JP5110848B2 - Formulation containing diphenhydramine salt - Google Patents
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- JP5110848B2 JP5110848B2 JP2006283111A JP2006283111A JP5110848B2 JP 5110848 B2 JP5110848 B2 JP 5110848B2 JP 2006283111 A JP2006283111 A JP 2006283111A JP 2006283111 A JP2006283111 A JP 2006283111A JP 5110848 B2 JP5110848 B2 JP 5110848B2
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Description
本発明は、保存安定性に優れ、かつ溶解性が向上したジフェンヒドラミン塩含有製剤に関する。 The present invention relates to a diphenhydramine salt-containing preparation having excellent storage stability and improved solubility.
従来からジフェンヒドラミン塩は抗ヒスタミン作用と中枢抑制作用を有し、催眠作用、制吐作用が認められていた。他にも動揺病（乗り物酔い）に対する抑制効果も認められていた。 Conventionally, diphenhydramine salt has an antihistaminic action and a central inhibitory action, and a hypnotic action and an antiemetic action have been recognized. In addition, a suppressive effect on motion sickness (motion sickness) was also recognized.
製剤化においては、ジフェンヒドラミン塩の粉末は光によって徐々に、ｂｅｎｚｏｐｈｅｎｏｎｅ又はｂｅｎｚｈｙｄｒｏｌ及びβ―ｄｉｍｅｔｈｙｌ―ａｍｉｎｏｅｔｈａｎｏｌなどに分解される。 In the formulation, the diphenhydramine salt powder is gradually decomposed by light into benzophenone or benzhydrol, β-dimethyl-aminoethanol and the like.
また、特許文献１においてもジフェンヒドラミン塩酸塩は光によって分解されるので遮光した箱や包装容器に保管する、或いはその固形剤を遮光物質で被覆することが必要であると記述している。
従来のジフェンヒドラミン塩製剤は光安定性が悪く、その固形剤においても遮光物質で被覆することが必要とされ、被覆することで製造工程が増え、更には被覆されているので十分な溶解性が得られないことを想起させるものであった。 Conventional diphenhydramine salt preparations have poor light stability, and it is necessary to coat the solid agent with a light-shielding substance, which increases the number of manufacturing steps and further provides sufficient solubility because it is coated. It reminded me that I couldn't.
尚、本発明者らの研究によれば、ジフェンヒドラミン塩を油液中に分散することにより、光による分解を抑制することができる。この場合においてもジフェンヒドラミン塩を固形剤とするためのカプセル皮膜等に、還元性等の化学反応性を有する該ジフェンヒドラミン塩が作用し、その皮膜等を経時劣化させ、皮膜の軟化、カプセル漏れ、皮膜の着色等の発生があることを認めた。 According to the study by the present inventors, the decomposition by light can be suppressed by dispersing the diphenhydramine salt in the oil liquid. Even in this case, the diphenhydramine salt having chemical reactivity such as reductivity acts on a capsule film or the like for using diphenhydramine salt as a solid agent, and the film or the like is deteriorated with time, and the film softens, capsule leaks, film It was recognized that there was the occurrence of coloring.
本発明の課題は、保存安定性に優れ、かつ溶解性が向上したジフェンヒドラミン塩含有製剤を提供することにある。 An object of the present invention is to provide a diphenhydramine salt-containing preparation having excellent storage stability and improved solubility.
請求項１の発明は、ジフェンヒドラミン塩、ビニルピロリドンの架橋重合物、及び食用油を含有した油状又は懸濁油状のジフェンヒドラミン塩含有製剤である。 The invention of claim 1 is an oily or suspension oily diphenhydramine salt-containing preparation containing a diphenhydramine salt, a vinylpyrrolidone cross-linked polymer, and an edible oil.
請求項２の発明は、請求項１の発明において更に、前記ジフェンヒドラミン塩がジフェンヒドラミン塩酸塩、ジフェンヒドラミンサリチル酸塩、及びジフェンヒドラミンラウリル硫酸塩からなる群から選ばれる１種以上であるようにしたものである。 The invention according to claim 2 is the invention according to claim 1, wherein the diphenhydramine salt is one or more selected from the group consisting of diphenhydramine hydrochloride, diphenhydramine salicylate, and diphenhydramine lauryl sulfate.
