JP2009029711A - Vitamin preparation soluble at use and method for producing the same - Google Patents
Vitamin preparation soluble at use and method for producing the same Download PDFInfo
- Publication number
- JP2009029711A JP2009029711A JP2007192058A JP2007192058A JP2009029711A JP 2009029711 A JP2009029711 A JP 2009029711A JP 2007192058 A JP2007192058 A JP 2007192058A JP 2007192058 A JP2007192058 A JP 2007192058A JP 2009029711 A JP2009029711 A JP 2009029711A
- Authority
- JP
- Japan
- Prior art keywords
- granulated product
- vitamin
- water
- mixing
- added
- 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.)
- Granted
Links
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- 150000003722 vitamin derivatives Chemical class 0.000 title claims abstract description 31
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 34
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000011709 vitamin E Substances 0.000 claims abstract description 34
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 34
- 229940046009 vitamin E Drugs 0.000 claims abstract description 34
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Landscapes
- Medicinal Preparation (AREA)
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Abstract
Description
本発明は、固形のビタミンＥ類と非イオン性界面活性剤とを混合し、水を添加しながら混合造粒して得た造粒物に、イノシトールヘキサニコチネート又は／及びニコチン酸類、更に製剤学的に許容される添加物を加えて、アルコールの存在下に混合造粒して得た造粒物からなることを特徴とする用時溶解型ビタミン製剤に関する。
更に詳細には、使用時に、水又は温水、好ましくは温水に添加したときに、製剤の一部が「ままこ（或いは「ダマ」という）」として、水面に浮くことがなく、均一に懸濁／溶解し得る用時溶解型造粒物（以下、用時溶解型造粒物という）及びその簡便な製造方法に関する。
The present invention relates to a granulated product obtained by mixing solid vitamin E and a nonionic surfactant and mixing and granulating the mixture while adding water to inositol hexanicotinate and / or nicotinic acids, and further a formulation. The present invention relates to a use-dissolving vitamin preparation characterized by comprising a granulated product obtained by mixing and granulating in the presence of alcohol with the addition of a pharmaceutically acceptable additive.
More specifically, at the time of use, when added to water or warm water, preferably warm water, a part of the preparation is “unusual” (or “dama”), and does not float on the surface of the water and is uniformly suspended. The invention relates to a meltable granule for use that can be dissolved (hereinafter referred to as meltable granule for use) and a simple production method thereof.
従来、生理活性成分は、錠剤、細粒剤、溶解シロップ剤或いはシロップ剤等の形態で処方され服用されている。一般的に錠剤は、嚥下能力の弱い小児や高齢者にとって服用しにくい製剤である。また、シロップ剤のような液剤は、固形製剤と比較して薬局や病院等での調剤業務に手間がかかるうえ、液状であることと重いこと等により携帯する場合には不便である。
そこで用時溶解型の造粒物からなる製剤が提案されている。この用時溶解型の造粒物は、軽量であり、携帯するのに便利な製剤である。
Conventionally, physiologically active ingredients are formulated and taken in the form of tablets, fine granules, dissolved syrups or syrups. In general, tablets are difficult to take for children and elderly people with weak swallowing ability. In addition, liquid preparations such as syrups are inconvenient when they are carried around due to the fact that they are liquid and heavy, as compared to solid preparations, they require more time for dispensing work at pharmacies and hospitals.
Therefore, a preparation comprising a granulated product which is soluble at the time of use has been proposed. This use-dissolving granulated product is lightweight and convenient for carrying.
ところが、生理活性成分が水に難溶性の性質を有する場合には、せっかく用時溶解型造粒物を調製しても、水又は温水に添加すると水に難溶性の生理活性成分が「ままこ」（いわゆるダマ）として、水面に浮いてしまうことがあった。
この「ままこ」（ダマ）の発生を防ぐために、多量の糖類又は崩壊剤を添加した製剤が提案されているが、かかる製剤は、必然的に一回の服用量が多くなり、服用、調剤、携帯の際に不便となり、また、製造コストが増大するという問題があった。
However, when the physiologically active ingredient has poor water-soluble properties, even if a granulated product that is soluble at the time of use is prepared, when it is added to water or warm water, the physiologically active ingredient that is poorly soluble in water is “ "(So-called lumps), sometimes floating on the surface of the water.
In order to prevent the occurrence of this “mamako” (dama), a preparation to which a large amount of saccharide or disintegrant is added has been proposed. However, such a preparation inevitably increases the dose at one time, and is taken and dispensed. There is a problem that it is inconvenient when being carried and the manufacturing cost increases.
用時溶解型造粒物は、シロップ剤に比べて軽量であり、用時調剤ができることから、携帯に便利である。しかしながら、用時溶解型造粒物の比容積が大きいものは、全体として嵩張るため、服用時、又は調剤での取扱いが不便である。したがって、有効成分、添加する賦形剤、崩壊剤等からなる混合物の造粒品であって、比容積が小さく、かつ流動性の良い用時溶解型造粒物及びその簡便な製造方法の開発が求められているのが現状である。 The use-dissolved granulated product is lighter than the syrup agent, and can be prepared for use, so it is convenient to carry. However, when the specific volume of the dissolution granule at the time of use is large as a whole, it is inconvenient to handle at the time of taking or dispensing. Therefore, development of a granulated product of a mixture comprising an active ingredient, an excipient to be added, a disintegrant, etc., having a small specific volume and good fluidity, and a simple production method thereof Is currently required.
最近、ビタミンＥの抗酸化作用によるＬＤＬの酸化防止、それに伴うＨＤＬの増大によるコレステロールの減少等での動脈効果の予防、更にはイノシトールが細胞膜を構成するリン脂質の重要な部分であることに着目し、固形のビタミンＥ類及びイノシトール等のビタミン類を含有するビタミンＥ含有製剤、或いはサプリメントが数多く登場してきているが、その多くは錠剤、カプセル剤等の形態であり、固形のビタミンＥ類を含有する用時溶解型のビタミン剤は、これまで開発されていない。 Recently, attention has been paid to the prevention of LDL oxidation by the antioxidant action of vitamin E, the prevention of arterial effects such as cholesterol reduction due to the increase of HDL, and the fact that inositol is an important part of phospholipids constituting cell membranes. However, many vitamin E-containing preparations or supplements containing solid vitamin E and vitamins such as inositol have appeared, many of which are in the form of tablets, capsules, etc. No on-the-spot vitamin preparation has been developed so far.
ところで、ショ糖脂肪酸エステルの水溶液又は水性の分散液に、固体のビタミンＥ類を分散させ、更にそこに固体のビタミンＣ類及び／又は他の有効成分を配合することによって、固体のビタミンＥ類、ビタミンＣ類及びショ糖脂肪酸エステルを含有する湿式造粒に適した、流動性及び安定性を有する粒状組成物が得られることが報告されている（例えば特許文献１参照）。 By the way, solid vitamin E is dispersed by dispersing solid vitamin E in an aqueous solution or aqueous dispersion of sucrose fatty acid ester, and further blending solid vitamin C and / or other active ingredients therein. It has been reported that a granular composition having fluidity and stability suitable for wet granulation containing vitamin C and sucrose fatty acid ester can be obtained (see, for example, Patent Document 1).
