thereon, and then compressed and compressed with a tableting pressure of 410 kg to produce a bilayer tablet. . The tablets were produced by simple compression molding with a static compressor using a 10.5 mm double-R side ridge.

3) Stability test method over time (storage conditions: 40 ° C., relative humidity 75%, storage for 6 months) and content measurement method are the same as in Examples 1 and 2.

2. Experimental Results Table 10 shows the residual ratio of dicetiamine hydrochloride after the aging stability test.

From the above results, it was clarified that when the bilayer tablet was used, the decrease in the residual rate of dicetiamine hydrochloride was suppressed.

２）錠剤製造法
エテンザミド、アセトアミノフェン、アリルイソプロピルアセチル尿素、無水カフェイン、カルメロースカルシウムおよび結晶セルロースを混合し、これに塩酸ジセチアミン、ＨＰＣ−ＳＬを溶解した水溶液を流動層造粒機内で噴霧して造粒、乾燥した後、調粒して造粒顆粒を得た（造粒条件は表５と同様）。
外部滑沢法の場合には、前記造粒顆粒にカルメロースカルシウムを混合し、表１２の条件で打錠操作をおこなった。
内部滑沢法の場合には、前記造粒顆粒にカルメロースカルシウムおよびステアリン酸マグネシウムを混合し、表５の条件で打錠操作をおこなった。

３）打錠障害の観察
錠剤製造後、打錠障害（スティッキングの有無等）を目視で観察した。

２．実験結果
１）打錠障害の有無
打錠障害の有無を表１３に示す。その結果、内部滑沢法において滑沢剤の配合量が２．０ｍｇ以下であると、打錠障害が生じた（スティッキング）。一方、外部滑沢法においては、滑沢剤であるステアリン酸マグネシウムの配合量を低減しても、打錠障害は生じなかった。

２）塩酸ジセチアミンの残存率
打錠障害が生じなかった錠剤A〜C、Fについて、４０℃、相対湿度７５％で０〜６月間保存し、塩酸ジセチアミン残存率の経時変化について図１に示す。その結果、内部滑沢法による錠剤（ステアリン酸マグネシウム ４ｍｇ）にくらべ、外部滑沢法による錠剤中（ステアリン酸マグネシウム ０．０８〜０．２１ｍｇ）の塩酸ジセチアミンの残存率は高かった。 E. Stability of dicetiamine hydrochloride with reduced lubricant Raw materials and experimental method 1) Raw materials, aging stability test method (storage conditions: 40 ° C., relative humidity 75%, stored for 0 to 6 months), and content measurement method are the same as in Examples 1 and 2. The tablet formulation is shown in Table 11.

2) Tablet manufacturing method Ethenzamid, acetaminophen, allyl isopropyl acetyl urea, anhydrous caffeine, carmellose calcium and crystalline cellulose are mixed and sprayed with an aqueous solution in which dicetiamine hydrochloride and HPC-SL are dissolved in a fluid bed granulator. After granulating and drying, granulation was performed to obtain granulated granules (granulation conditions are the same as in Table 5).
In the case of the external lubrication method, carmellose calcium was mixed with the granulated granules, and tableting was performed under the conditions shown in Table 12.
In the case of the internal lubrication method, carmellose calcium and magnesium stearate were mixed with the granulated granules, and tableting was performed under the conditions shown in Table 5.

3) Observation of tableting failure After tablet production, tableting failure (presence of sticking, etc.) was visually observed.

2. Experimental results 1) Presence or absence of tableting failure Table 13 shows the presence or absence of tableting failure. As a result, when the blending amount of the lubricant was 2.0 mg or less in the internal lubricant method, a tableting failure occurred (sticking). On the other hand, in the external lubrication method, even if the blending amount of magnesium stearate as a lubricant was reduced, no tableting trouble occurred.

2) Residual rate of dicetiamine hydrochloride Tablets A to C and F, in which no tableting trouble occurred, were stored at 40 ° C. and 75% relative humidity for 0 to 6 months. As a result, the residual ratio of dicetiamine hydrochloride in the tablet by the external lubrication method (magnesium stearate 0.08 to 0.21 mg) was higher than that of the tablet by the internal lubrication method (magnesium stearate 4 mg).

Temporal change of residual ratio of disethiamine hydrochloride in tablets manufactured by external lubrication method and internal lubrication method

Claims (6)

Contains acetaminophen, vitamin B1 derivative, magnesium stearate and amino acid salt, and vitamin B1 derivative is thiamine nitrate, dibenzoylthiamine, octothiamine, thiamine disulfide, bisibutamine, bisbenchamine, fursultiamine, benfotiamine 1 or 2 or more selected from dicetiamine hydrochloride and thiamine hydrochloride, and the amino acid salt is 1 or 2 or more selected from L-glutamate hydrochloride, glycine hydrochloride and L-cysteine hydrochloride Solid formulation. The solid preparation according to claim 1, wherein the vitamin B1 derivative is dicetiamine hydrochloride and the amino acid salt is one or more selected from L-glutamate hydrochloride, glycine hydrochloride and L-cysteine hydrochloride. The solid preparation according to claim 1 or 2, wherein the solid preparation is one preparation selected from tablets, granules and powders. The solid preparation according to claim 1 or 2, which is a tablet. It contains acetaminophen, vitamin B1 derivative and magnesium stearate, the blending ratio of magnesium stearate per tablet is 0.01 to 0.15 (w / w) %, vitamin B1 derivative is thiamine nitrate, di One or more selected from benzoylthiamine, octothiamine, thiamine disulfide, bisibhiamine, bisbenchamine, fursultiamine, benfotiamine, dicetiamine hydrochloride and thiamine hydrochloride, and manufactured by an external lubrication method Features tablets. Tablet of claim 5 Symbol mounting vitamin B1 derivatives are hydrochloric dicethiamine.

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