請求項３の発明は、請求項１又は２の発明において更に、前記食用油が中鎖脂肪酸トリグリセリド、ダイズ油、小麦胚芽油、綿実油、しそ油、ヒマワリ油、サフラワー油、オリブ油、ツバキ油、ナタネ油、ヤシ油からなる群から選ばれる１種以上であるようにしたものである。 The invention of claim 3 is the invention of claim 1 or 2, wherein the edible oil is a medium chain fatty acid triglyceride, soybean oil, wheat germ oil, cottonseed oil, perilla oil, sunflower oil, safflower oil, olive oil, camellia oil And at least one selected from the group consisting of rapeseed oil and coconut oil.
請求項４の発明は、請求項１〜３のいずれかに記載のジフェンヒドラミン塩含有製剤を内容物として用いたカプセル剤である。 Invention of Claim 4 is the capsule which used the diphenhydramine salt containing formulation in any one of Claims 1-3 as a content.
請求項５の発明は、請求項１〜３のいずれかに記載のジフェンヒドラミン塩含有製剤を内容物として用いた軟カプセル剤である。 Invention of Claim 5 is a soft capsule which used the diphenhydramine salt containing formulation in any one of Claims 1-3 as a content.
ジフェンヒドラミン塩を食用油の油液中に溶解又は分散することにより、光による分解を抑制することができ、更にビニルピロリドンの架橋重合物を添加することにより、それらの組成物をカプセル化した場合においても、ジフェンヒドラミン塩がその有効性を損なうことなく、カプセル皮膜等を経時劣化させないことができた。これはジフェンヒドラミン塩が油液中でビニルピロリドンの架橋重合物に包接され、更にビニルピロリドンの架橋重合物が体内胃液等の水液中に放散されることでその包接が解け、ジフェンヒドラミン塩が遊離され速やかに体内に吸収されることとなることが推測された。 When diphenhydramine salt is dissolved or dispersed in an oil liquid of cooking oil, decomposition by light can be suppressed, and further, when these compositions are encapsulated by adding a vinylpyrrolidone cross-linked polymer However, the diphenhydramine salt could not degrade the capsule film and the like over time without impairing its effectiveness. This is because the diphenhydramine salt is encapsulated in a cross-linked polymer of vinyl pyrrolidone in an oil solution, and further the cross-linked polymer of vinyl pyrrolidone is dissipated in an aqueous solution such as gastric juice in the body, so that the inclusion is released. It was speculated that it was released and quickly absorbed by the body.
尚、本発明者らは、ジフェンヒドラミン塩以外の他の生理活性物質であって、他の成分との相互作用が伴なう生理活性物質にビニルピロリドンの架橋重合物を添加すれば、当該生理活性物質を含有しながら安定性に優れる剤を製造できることも認めた。この生理活性物質としては、ベンフォチアミン、Ｌ−システイン、リゾチーム塩酸塩、アスコルビン酸、イブプロフェン、有胞子性乳酸菌、ビタミンＤ類等を挙げることができる。 In addition, the present inventors can add a physiologically active substance other than the diphenhydramine salt to the physiologically active substance that interacts with other components by adding a vinylpyrrolidone cross-linked polymer. It was also recognized that an agent having excellent stability while containing a substance can be produced. Examples of this physiologically active substance include benfotiamine, L-cysteine, lysozyme hydrochloride, ascorbic acid, ibuprofen, spore-forming lactic acid bacteria, vitamin Ds and the like.
本発明のジフェンヒドラミン塩含有製剤において、食用油の好適添加量は、ジフェンヒドラミン塩量16.7重量％に対し30〜80重量％であり、更に好ましくは40〜70重量％である。ビニルピロリドンの架橋重合物の好適添加量はジフェンヒドラミン塩量16.7重量％に対し2〜10重量％であり、更に好ましくは3〜8重量％である。 In the diphenhydramine salt-containing preparation of the present invention, the preferred addition amount of edible oil is 30 to 80% by weight, more preferably 40 to 70% by weight with respect to the diphenhydramine salt amount of 16.7% by weight. The preferred amount of the vinylpyrrolidone crosslinked polymer added is 2 to 10% by weight, more preferably 3 to 8% by weight, based on the amount of diphenhydramine salt of 16.7% by weight.