また、水に難溶性の生理活性成分と、非イオン性界面活性剤及び／又はアニオン系界面活性剤とを混合し、次いで水膨潤性高分子化合物に担持させた後、造粒することにより、水に難溶性の生理活性成分の溶出性に優れ、さらに適切な硬度を有する固体製剤が製造できることが報告されている（例えば特許文献２参照）。
しかしながら、この従来の製剤にあっては、例えば特許文献１に記載の粒状組成物の場合は、固体のビタミンＥ類をショ糖脂肪酸エステルの水溶液に分散させた分散液を用いる方法であり、また、特許文献２に記載の固形製剤の場合には、水に難溶性の生理活性成分を、液状の非イオン界面活性剤及び／又はアニオン界面活性剤に添加して撹拌して、単に均一分散させる方法でしかない。
そのため、調製された粒状組成物、或いは固形製剤は、その服用にあたって水又は温水に添加したときに、不溶物である「ままこ」が水面に浮くことが散見されている。
したがって、服用時に、水又は温水に添加したときに「ままこ」として、水面に不溶物が浮くことなく、速やかに均一に懸濁／溶解し得る用時溶解型の、固形のビタミンＥ類含有の造粒物、及びその簡便な製造方法が望まれていた。
However, in this conventional preparation, for example, in the case of the granular composition described in Patent Document 1, it is a method of using a dispersion in which solid vitamin E is dispersed in an aqueous solution of sucrose fatty acid ester. In the case of the solid preparation described in Patent Document 2, a physiologically active component hardly soluble in water is added to a liquid nonionic surfactant and / or anionic surfactant and stirred, and simply dispersed uniformly. It ’s just the way.
For this reason, when the prepared granular composition or solid preparation is added to water or warm water during its use, it has been found that “mamako” which is an insoluble substance floats on the water surface.
Therefore, when taken to water or warm water, it contains a solid vitamin E that can be quickly and uniformly suspended / dissolved without causing insoluble matter to float on the water surface when added to water or warm water. A granulated product and a simple production method thereof have been desired.
本発明は、上記の現状を鑑み、従来品に比べて比容積が小さく、かつ流動性が良く、さらには有効成分の不快味を軽減させ、服用、調剤ならびに携帯に便利であって、あるいは温湯、水等に速やかに溶解させることにより、容易に服用することができるビタミンＥ類を含有する用時溶解型造粒物を提供することを課題とする。 In view of the above-mentioned present situation, the present invention has a smaller specific volume and better fluidity than conventional products, and further reduces the unpleasant taste of active ingredients, and is convenient for taking, dispensing and carrying, or hot water. It is an object of the present invention to provide an on-use dissolution type granulated product containing vitamin E that can be easily taken by quickly dissolving it in water or the like.
本発明者らは、上記課題を解決するために鋭意検討した結果、固形のビタミンＥ類と非イオン性界面活性剤とを混合し、水を添加しながら混合造粒して得た造粒物に、イノシトールヘキサニコチネート又は／及びニコチン酸類、更に製剤学的に許容される添加物を加えて、アルコールの存在下に混合造粒して得た造粒物が、上記の問題点を解決するものであること確認し、本発明を完成させるに至った。 As a result of intensive studies to solve the above problems, the present inventors have mixed a solid vitamin E and a nonionic surfactant, and obtained a granulated product obtained by mixing and granulating while adding water. In addition, inositol hexanicotinate and / or nicotinic acid and further pharmaceutically acceptable additives are added, and the granulated product obtained by mixing and granulating in the presence of alcohol solves the above problems. It was confirmed that the present invention was completed.
したがって本発明は、その基本的態様として、固形のビタミンＥ類と非イオン性界面活性剤とを混合し、水を添加しながら混合造粒して得た造粒物に、イノシトールヘキサニコチネート又は／及びニコチン酸類、更に製剤学的に許容される添加物を加えて、アルコールの存在下に混合造粒して得た造粒物からなることを特徴とする用時溶解型ビタミン製剤である。 Therefore, in the present invention, as a basic aspect, inositol hexanicotinate or inositol hexanicotinate is added to a granulated product obtained by mixing solid vitamin E and a nonionic surfactant and mixing and granulating the mixture while adding water. And / or a nicotinic acid, and further a pharmaceutically acceptable additive, and a granulated product obtained by mixing and granulating in the presence of alcohol.
より具体的には、本発明は、固形のビタミンＥ類がコハク酸トコフェロールカルシウムであり、非イオン性界面活性剤が、ショ糖脂肪酸エステルである用時溶解型ビタミン製剤である。 More specifically, the present invention is a vitamin preparation at the time of use in which the solid vitamin E is tocopherol calcium succinate and the nonionic surfactant is a sucrose fatty acid ester.
したがって、最も具体的な本発明は、コハク酸トコフェロールカルシウムとショ糖脂肪酸エステルとを混合し、該混合物に水を添加しながら混合造粒して得た造粒物に、イノシトールヘキサニコチネート及びニコチン酸類、更に製剤学的に許容される添加物を加え、アルコールの存在下に混合造粒して得た造粒物からなることを特徴とする用時溶解型ビタミン製剤である。 Therefore, the most specific of the present invention is that inositol hexanicotinate and nicotine are obtained by mixing tocopherol calcium succinate and sucrose fatty acid ester and mixing and granulating the mixture while adding water. It is a vitamin preparation which is dissolved at the time of use, comprising a granulated product obtained by mixing and granulating an acid and further a pharmaceutically acceptable additive and in the presence of alcohol.
また本発明は、別の態様として上記の用時溶解型ビタミン製剤の製造方法であり、具体的には、固形のビタミンＥ類と非イオン性界面活性剤とを混合し、水を添加しながら造粒して得た造粒物に、イノシトールヘキサニコチネート又は／及びニコチン酸類、更に製剤学的に許容される添加物を加えて、アルコールの存在下に混合造粒したことを特徴とする用時溶解型ビタミン製剤の製造方法である。
なお、本発明において「用時溶解」とは、服用時に、水又は温水に添加したときに完全に溶解するか、一部懸濁状態で溶解し、分散していることを意味する。
Moreover, the present invention is a method for producing the above-mentioned use-dissolving vitamin preparation as another aspect, specifically, while mixing solid vitamin E and a nonionic surfactant and adding water. Ingredients obtained by adding inositol hexanicotinate and / or nicotinic acid and further pharmaceutically acceptable additives to the granulated product obtained by granulation, and mixing and granulating in the presence of alcohol This is a method for producing a time-dissolving vitamin preparation.
In the present invention, “dissolving at the time of use” means that it is dissolved completely when added to water or warm water at the time of taking or partially dissolved and dispersed.
本発明により、比容積が小さく、流動性の良い、製造時に生理活性成分同士の凝集や製造機器への付着等を起こすことなく、極めて容易に造粒、製剤化を行うことができる、ビタミンＥ類及びイノシトールヘキサニコチネート又は／及びニコチン酸を含有する用時溶解型造粒物を提供することができる。
本発明により提供される用時溶解型造粒物は、安定性に優れ、保管時に変色しにくく、含有されるビタミンＥ類等の生理活性成分の溶出性に優れ、さらに適切な硬度を有するものである。また、生理活性成分の苦みを軽減させると共に、嵩張らないで、処方や携帯に便利であり、必要なときに、そのままでも、あるいは水又は温水に懸濁／溶解させても「ままこ」にならず、簡便に服用することができる利点を有している。
According to the present invention, vitamin E has a small specific volume, good fluidity, and can be granulated and formulated very easily without causing aggregation of physiologically active ingredients and adhesion to production equipment during production. And an inositol hexanicotinate or / and nicotinic acid can be provided.