これらジフェンヒドラミン塩、ビニルピロリドンの架橋重合物、及び食用油を含有することを特徴とするジフェンヒドラミン塩含有製剤は、他添加剤として中鎖脂肪酸モノグリセリド、硬化油、レシチン、及び抗酸化剤を含むことができる。中鎖脂肪酸モノグリセリドとしてはグリセリンモノカプロン酸エステル、グリセリンモノカプリル酸エステル、グリセリンモノカプリン酸エステル及びグリセリンモノラウリル酸エステル等の１種又は２種以上が好適に用いられる。硬化油としてはミツロウ、サラシミツロウ、キャンデリラワックス、カルナバワックス、ラノリンワックス、シンクロワックス、モクロウ等の１種又は２種以上が好適に用いられる。 The diphenhydramine salt-containing preparation characterized by containing a diphenhydramine salt, a cross-linked polymer of vinyl pyrrolidone, and an edible oil may contain a medium-chain fatty acid monoglyceride, hardened oil, lecithin, and an antioxidant as other additives. it can. As the medium chain fatty acid monoglyceride, one kind or two or more kinds of glycerin monocaproic acid ester, glycerin monocaprylic acid ester, glycerin monocapric acid ester and glycerin monolauric acid ester are suitably used. As the hardened oil, one kind or two or more kinds of beeswax, white beeswax, candelilla wax, carnauba wax, lanolin wax, synchrowax, mollusc and the like are preferably used.
本発明であるジフェンヒドラミン塩含有油状液又は油状懸濁液を製造するにはジフェンヒドラミン塩以外の各成分を混合機に量り取り、必要に応じ約80℃で加温溶解し、冷後ジフェンヒドラミン塩を加える。 In order to produce the diphenhydramine salt-containing oily liquid or oily suspension according to the present invention, each component other than the diphenhydramine salt is weighed in a mixer and dissolved by heating at about 80 ° C. if necessary. After cooling, the diphenhydramine salt is added. .
本発明であるジフェンヒドラミン塩含有油状液又は油状懸濁液は、軟カプセル剤又は硬カプセル剤等の固形剤の内容物として用いられる。 The diphenhydramine salt-containing oily liquid or oily suspension according to the present invention is used as the content of a solid preparation such as a soft capsule or a hard capsule.
本発明であるジフェンヒドラミン塩含有油状液又は油状懸濁液を軟カプセル剤にするとき、ジフェンヒドラミン塩の粒子径は50〜300μmが良い。更に好ましくは80〜150μmである。ジフェンヒドラミン塩の粒子径が50μm未満であると油状液又は油状懸濁液を調合する場合、飛散防止に多大な注意を要し作業効率及び作業者の安全性に留意する必要がある。また、ジフェンヒドラミン塩の粒子径が300μm以上であると軟カプセル剤の製法上不具合が生じる。尚、カプセル皮膜の基剤としてはコハク化ゼラチン、でんぷん、デキストリン及びグリセリンを用いる。 When the diphenhydramine salt-containing oily liquid or oily suspension of the present invention is used as a soft capsule, the particle size of the diphenhydramine salt is preferably 50 to 300 μm. More preferably, it is 80-150 micrometers. When an oily liquid or oily suspension is prepared with a diphenhydramine salt having a particle size of less than 50 μm, great care must be taken to prevent scattering and attention must be paid to work efficiency and worker safety. In addition, when the particle size of the diphenhydramine salt is 300 μm or more, there is a problem in the manufacturing method of the soft capsule. Note that succinylated gelatin, starch, dextrin, and glycerin are used as the base of the capsule film.