The on-use dissolution granule provided by the present invention has excellent stability, hardly discolors during storage, has excellent elution properties of physiologically active components such as vitamin E contained therein, and has an appropriate hardness. It is. In addition, it reduces the bitterness of physiologically active ingredients and is not bulky. It is convenient for prescription and portability. When necessary, it can be left “as is” or suspended or dissolved in water or warm water. Therefore, it has an advantage that it can be taken easily.
以下に、本発明を詳細に説明する。
本明細書中の用語において、固形のビタミンＥ類とは、例えば、トコフェロールニコチン酸エステル、コハク酸トコフェロール、コハク酸トコフェロールカルシウム等、常温下で固形のものであり、好ましくはコハク酸トコフェロールカルシウムである。
The present invention is described in detail below.
In the terminology in the present specification, solid vitamin E is, for example, a tocopherol nicotinic acid ester, a tocopherol succinate, a tocopherol calcium succinate or the like, which is solid at room temperature, preferably tocopherol calcium succinate. .
コハク酸トコフェロールカルシウムは、白色〜帯黄白色の粉末でにおいはない。水、エタノール（９５％）に殆ど溶けず、物理的にも化学的にも安定な粉末として、製剤上、特に錠剤直打用のビタミンＥ原薬として配合され、繁用されているビタミンＥである。 Tocopherol calcium succinate is a white to yellowish white powder and does not smell. Vitamin E is a commonly used vitamin E drug substance that is hardly soluble in water and ethanol (95%) and is physically and chemically stable, and formulated as a vitamin E drug substance for direct tableting. is there.
この固形のビタミンＥ類、好ましくはコハク酸トコフェロールカルシウムと混合される非イオン界面活性剤としては、ショ糖脂肪酸エステル、モノステアリン酸グリセリド、ポリソルベート４０（ポリオキシエチレンソルビタンモノパルミテート）、ポリソルベート６０（ポリオキシエチレンソルビタンモノステアレート）、ポリソルベート８０（モノオレイン酸ポリオキシエチレンソルビタン）、モノパルミチン酸ソルビタン、ポリオキシエチレン硬化ヒマシ油等が用いられる。その中でもショ糖脂肪酸エステルが好ましい。 Nonionic surfactants mixed with this solid vitamin E, preferably calcium tocopherol succinate, include sucrose fatty acid ester, monostearate glyceride, polysorbate 40 (polyoxyethylene sorbitan monopalmitate), polysorbate 60 ( Polyoxyethylene sorbitan monostearate), polysorbate 80 (polyoxyethylene sorbitan monooleate), sorbitan monopalmitate, polyoxyethylene hydrogenated castor oil and the like are used. Of these, sucrose fatty acid esters are preferred.
かかるショ糖脂肪酸エステルには、ショ糖の中級ないし高級脂肪酸のエステルが含まれ、例えば脂肪酸の炭素数が通常６〜２４、好ましくは８〜２２の飽和及び／又は不飽和脂肪酸の１種又は２種以上のものが用いられる。そのような脂肪酸としては、例えば、カプリル酸、カプリン酸、ラウリン酸、パルミチン酸、ステアリン酸、オレイン酸、エルカ酸、ミリスチン酸、ベヘニン酸等のエステルが挙げられ、好ましくは脂肪酸部分がパルミチン酸から成るショ糖脂肪酸エステルである。 Such sucrose fatty acid esters include intermediate to higher fatty acid esters of sucrose. For example, one or two saturated and / or unsaturated fatty acids having a fatty acid usually having 6 to 24 carbon atoms, preferably 8 to 22 carbon atoms. More than seeds are used. Examples of such fatty acids include esters such as caprylic acid, capric acid, lauric acid, palmitic acid, stearic acid, oleic acid, erucic acid, myristic acid, and behenic acid, and preferably the fatty acid moiety is from palmitic acid. A sucrose fatty acid ester.
固形のビタミンＥ類、好ましくはコハク酸トコフェロールカルシウムに対する非イオン性界面活性剤の含有量は、通常は、固形のビタミンＥ類１００重量部に対して２〜８０重量部、好ましくは３０〜７０重量部使用するのが良い。 The content of the nonionic surfactant with respect to solid vitamin E, preferably tocopherol calcium succinate, is usually 2 to 80 parts by weight, preferably 30 to 70 parts by weight with respect to 100 parts by weight of solid vitamin E. Good to use part.
本発明が提供する造粒物の形態を有する用時溶解型造粒物のビタミン製剤は、上記した固形のビタミンＥ類及び非イオン性界面活性剤との混合物に水を添加しながら混合造粒して得た造粒物に、イノシトールヘキサニコチネート又は／及びニコチン酸類、更に製剤学的に許容される添加物を加えて、アルコールの存在下に混合造粒して得た造粒物からなることを特徴とする用時溶解型ビタミン製剤である。
これまで特許公報等により提案されている造粒物の製法が、ショ糖脂肪酸エステルを水に完全に溶解又は分散させた液として使用しているのに対して、本発明では溶解することなく、固形のビタミンＥ類と混合し、水を添加しながら造粒する点で大きく異なるものである。
The vitamin preparation of the granule for use having the form of granulation provided by the present invention is prepared by mixing granulation while adding water to the mixture of the above-mentioned solid vitamin E and nonionic surfactant. Inositol hexanicotinate or / and nicotinic acid and further pharmaceutically acceptable additives are added to the granulated product obtained in this manner, and the granulated product is obtained by mixing and granulating in the presence of alcohol. This is a vitamin preparation that is soluble at the time of use.
Whereas the production method of the granulated product proposed so far by the patent gazette or the like is used as a liquid in which the sucrose fatty acid ester is completely dissolved or dispersed in water, it does not dissolve in the present invention, It differs greatly in that it is mixed with solid vitamin E and granulated while adding water.
この場合の、水の添加量は、固形のビタミンＥ類の種類、使用量、又は非イオン性界面活性剤の種類、その含有量等により異なり、一概に限定することはできないが、例えば、固形のビタミンＥ類としてコハク酸トコフェロールカルシウムを、非イオン性界面活性剤としてショ糖脂肪酸エステルを用いる場合には、両者の合計量１００重量部に対して０．１〜１０重量部、好ましくは１〜６重量部使用するのが良い。
この段階における造粒は、造粒に使用する水の添加量が少ないため、得られた造粒物は、特に乾燥しなくても、次工程にそのまま付することができるが、必要ならば、乾燥し、整粒して用いることもできる。
In this case, the amount of water added varies depending on the type of solid vitamin E, the amount used, or the type of nonionic surfactant, the content thereof, etc., and cannot be generally limited. When tocopherol calcium succinate is used as the vitamin E, and sucrose fatty acid ester is used as the nonionic surfactant, 0.1 to 10 parts by weight, preferably 1 to 10 parts by weight with respect to 100 parts by weight of both. It is better to use 6 parts by weight.