軟カプセル剤の製法の一つとしてロータリーダイ式があり、これは皮膜組成物の溶液をカプセル充填機の両側にある回転ドラムに展延することによりシート状とし、その皮膜シートを回転する円筒金型（ダイロール）の間に送り、これと連動するポンプのピストンで内容物を圧入し、両金型の圧切によってカプセルを形成する。もう一つの方法として平板法があり、これは原理的にはロータリーダイ式と同等であり、上下平板金型の間に上下皮膜シート、その上下皮膜シート間に内容物を置き、両金型の圧切によってカプセルを形成する。 One of the methods for producing soft capsules is a rotary die type, in which a coating composition solution is spread on rotating drums on both sides of a capsule filling machine to form a sheet, and the coating sheet is a cylindrical metal that rotates. The contents are press-fitted with a piston of a pump that is fed between molds (die rolls) and interlocked therewith, and a capsule is formed by cutting both molds. Another method is the flat plate method, which is equivalent to the rotary die method in principle, and places the upper and lower coating sheets between the upper and lower flat plate molds, and puts the contents between the upper and lower coating sheets. Capsule is formed by pressing.
一方、軟カプセル剤の他の製法である、シームレスカプセルの製法は、外側がカプセル皮膜液、内側がカプセル内容液からなる二層性の液流を、一定間隔で切断しながら疎水性の油液等に導入することにより、球体となる皮膜液により内容物を包んで充填カプセルを作り、次いでその充填カプセルを乾燥して軟カプセル剤を得る。 On the other hand, the manufacturing method of seamless capsules, which is another method for producing soft capsules, is a hydrophobic oil solution while cutting a two-layered flow consisting of a capsule film solution on the outside and a capsule content solution on the inside at regular intervals. And so on to make a filled capsule by wrapping the contents with a coating solution that becomes a sphere, and then the filled capsule is dried to obtain a soft capsule.
硬カプセル剤の製法としては、ディッピング法があり、これは皮膜組成物の溶液にカプセル形成用ピンを浸漬し、ピン上に溶液を付着させ、ついでピンを引き上げ、乾燥後、フィルムをピンから引き抜いて、硬カプセル剤を得る。 As a method for producing hard capsules, there is a dipping method, in which a capsule-forming pin is immersed in a solution of a film composition, the solution is attached onto the pin, then the pin is pulled up, dried, and then the film is pulled out from the pin. To obtain a hard capsule.
以下、実施例により本発明を具体的に説明するが、本発明はそれに限定されるものではない。 EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
（比較例１及び実施例１）
表１に示した比較例１及び実施例１に示す処方に基づき、各成分をガラス製シャーレーに取り、均一に攪拌混和したものに、耐光試験機（Heraeus社製）を用いて光照射（1000ルクス、1、2、4週間相当）した後に評価した。光照射中の耐光試験機内の最大温度は36℃であった。
(Comparative Example 1 and Example 1)
Based on the prescriptions shown in Comparative Example 1 and Example 1 shown in Table 1, each component was taken into a glass petri dish and uniformly stirred and mixed, and then irradiated with light using a light resistance tester (Heraeus) (1000 Lux, equivalent to 1, 2 and 4 weeks). The maximum temperature in the light resistance tester during light irradiation was 36 ° C.
表１に示す如く、ジフェンヒドラミン塩酸塩の含量（重量）の変化についてみると、光照射後は、比較例１の減量は多量であり、実施例１の減量は少量である。ジフェンヒドラミン塩を油液中に分散することにより、光による分解を抑制できることが認められる。 As shown in Table 1, regarding the change in the content (weight) of diphenhydramine hydrochloride, after light irradiation, the weight loss of Comparative Example 1 is large, and the weight loss of Example 1 is small. It is recognized that the decomposition by light can be suppressed by dispersing the diphenhydramine salt in the oil liquid.
（比較例２及び実施例２〜３）
表２に示した比較例２及び実施例２〜３に示す処方に基づき、ジフェンヒドラミン塩酸塩以外の各成分をビーカーに量り取り、約70〜80℃の湯せんで加温溶解し、冷後ジフェンヒドラミン塩酸塩を加え、均一に攪拌混和したものに、皮膜シート（基剤としてコハク化ゼラチン、グリセリンを使用）を入れ、それを恒温槽（40℃）に入れ１ヶ月後に皮膜シート状態を評価した。
(Comparative Example 2 and Examples 2-3)
Based on the formulations shown in Comparative Example 2 and Examples 2-3 shown in Table 2, each component other than diphenhydramine hydrochloride is weighed into a beaker and dissolved by heating in a hot water bath of about 70-80 ° C. After cooling, diphenhydramine hydrochloride A film sheet (succinated gelatin and glycerin were used as a base) was added to a mixture obtained by adding salt and uniformly stirred and mixed, and the film sheet was put in a thermostatic chamber (40 ° C.) and evaluated for the state of the film sheet after one month.
表２に示す如く、皮膜シートの経時変化についてみると、比較例２は軟化（大）であり、実施例１〜２は軟化したもののその程度は僅かである。ジフェンヒドラミン塩にビニルピロリドンの架橋重合物を添加することにより、皮膜シートを軟化させないことが認められる。 As shown in Table 2, regarding the change with time of the coating sheet, Comparative Example 2 was softened (large), while Examples 1-2 were softened, but the degree thereof was slight. It can be seen that addition of a vinylpyrrolidone crosslinked polymer to the diphenhydramine salt does not soften the coating sheet.
（比較例３及び実施例４〜５）
表３に示した比較例３及び実施例４〜５に示す処方に基づき、ジフェンヒドラミン塩酸塩以外の各成分をビーカーに量り取り、約70〜80℃の湯せんで加温溶解し、冷後ジフェンヒドラミン塩酸塩を加え、均一に攪拌混和したものに、内容物として中鎖脂肪酸トリグリセリドを封入した軟カプセル（基剤としてゼラチン、グリセリンを使用）を入れ、それを恒温槽（40℃）に入れ１ヶ月後に軟カプセルの状態を評価した。
(Comparative Example 3 and Examples 4 to 5)
Based on the formulation shown in Comparative Example 3 and Examples 4 to 5 shown in Table 3, each component other than diphenhydramine hydrochloride was weighed into a beaker, heated and dissolved in a hot water bath of about 70 to 80 ° C., and after cooling, diphenhydramine hydrochloride Add a soft capsule (with gelatin and glycerin as the base material) containing medium-chain fatty acid triglyceride as the contents, add salt, and stir and mix evenly. Place it in a thermostatic chamber (40 ° C) and after 1 month The state of the soft capsule was evaluated.
表３に示す如く、軟カプセルの経時変化についてみると、比較例３は着色（不均一な黄色）があり、実施例４〜５はない。ジフェンヒドラミン塩にビニルピロリドンの架橋重合物を添加したものが、軟カプセルの皮膜を着色させないことが認められる。 As shown in Table 3, regarding the change with time of the soft capsule, Comparative Example 3 is colored (non-uniform yellow), and Examples 4 to 5 are not present. It can be seen that the addition of a crosslinked polymer of vinyl pyrrolidone to diphenhydramine salt does not color the soft capsule film.
（比較例４及び実施例６〜７）
表４に示した比較例４及び実施例６〜７に示す処方に基づき、ジフェンヒドラミン塩以外の各成分をアジホモミクサーＭ型（特殊機化工業（株）製）に量り取り、約80℃で加温溶解し、冷後ジフェンヒドラミン塩を加え、−0.05MPa以下に減圧しながら均一に攪拌混和したものをソフトカプセル充填機（富士カプセル（株）製）を用い軟カプセル剤を得、それを恒温恒湿庫（40℃、75％RH）に入れ３ヶ月後に評価した。
(Comparative Example 4 and Examples 6-7)
Based on the formulations shown in Table 4 and Comparative Examples 4 and Examples 6-7, each component other than the diphenhydramine salt was weighed into an Ajihomomixer M type (manufactured by Tokushu Kika Kogyo Co., Ltd.) at about 80 ° C. Dissolve with heating, add diphenhydramine salt after cooling, and obtain a soft capsule using a soft capsule filling machine (Fuji Capsule Co., Ltd.) with stirring and mixing uniformly while reducing the pressure to -0.05 MPa or less. Evaluation was conducted after 3 months in a damp chamber (40 ° C., 75% RH).