Since granulation at this stage is small in the amount of water used for granulation, the obtained granulated product can be directly applied to the next step without particularly drying, but if necessary, It can also be dried and sized.
ついで、得られた造粒物にイノシトールヘキサニコチネート又は／及びニコチン酸類、更に製剤学的に許容される添加物を加えて、アルコールの存在下に混合造粒することにより、本発明が目的とする用時溶解型造粒物のビタミン製剤が調製される。 Subsequently, inositol hexanicotinate and / or nicotinic acid and further pharmaceutically acceptable additives are added to the obtained granulated product, and the mixture is granulated in the presence of alcohol, and the object of the present invention is achieved. When used, a vitamin preparation is prepared as a soluble granulated product.
上記の添加剤としては、賦形剤、粘稠剤、乳化剤、矯味剤、結合剤等から選ばれる１種以上が挙げられる。
賦形剤としては、デンプン、α化デンプン、部分α化デンプン、コーンスターチ、結晶セルロース、デキストラン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、果糖、キシリトール、マクロゴール、炭酸マグネシウム、炭酸カルシウム、カオリン、Ｌ−システイン、アラビアゴム、エチルセルロース、カカオ脂、クエン酸又はその塩（例えばナトリウム塩）、ステアリン酸又はその塩、リン酸水素カルシウム、リン酸水素ナトリウム等が挙げられ、好ましくはエリスリトール、α化デンプン、クエン酸ナトリウムである。
As said additive, 1 or more types chosen from an excipient | filler, a thickener, an emulsifier, a corrigent, a binder, etc. are mentioned.
Excipients include starch, pregelatinized starch, partially pregelatinized starch, corn starch, crystalline cellulose, dextran, hydroxypropylcellulose, hydroxypropylmethylcellulose, fructose, xylitol, macrogol, magnesium carbonate, calcium carbonate, kaolin, L-cysteine Arabic gum, ethyl cellulose, cacao butter, citric acid or its salt (for example, sodium salt), stearic acid or its salt, calcium hydrogen phosphate, sodium hydrogen phosphate, etc., preferably erythritol, pregelatinized starch, citric acid Sodium.
粘稠剤としては、キサンタンガム、ポリビニルアルコール（完全又は部分ケン化物）、ポリビニルピロリドン［コリドン（登録商標）Ｋ２５、コリドンＫ３０、コリドンＫ９０等］、カルボキシビニルポリマー、ポリオキシエチレン−ポリオキシプロピレンブロックコポリマー（BASF Wyandotte Corporation、プルロニック、テトロニック等）、セルロース誘導体［メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース（２２０８、２９０６、２９１０等）、カルボキシメチルセルロース、カルボキシエチルセルロース、ニトロセルロース又はそれらの塩等］、ポリエチレングリコール（マクロゴール３００、マクロゴール４００、マクロゴール１５００、マクロゴール４０００等）、コンドロイチン硫酸ナトリウム、アラビアゴム、トラガント、デキストラン（４０、７０等）、ブドウ糖、ソルビトール等を挙げることができる。 As the thickener, xanthan gum, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone [Collidon (registered trademark) K25, Kollidon K30, Kollidon K90, etc.], carboxyvinyl polymer, polyoxyethylene-polyoxypropylene block copolymer ( BASF Wyandotte Corporation, Pluronic, Tetronic, etc.), cellulose derivatives [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910, etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or their salts ], Polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 1500, Mac Goal 4000, etc.), sodium chondroitin sulfate, gum arabic, tragacanth, dextran (40, 70, etc.), may be mentioned glucose, sorbitol and the like.
そのなかでも、キサンタンガム、ポリビニルアルコール（完全又は部分ケン化物）、ポリビニルピロリドン［コリドン（登録商標）Ｋ２５、コリドンＫ３０、コリドンＫ９０等］、セルロース誘導体［メチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース（２２０８、２９０６、２９１０）、カルボキシメチルセルロース又はその塩、ポリエチレングリコール（マクロゴール３００、マクロゴール４００）、デキストラン（７０）］が好ましく使用される。 Among them, xanthan gum, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone [Kollidon (registered trademark) K25, Kollidon K30, Kollidon K90, etc.], cellulose derivatives [methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose ( 2208, 2906, 2910), carboxymethylcellulose or a salt thereof, polyethylene glycol (Macrogol 300, Macrogol 400), dextran (70)] are preferably used.
さらに好ましくは、キサンタンガム、ポリビニルアルコール、ポリビニルピロリドン、メチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース又はその塩、ポリエチレングリコール、デキストランであり、特に好ましくはポリビニルアルコール、メチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、カルボキシメチルセルロース又はその塩、ポリエチレングリコール、デキストランであり、最も好ましくはキサンタンガム、ヒドロキシエチルセルロース、カルボキシメチルセルロースナトリウムがある。 More preferably, xanthan gum, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose or a salt thereof, polyethylene glycol, dextran, particularly preferably polyvinyl alcohol, methyl cellulose, hydroxyethyl cellulose, hydroxy Propyl cellulose, carboxymethyl cellulose or a salt thereof, polyethylene glycol, and dextran, most preferably xanthan gum, hydroxyethyl cellulose, and sodium carboxymethyl cellulose.
これらの粘稠剤は、１種又は２種以上を任意に組み合わせて使用してもよいが、好ましくはキサンタンガム、カルボキシメチルセルロースナトリウムを適当な配合比で使用するのがよい。 These thickening agents may be used alone or in combination of two or more, but preferably xanthan gum and sodium carboxymethylcellulose are preferably used in an appropriate blending ratio.
乳化剤としては、合成添加物であるグリセリン脂肪酸エステルやその誘導体およびショ糖脂肪酸エステル、カルボキシメチルセルロースナトリウム、天然添加物であるレシチン、天然物由来のグァーガム、アラビアゴム、大豆多糖類、タンパク質等がある。これらの乳化剤は、１種又は２種以上を任意に組み合わせて使用してもよい。
好ましくは、グァーガム、カルボキシメチルセルロースナトリウムの両者を適当な配合比として使用するのがよい。
Examples of emulsifiers include glycerin fatty acid esters and derivatives thereof, which are synthetic additives, sucrose fatty acid esters, sodium carboxymethylcellulose, lecithin, which is a natural additive, guar gum derived from natural products, gum arabic, soybean polysaccharide, protein, and the like. These emulsifiers may be used alone or in combination of two or more.
Preferably, both guar gum and sodium carboxymethyl cellulose are used as appropriate blending ratios.
矯味剤としては、アスパルテーム、塩化ナトリウム、カカオ末、キシリトール、クエン酸又はその塩、グリチルリチン酸又はその塩、サッカリン、サッカリンナトリウム、白糖、乳糖、ブドウ糖、マルトース、Ｄ−マンニトール、ｌ−メントール、ＤＬ−リンゴ酸又はその塩を挙げることができ、好ましくはアスパルテーム、サッカリンナトリウム、クエン酸、クエン酸ナトリウムである。 As a corrigent, aspartame, sodium chloride, cacao powder, xylitol, citric acid or salt thereof, glycyrrhizic acid or salt thereof, saccharin, sodium saccharin, sucrose, lactose, glucose, maltose, D-mannitol, 1-menthol, DL-apple An acid or a salt thereof can be mentioned, and aspartame, sodium saccharin, citric acid and sodium citrate are preferable.