表４に示す如く、軟カプセル剤中のジフェンヒドラミン塩酸塩の含量（重量）の経時変化についてみると、軟カプセル剤の恒温恒湿庫への投入開始（表４の「開始」）から３ヶ月経過（表４の「３ヶ月」）により、比較例４の減量は多量であり、実施例６の減量は少量である。また、カプセルの状態は３ヶ月経過（表４の「３ヶ月」）により、比較例４は皮膜の軟化、カプセル漏れ、皮膜の着色の発生があり、実施例６〜７では皮膜の軟化、カプセル漏れ、皮膜の着色の発生がない。本発明の適用により、ジフェンヒドラミン塩酸塩の劣化を抑制でき、かつ皮膜の軟化、カプセル漏れ、皮膜の着色の発生を防ぐことが認められる。 As shown in Table 4, the change over time in the content (weight) of diphenhydramine hydrochloride in the soft capsule is 3 months from the start of charging the soft capsule into the constant temperature and humidity chamber ("Start" in Table 4) According to (“3 months” in Table 4), the weight loss in Comparative Example 4 is large and the weight loss in Example 6 is small. Further, the capsule state was 3 months later ("3 months" in Table 4), and in Comparative Example 4, the film was softened, the capsule leaked, and the film was colored. In Examples 6 to 7, the film was softened, There is no leakage or coloration of the film. By applying the present invention, it is recognized that the degradation of diphenhydramine hydrochloride can be suppressed and the occurrence of softening of the film, leakage of capsules, and coloring of the film can be prevented.
（比較例５及び実施例８）
表５に示した比較例５及び実施例８に示す処方に基づき、ベンフォチアミン、有効成分（Ｘ）以外の各成分をアジホモミクサーＭ型（特殊機化工業（株）製）に量り取り、約80℃で加温溶解し、冷後ベンフォチアミン、有効成分（Ｘ）を加え、−0.05MPa以下に減圧しながら均一に攪拌混和したものをソフトカプセル充填機（富士カプセル（株）製）を用い軟カプセル剤を得、それを恒温恒湿庫（40℃、75％RH）に入れ６ヶ月後に評価した。
(Comparative Example 5 and Example 8)
Based on the prescriptions shown in Comparative Example 5 and Example 8 shown in Table 5, each component other than benfotiamine and the active ingredient (X) is weighed into Ajihomomixer M type (manufactured by Special Machine Industries Co., Ltd.). Soft capsule filling machine (manufactured by Fuji Capsule Co., Ltd.), which was dissolved by heating at about 80 ° C, and after cooling, added benfotiamine and active ingredient (X), and stirred and mixed uniformly while reducing the pressure to -0.05 MPa or less Was used to obtain a soft capsule, which was placed in a constant temperature and humidity chamber (40 ° C., 75% RH) and evaluated after 6 months.
（有効成分（Ｘ））
有効成分（Ｘ）は本例では、リボフラビン酪酸エステル、ピリドキシン塩酸塩、ｄ−α−トコフェノール、γ−オリザノール、加工大蒜、シアノコバラミンの６成分からなる混合物である。本実施例が適用される軟カプセル剤等のカプセル剤に充填できる有効成分（Ｘ）は、上述の６成分に限らず、ｄｌ−α−トコフェロール、ｄｌ−α−トコフェロール酢酸エステル等のビタミンＥエステル類、リボフラビン、リン酸リボフラビンナトリウム、リン酸ピリドキサール、ヒドロキソコバラミン、ヒドロキソコバラミン酢酸塩、ヒドロキソコバラミン塩酸塩等であっても良く、またそれらの混合物に限らず、それらの単一成分からなるものでも良い。
(Active ingredient (X))
In this example, the active ingredient (X) is a mixture composed of six components of riboflavin butyrate, pyridoxine hydrochloride, d-α-tocophenol, γ-oryzanol, processed potato, and cyanocobalamin. The active ingredient (X) that can be filled in a capsule such as a soft capsule to which this embodiment is applied is not limited to the above six ingredients, but vitamin E esters such as dl-α-tocopherol and dl-α-tocopherol acetate. Riboflavin, sodium riboflavin phosphate, pyridoxal phosphate, hydroxocobalamin, hydroxocobalamin acetate, hydroxocobalamin hydrochloride, etc., and not only a mixture thereof but also a single component thereof .