結合剤としては、デンプン、α化デンプン、部分α化デンプン、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、デキストリン、ポリビニルピロリドン、プルラン、アラビアゴム、ゼラチン等が挙げられ、好ましくはポリビニルピロリドンである。 Examples of the binder include starch, pregelatinized starch, partially pregelatinized starch, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, polyvinylpyrrolidone, pullulan, gum arabic, and gelatin. Is polyvinylpyrrolidone.
この造粒段階において、更に各種活性成分を添加することも可能であり、総合ビタミン剤として要求される各種ビタミン類、或いは特定のビタミン類を添加することもできる。そのようなビタミン類としては、ビタミンＢ群、ビタミンＣ等の各種ビタミン類を挙げることができる。 In this granulation stage, various active ingredients can be further added, and various vitamins required as a comprehensive vitamin preparation or specific vitamins can be added. Examples of such vitamins include various vitamins such as vitamin B group and vitamin C.
本発明にあっては、上記した製剤学的に許容される添加物に限定されるものではなく、さらに必要に応じて、崩壊剤、崩壊補助剤、流動化剤、滑沢剤等を添加することができる。
崩壊剤としては、アルファー化デンプン、カルボキシメチルスターチナトリウム、カルボキシメチルセルロース又はその塩、含水二酸化ケイ素、グァーガム、クエン酸カルシウム、クロスカルメロースナトリウム、軽質無水ケイ酸、ショ糖脂肪酸エステル、炭酸水素ナトリウム、炭酸マグネシウム、沈降炭酸カルシウム、低置換度ヒドロキシプロピルセルロース、デキストリン、セルロース又はその誘導体、デンプン又はその誘導体等を挙げることができる。
In the present invention, it is not limited to the above-mentioned pharmaceutically acceptable additives, and a disintegrating agent, a disintegrating aid, a fluidizing agent, a lubricant, etc. are further added as necessary. be able to.
Disintegrating agents include pregelatinized starch, sodium carboxymethyl starch, carboxymethyl cellulose or salts thereof, hydrous silicon dioxide, guar gum, calcium citrate, croscarmellose sodium, light anhydrous silicic acid, sucrose fatty acid ester, sodium bicarbonate, carbonate Examples thereof include magnesium, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, dextrin, cellulose or a derivative thereof, starch or a derivative thereof.
崩壊補助剤としては、カルボキシメチルセルロース又はその塩、セルロース又はその誘導体、ステアリン酸、炭酸水素ナトリウム、ヒドロキシプロピルセルロース等を挙げることができる。 Examples of the disintegration aid include carboxymethyl cellulose or a salt thereof, cellulose or a derivative thereof, stearic acid, sodium hydrogen carbonate, hydroxypropyl cellulose and the like.
流動化剤ないし滑沢剤としては、タルク、ステアリン酸マグネシウム、軽質無水ケイ酸、含水二酸化ケイ素、乾燥水酸化アルミニウムゲル、ケイ酸マグネシウム、アラビアゴム、カカオ脂、カルナバロウ、グリセリン、流動パラフィン、ステアリルアルコール、ステアリン酸、乳糖、白糖、フマル酸、ミツロウ等を挙げることができる。
なお、矯味剤は、各造粒物の各製造工程において、必要に応じて同一又は異なった種類のものを添加することができる。
Fluidizers or lubricants include talc, magnesium stearate, light anhydrous silicic acid, hydrous silicon dioxide, dry aluminum hydroxide gel, magnesium silicate, gum arabic, cacao butter, carnauba wax, glycerin, liquid paraffin, stearyl alcohol , Stearic acid, lactose, sucrose, fumaric acid, beeswax and the like.
In addition, the same or different kind of flavoring agent can be added as needed in each manufacturing process of each granulated product.
例えば、本発明の用時溶解型ビタミン剤を得る最終造粒工程において用いられる矯味剤としては、無水クエン酸が好ましい。
この段階において、香料を添加することも可能であり、そのような香料としては、ｌ−メントール、レモン等を挙げることができ、好ましくはレモンである。
なお、本発明においては、必要に応じて、さらに、各種着色剤、安定化剤、吸着剤、防腐剤、湿潤剤、帯電防止剤等、製剤学的に常用・許容されている添加剤を添加することができる。これらの製剤学的に常用・許容される添加剤は、本発明の効果を妨げない範囲で配合することができる。
For example, anhydrous citric acid is preferred as a taste-masking agent used in the final granulation step for obtaining the on-use soluble vitamin preparation of the present invention.
At this stage, a fragrance can be added, and examples of such a fragrance include l-menthol and lemon, preferably lemon.
In the present invention, if necessary, additives such as various colorants, stabilizers, adsorbents, preservatives, wetting agents, antistatic agents and the like that are commonly used and accepted pharmaceutically are added. can do. These pharmaceutically acceptable and acceptable additives can be blended within a range that does not impede the effects of the present invention.
以下、本発明の用時溶解型造粒物であるビタミン剤の製造方法について説明する。
本発明が提供する用時溶解型造粒物であるビタミン剤にあっては、第一工程として、固形のビタミンＥ類と非イオン性界面活性剤とを混合し、水を添加しながら混合造粒して造粒物を調製（一次造粒物：造粒物Ａ）する。
次いで、第二工程として、得られた一次造粒物に、イノシトールヘキサニコチネート又は／及びニコチン酸類、更に製剤学的に許容される添加物を加えて、アルコールの存在下に混合造粒することにより、目的とする本発明の用時溶解型造粒物であるビタミン製剤が、二次造粒物（造粒物Ｂ）として調製される。
これらの各工程は、温度条件は特に制限なく、通常は、室温で行うことができる。
Hereinafter, the manufacturing method of the vitamin preparation which is a melt-on-use granulated product of this invention is demonstrated.
In the vitamin preparation that is a granulation product at the time of use provided by the present invention, as a first step, a solid vitamin E and a nonionic surfactant are mixed and mixed with water. Granulate to prepare a granulated product (primary granulated product: granulated product A).
Next, as a second step, inositol hexanicotinate and / or nicotinic acid and further pharmaceutically acceptable additives are added to the obtained primary granulated product, and mixed and granulated in the presence of alcohol. As a result, a vitamin preparation which is the intended use-dissolving granulated product of the present invention is prepared as a secondary granulated product (granulated product B).
Each of these steps is not particularly limited in temperature conditions, and can usually be performed at room temperature.
本発明にあっては、一次工程で得られた一次造粒物Ａを、第二工程でイノシトールヘキサニコチネート又は／及びニコチン酸類、更に製剤学的に許容される添加物を加えて造粒するに際し、アルコールの存在下に造粒し、二次造粒物Ｂとすることが特徴である。
すなわち、本発明にあっては、この造粒工程を、アルコールを用いて行うことにより、懸濁／溶解時に「ままこ」の発生を抑制した、用時溶解型の造粒物が得られるのである。
In the present invention, the primary granulated product A obtained in the primary step is granulated by adding inositol hexanicotinate or / and nicotinic acids and further pharmaceutically acceptable additives in the second step. In this case, it is characterized in that it is granulated in the presence of alcohol to obtain a secondary granulated product B.
That is, in the present invention, by performing this granulation step using alcohol, a use-dissolved granulated product that suppresses the occurrence of “makko” during suspension / dissolution is obtained. is there.
この場合に使用するアルコールとしては、炭素数１〜４の低級アルコールであり、好ましくはエタノールである。
本発明が提供する造粒物（用時溶解型ビタミン製剤）の製造に用いられる有効成分の水に対する溶解性は、日本薬局方の規定によれば、例えば、コハク酸トコフェロールカルシウムは「水に殆ど溶けない」、イノシトールヘキサニコチネートは「水に殆ど溶けない」、ニコチン酸は「水にやや溶けにくい」で表され、ショ糖脂肪酸エステルについては「水にやや溶けやすいものから、殆ど溶けない」ものがある。
The alcohol used in this case is a lower alcohol having 1 to 4 carbon atoms, preferably ethanol.
According to the provisions of the Japanese Pharmacopoeia, for example, the tocopherol calcium succinate is almost free from water in the solubility of the active ingredient used for the production of the granulated product (dissolved vitamin preparation at the time of use) provided by the present invention. “Insoluble”, inositol hexanicotinate is “not very soluble in water”, nicotinic acid is “slightly insoluble in water”, and sucrose fatty acid esters are “insoluble in water because they are slightly soluble” There is something.
また、所望により添加する製剤学的に許容される添加剤のなかで、キサンタンガムについては「水又は熱湯に溶けやすい」、グァーガムについては「水に徐々にとける、粘稠な液となる」、アスパルテームについては「水に溶けにくい」、サッカリンナトリウムは「水に溶けやすい」、クエン酸ナトリウムについては「水に溶けやすい」、α化デンプンについては「水を加えると膨潤し、粘稠なのり状の液になる」、エリスリトールについては「水にやや溶けやすい」、ポリビニルピロリドンについては「水に溶けやすい。吸湿性である」ことが知られている。 Among the pharmaceutically acceptable additives to be added as desired, xanthan gum is “easily soluble in water or hot water”, and guar gum “is gradually dissolved in water and becomes a viscous liquid”, aspartame Is "not easily soluble in water", saccharin sodium is "soluble in water", sodium citrate is "easily soluble in water", and pregelatinized starch is "swelled when added with water to form a viscous paste-like liquid" It is known that erythritol is “slightly soluble in water” and polyvinylpyrrolidone is “easily soluble in water. Hygroscopic”.
また、本発明が提供する造粒物（用時溶解型ビタミン製剤）の製造に用いられる有効成分のアルコールに対する溶解性は、例えば、エタノール（９５％）に対し、コハク酸トコフェロールカルシウムは「殆ど溶けない」、イノシトールヘキサニコチネートは「殆ど溶けない」、ニコチン酸は「エタノールに可溶」で表され、ショ糖脂肪酸エステルについては「エタノールにやや溶けやすいものから、殆ど溶けない」ものがある。 Further, the solubility of the active ingredient used in the production of the granulated product (dissolved vitamin preparation for use) provided by the present invention in alcohol is, for example, that tocopherol calcium succinate is almost soluble in ethanol (95%). No, inositol hexanicotinate is expressed as “almost insoluble”, nicotinic acid is expressed as “soluble in ethanol”, and sucrose fatty acid esters include “slightly soluble in ethanol, so hardly soluble”.
また、所望により添加する製剤学的に許容される添加剤のなかで、キサンタンガムについては「殆ど溶けない」、グァーガムについては「殆ど溶けない」、アスパルテームについては「殆ど溶けない」、サッカリンナトリウムは「やや溶けない」、クエン酸ナトリウムについては「殆ど溶けない」、α化デンプンについては「溶けない」、エリスリトールについては「溶けにくい」、ポリビニルピロリドンについては「溶けやすい」ことが知られている。 Among the pharmaceutically acceptable additives to be added as desired, xanthan gum is “insoluble”, guar gum is “insoluble”, aspartame is “insoluble”, saccharin sodium is “slightly soluble”. It is known that it does not dissolve, sodium citrate is almost insoluble, pregelatinized starch is insoluble, erythritol is insoluble, and polyvinylpyrrolidone is insoluble.
したがって、これらの組合せにより、本発明の造粒物（用時溶解型ビタミン製剤）は、水等で懸濁／溶解させた場合には、「ままこ（或いは「ダマ」）」とならず、水面に浮くことにならないことも考えられる。 Therefore, by the combination of these, the granulated product of the present invention (in-use dissolved vitamin preparation) does not become “mako” (or “dama”) when suspended / dissolved in water or the like, It is also possible that it will not float on the surface of the water.
本発明が提供する用時溶解型造粒物であるビタミン製剤は、上記のようにして得られた二次造粒物である造粒物Ｂからなる、用時溶解型ビタミン製剤である。
なお、本発明の用時溶解型ビタミン製剤である造粒物Ｂの製造過程で用いる賦形剤であるアルファー化デンプンは、単に水を加えると「ままこ」となってしまう傾向がある。特に、お湯で分散するときに粘稠性を有する「ままこ」ができ、この「ままこ」はなかなか分散しない。したがって、本発明にあっては、目的とする用時溶解型ビタミン製剤である造粒段階で、賦形剤、分散剤、矯味剤、崩壊剤または崩壊補助剤等を添加するのがよい。
なお、得られた本発明の用時溶解型ビタミン製剤（造粒物Ｂ）は、そのまま水、温水等に用時懸濁／溶解し、服用することができるが、さらに、矯味剤、滑沢剤及び香料から選ばれる１種以上を配合した三次造粒物である造粒物Ｃとして、用いることもできる。
The vitamin preparation which is the use-dissolving granule provided by the present invention is a use-dissolving vitamin preparation comprising the granulation B which is the secondary granulation product obtained as described above.
It should be noted that pregelatinized starch, which is an excipient used in the production process of granulated product B, which is a use-dissolving vitamin preparation of the present invention, tends to be “mako” when water is simply added. In particular, when dispersed with hot water, a “mamako” having a consistency can be formed, and this “mamako” is not easily dispersed. Therefore, in the present invention, it is preferable to add an excipient, a dispersant, a corrigent, a disintegrating agent, a disintegrating aid, or the like at the granulation stage, which is the intended use-soluble vitamin preparation.
The obtained use-dissolving vitamin preparation (granulated product B) of the present invention can be suspended / dissolved in water, warm water or the like as it is, and can be taken. It can also be used as the granulated product C which is a tertiary granulated product in which one or more selected from agents and fragrances are blended.
以下に本発明を、実施例により具体的に説明するが、本発明はこれら実施例に限定されるものではない。 EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
実施例１：
［工程１］一次造粒物（Ａ１）の製造方法：
コハク酸トコフェロールカルシウム４１６．４ｇ、ショ糖パルミチン酸エステル２１６．０ｇとをハイスピードミキサー（ＦＳＧＳ４０Ｊ、深江パウテック（株）製）を用いて混合した後、得られた混合物に精製水２５．２ｇを加えて混合し、一次造粒物（Ａ１）を得た。
Example 1 :
[Step 1] Method for producing primary granulated product (A1):
416.4 g of tocopherol calcium succinate and 216.0 g of sucrose palmitate ester were mixed using a high speed mixer (FSGS40J, manufactured by Fukae Pautech Co., Ltd.), and then 25.2 g of purified water was added to the resulting mixture. And mixed to obtain a primary granulated product (A1).