表５に示す如く、軟カプセル剤中のベンフォチアミンの含量（重量）の経時変化についてみると、軟カプセル剤の恒温恒湿庫への投入開始（表５の「開始」）から６ヶ月経過（表５の「６ヶ月」）により、比較例５の減量は多量であり、実施例８の減量は少量である。本発明の適用により、ビニルピロリドンの架橋重合物を添加することによりベンフォチアミンの劣化を抑制できたことが認められる。 As shown in Table 5, regarding the time-dependent change in the content (weight) of benfotiamine in the soft capsule, 6 months have passed since the start of the soft capsule in the constant temperature and humidity chamber ("Start" in Table 5). ("6 months" in Table 5), the weight loss of Comparative Example 5 is large, and the weight loss of Example 8 is small. It can be seen that by applying the present invention, the degradation of benfotiamine could be suppressed by adding a vinylpyrrolidone cross-linked polymer.
（比較例６及び実施例９〜１０）
表６に示した比較例６及び実施例９〜１０に示す処方に基づき、ベンフォチアミン、有効成分（Ｘ）以外の各成分をアジホモミクサーＭ型（特殊機化工業（株）製）に量り取り、約80℃で加温溶解し、冷後ベンフォチアミン、有効成分（Ｘ）を加え、−0.05MPa以下に減圧しながら均一に攪拌混和したものをソフトカプセル充填機（富士カプセル（株）製）を用い軟カプセル剤を得、それを恒温恒湿庫（40℃、75％ＲＨ）に入れ１ヶ月、６ヶ月後に評価した。
(Comparative Example 6 and Examples 9 to 10)
Based on the prescriptions shown in Comparative Example 6 and Examples 9 to 10 shown in Table 6, each component other than benfotiamine and the active ingredient (X) is added to Ajihomomixer M type (manufactured by Special Machine Industries Co., Ltd.). Weigh out and dissolve at about 80 ° C with heating. After cooling, add benfotiamine and active ingredient (X), and stir and mix evenly under reduced pressure to -0.05 MPa or less. Soft capsule filling machine (Fuji Capsule Co., Ltd.) Soft capsules were obtained and placed in a constant temperature and humidity chamber (40 ° C., 75% RH) and evaluated after 1 month and 6 months.
（有効成分（Ｘ））
有効成分（Ｘ）は表５におけると同一であり、本例では表５におけると同様の６成分からなる混合物である。ビニルピロリドンの架橋重合物（Ｓ）は粒子径が約10μmであり、ビニルピロリドンの架橋重合物（Ｌ）は粒子径が約100μmである。
(Active ingredient (X))
The active ingredient (X) is the same as in Table 5, and in this example, it is a mixture comprising the same 6 ingredients as in Table 5. The vinyl pyrrolidone crosslinked polymer (S) has a particle size of about 10 μm, and the vinyl pyrrolidone crosslinked polymer (L) has a particle size of about 100 μm.
表６に示す如く、軟カプセル剤中のベンフォチアミンの含量（重量）の経時変化についてみると、軟カプセル剤の恒温恒湿庫への投入開始（表６の「開始」）から１ヶ月経過（表６の「１ヶ月」）、６ヶ月経過（表６の「６ヶ月」）により、比較例６の減量は多量であり、実施例９及び実施例１０の減量は少量であり、更に実施例９よりも実施例１０の減量が少量である。本実施例により、粒子径大のビニルピロリドンの架橋重合物を添加することによりベンフォチアミンの劣化をより抑制できたことが認められる。 As shown in Table 6, regarding the time-dependent change in the content (weight) of benfotiamine in the soft capsule, one month has elapsed since the start of charging the soft capsule into the constant temperature and humidity chamber ("Start" in Table 6). (Table 6 “1 month”), 6 months (“6 months” in Table 6), the weight loss of Comparative Example 6 is large, the weight loss of Example 9 and Example 10 is small, further implementation The weight loss of Example 10 is smaller than Example 9. It can be seen from this example that the degradation of benfotiamine could be further suppressed by adding a vinylpyrrolidone crosslinked polymer having a large particle size.
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