［工程２］二次造粒物（Ｂ１）の製造方法：
更に予めロータースピードミル（Ｐ−１４、フリッチェ社製）で粉砕したイノシトールヘキサニコチネート７５６．０ｇ及びクエン酸ナトリウム１０８０ｇ、ニコチン酸１１３．４ｇ、キサンタンガム１０８ｇ、グァーガム１８０ｇ、アスパルテーム３９．６ｇ、サッカリンナトリウム１４．４ｇ、アルファー化デンプン８１６．６ｇ、エリスリトール５７７８ｇ、ポリビニルピロリドン１８３．６ｇ及び一次粒物（造粒物（Ａ１））を、前記ハイスピードミキサーを用いて混合した後、無水エタノールで造粒した。これを常法によりエタック高温槽（楠本化成（株）製）で５０℃、１６時間乾燥させた後、篩にて整粒を行い、二次造粒物（造粒物（Ｂ１））を得た。
[Step 2] Method for producing secondary granulated product (B1):
Further, 756.0 g of inositol hexanicotinate and 1080 g of sodium citrate, 113.4 g of nicotinic acid, 108 g of xanthan gum, 180 g of guar gum, 39.6 g of aspartame, 14% sodium saccharin and 14% saccharin sodium previously pulverized by a rotor speed mill (P-14, manufactured by Fritche). 4 g, pregelatinized starch 816.6 g, erythritol 5778 g, polyvinylpyrrolidone 183.6 g and primary granules (granulated product (A1)) were mixed using the high-speed mixer, and then granulated with absolute ethanol. This was dried at 50 ° C. for 16 hours in an ETAC high temperature bath (manufactured by Enomoto Kasei Co., Ltd.) by a conventional method and then sized with a sieve to obtain a secondary granulated product (granulated product (B1)). It was.
［工程３］三次造粒物（Ｃ１）の製造方法：
上記で得た造粒物（Ｂ１）４８５１ｇ、無水クエン酸４５０ｇ、軽質無水ケイ酸４５．０ｇ及びプレミックス香料５４．０ｇをボーレコンテナミキサー（ＬＭ２０ ＭＣ２０、コトブキ技研工業（株）製）を用いて混合することで、本発明の用時溶解型ビタミン剤（造粒物（Ｃ１））を得た。
[Step 3] Method for producing tertiary granulated product (C1):
4851 g of the granulated product (B1) obtained above, 450 g of anhydrous citric acid, 45.0 g of light anhydrous silicic acid, and 54.0 g of premixed fragrance were used using a Boule container mixer (LM20 MC20, manufactured by Kotobuki Giken Co., Ltd.). By mixing, the use-soluble vitamin preparation (granulated product (C1)) of the present invention was obtained.
実施例２：
［工程１］一次造粒物（Ａ２）の製造方法：
前記コハク酸トコフェロールカルシウム２２２．６ｇ、前記ショ糖パルミチン酸エステル１２０．０ｇとを前記ハイスピードミキサーを用いて混合した後、精製水１４．０ｇを加えて混合し、一次造粒物（Ａ２）を得た。
Example 2 :
[Step 1] Method for producing primary granulated product (A2):
After mixing the said tocopherol calcium succinate 222.6g and the said sucrose palmitate ester 120.0g using the said high speed mixer, 14.0g of purified water is added and mixed, and a primary granulated material (A2) is obtained. Obtained.
［工程２］二次医造粒物（Ｂ２）の製造方法：
更に予め前記ロータースピードミルで粉砕した前記イノシトールヘキサニコチネート４００ｇ及びクエン酸ナトリウム６００ｇ、ニコチン酸６０ｇ、キサンタンガム６０ｇ、グァーガム１００ｇ、アスパルテーム２２ｇ、サッカリンナトリウム８．０ｇ、アルファー化デンプン４８５．４ｇ、エリスリトール３２１０ｇ、ポリビニルピロリドン１０２ｇ及び一次造粒物（Ａ２）を、前記ハイスピードミキサーを用いて混合した後、無水エタノールで造粒する。これを常法により前記エタック高温槽で５０℃、１６時間乾燥させた後、篩にて整粒を行い、二次造粒物（Ｂ２）とした。
[Step 2] Method for producing secondary medicine granulated product (B2):
Further, 400 g of the inositol hexanicotinate and 600 g of sodium citrate, 60 g of nicotinic acid, 60 g of xanthan gum, 100 g of guar gum, 22 g of aspartame, 8.0 g of saccharin sodium, 485.4 g of pregelatinized starch, 3210 g of erythritol, polyvinyl Pyrrolidone 102g and primary granulated product (A2) are mixed using the high speed mixer and then granulated with absolute ethanol. This was dried at 50 ° C. for 16 hours in the above-mentioned Etak high-temperature bath by a conventional method, and then sized with a sieve to obtain a secondary granulated product (B2).
［工程３］三次造粒物（Ｃ２）の製造方法：
上記で得た二次造粒物（Ｂ２）５３９０ｇ、無水クエン酸５００ｇ、軽質無水ケイ酸５０ｇ及び香料６０ｇを、ボーレコンテナミキサーを用いて混合することで、本発明の用時溶解型ビタミン剤（三次造粒物（Ｃ２））を得た。
[Step 3] Method for producing tertiary granulated product (C2):
By mixing 5390 g of the secondary granulated product (B2) obtained above, 500 g of anhydrous citric acid, 50 g of light anhydrous silicic acid, and 60 g of fragrance using a Boule container mixer, the use-dissolving vitamin preparation of the present invention ( A tertiary granulated product (C2)) was obtained.
比較例１：
前記実施例１の工程１における一次造粒物（Ａ１）の造粒において、溶媒としてエチルアルコールを用いて造粒したところ、コハク酸トコフェロールカルシウムとショ糖パルミチン酸エステルが分離した。
この分離した造粒物を用いて、以下実施例１の工程２及び工程３の方法に準拠して、最終造粒物（三次造粒物）を調製した。得られた造粒物３．０ｇを水１００ｇに溶解分散させようとしたがままこになった。
Comparative Example 1 :
In the granulation of the primary granulated product (A1) in Step 1 of Example 1, granulation was performed using ethyl alcohol as a solvent. As a result, tocopherol calcium succinate and sucrose palmitate were separated.
Using this separated granulated product, a final granulated product (tertiary granulated product) was prepared according to the method of Step 2 and Step 3 of Example 1 below. An attempt was made to dissolve and disperse 3.0 g of the obtained granulated product in 100 g of water, but it remained.
比較例２：
前記実施例２の工程１における一次造粒物（Ａ２）の造粒において、溶媒としてエチルアルコールを用いて造粒したところ、コハク酸トコフェロールカルシウムとショ糖パルミチン酸エステルが分離した。
この分離した造粒物を用いて、以下実施例１の工程２及び工程３の方法に準拠して、最終造粒物（三次造粒物）を調製した。得られた造粒物３．０ｇを水１００ｇに溶解分散させようとしたがままこになった。
Comparative Example 2 :
In the granulation of the primary granulated product (A2) in Step 1 of Example 2, when granulation was performed using ethyl alcohol as a solvent, tocopherol calcium succinate and sucrose palmitate were separated.
Using this separated granulated product, a final granulated product (tertiary granulated product) was prepared according to the method of Step 2 and Step 3 of Example 1 below. An attempt was made to dissolve and disperse 3.0 g of the obtained granulated product in 100 g of water, but it remained.
比較例３：
［工程１］
上記実施例１の［工程１］と同様にして、一次造粒物（Ａ１）を得た。
Comparative Example 3 :
[Step 1]
In the same manner as in [Step 1] of Example 1, a primary granulated product (A1) was obtained.
［工程２］二次造粒物（Ｂ３）の製造方法（溶媒として水を使用）：
更に予め前記ロータースピードミルで粉砕したイノシトールヘキサニコチネート７．５６ｇ、クエン酸ナトリウム１０．８０ｇ、ニコチン酸１．１３４ｇ、キサンタンガム１．０８ｇ、グァーガム１．８０ｇ、アスパルテーム０．３９６ｇ、サッカリンナトリウム０．１４４ｇ、アルファー化デンプン８．１６６ｇ、エリスリトール５７．７８ｇ、ポリビニルピロリドン１．８３６ｇ及び一次造粒物（Ａ１）６．５７ｇを、乳鉢を用いて混合後乳鉢内に精製水約６ｇを添加し、混合造粒する。これを常法により前記エタック高温槽で５０℃、１６時間乾燥させた後、篩にて整粒を行い、二次造粒物（Ｂ３）とした。
[Step 2] Method for producing secondary granulated product (B3) (using water as solvent):
Furthermore, 7.56 g of inositol hexanicotinate previously ground in the rotor speed mill, 10.80 g of sodium citrate, 1.134 g of nicotinic acid, 1.08 g of xanthan gum, 1.80 g of guar gum, 0.396 g of aspartame, 0.144 g of saccharin sodium, 8.166 g of pregelatinized starch, 57.78 g of erythritol, 1.836 g of polyvinylpyrrolidone and 6.57 g of primary granulated product (A1) were mixed using a mortar, and then about 6 g of purified water was added to the mortar and mixed granulated. To do. This was dried at 50 ° C. for 16 hours in the above-mentioned Etak high-temperature bath by a conventional method, and then sized with a sieve to obtain a secondary granulated product (B3).
［工程３］三次造粒物（Ｃ３）の製造方法：
上記工程２で得られた二次造粒物（Ｂ３）４８．５１ｇ、無水クエン酸４．５０ｇ、軽質無水ケイ酸０．４５０ｇ、及びプレミックス香料０．５４０ｇを、前記ボーレコンテナミキサーを用いて混合することで本品（造粒物（Ｃ３））を得た。
この造粒物（Ｃ３）３．０ｇを水１００ｇに溶解分散させようとしたが、ままこになった。
[Step 3] Method for producing tertiary granulated product (C3):
48.51 g of the secondary granulated product (B3) obtained in Step 2 above, 4.50 g of anhydrous citric acid, 0.450 g of light anhydrous silicic acid, and 0.540 g of premix fragrance were added using the Bole container mixer. This product (granulated product (C3)) was obtained by mixing.
An attempt was made to dissolve and disperse 3.0 g of this granulated product (C3) in 100 g of water, but it remained.
比較例４：
［工程１］
上記実施例１の［工程１］と同様にして、一次造粒物（Ａ１）を得た。
Comparative Example 4 :
[Step 1]
In the same manner as in [Step 1] of Example 1, a primary granulated product (A1) was obtained.
［工程２］二次造粒物（Ｂ４）の製造方法（溶媒の無使用）：
更に予め前記ロータースピードミルで粉砕したイノシトールヘキサニコチネート７．５６ｇ、クエン酸ナトリウム１０．８０ｇ、ニコチン酸１．１３４ｇ、キサンタンガム１．０８ｇ、グァーガム１．８０ｇ、アスパルテーム０．３９６ｇ、サッカリンナトリウム０．１４４ｇ、アルファー化デンプン８．１６６ｇ、エリスリトール５７．７８ｇ、ポリビニルピロリドン１．８３６ｇ及び一次造粒物（Ａ１）６．５７ｇを、溶媒を添加することなく、乳鉢を用いて混合造粒する。これを常法により前記エタック高温槽で５０℃、１６時間乾燥させた後、篩にて整粒を行い、二次造粒物（Ｂ４）とした。
[Step 2] Method for producing secondary granulated product (B4) (no solvent used):
Furthermore, 7.56 g of inositol hexanicotinate previously ground in the rotor speed mill, 10.80 g of sodium citrate, 1.134 g of nicotinic acid, 1.08 g of xanthan gum, 1.80 g of guar gum, 0.396 g of aspartame, 0.144 g of saccharin sodium, 8.166 g of the pregelatinized starch, 57.78 g of erythritol, 1.836 g of polyvinylpyrrolidone and 6.57 g of the primary granulated product (A1) are mixed and granulated using a mortar without adding a solvent. This was dried at 50 ° C. for 16 hours in the above-mentioned Etak high-temperature bath by a conventional method, and then sized with a sieve to obtain a secondary granulated product (B4).
［工程３］三次造粒物（Ｃ４）の製造方法：
上記工程２で得られた二次造粒物（Ｂ４）４８．５１ｇ、無水クエン酸４．５０ｇ、軽質無水ケイ酸０．４５０ｇ、及びプレミックス香料０．５４０ｇを、前記ボーレコンテナミキサーを用いて混合することで三次造粒物（Ｃ４）を得た。
この三次造粒物（Ｃ４）３．０ｇを水１００ｇに溶解分散させようとしたが、ままこになった。
[Step 3] Method for producing tertiary granulated product (C4):
48.51 g of the secondary granulated product (B4) obtained in Step 2 above, 4.50 g of anhydrous citric acid, 0.450 g of light anhydrous silicic acid, and 0.540 g of premix fragrance were added using the Boule container mixer. A tertiary granulated product (C4) was obtained by mixing.
An attempt was made to dissolve and disperse 3.0 g of this tertiary granulated product (C4) in 100 g of water, but it remained untreated.
試験例１：流動性の評価
造粒物の流動性を、ガラス容器に対する付着性により、以下の方法で評価した。
（１）実施例１〜２及び比較例１〜４で得られた二次造粒物の一定量を試験管に充填して、試験管底を数回叩いた後、試験管を逆さにし、造粒物が滑らかに落下するか、叩けば落下するか、叩いても落下しにくいかを目視で評価して比較した。
その結果、実施例１〜２の造粒物の流動性は比較例１〜４の造粒物に比して良好であった。
Test Example 1: Evaluation of fluidity The fluidity of the granulated product was evaluated by the following method based on adhesion to a glass container.
(1) After filling a certain amount of the secondary granulated product obtained in Examples 1-2 and Comparative Examples 1-4 into a test tube and hitting the bottom of the test tube several times, the test tube was inverted, A comparison was made by visually evaluating whether the granulated material falls smoothly, if it is tapped, or if it is difficult to fall even if tapped.
As a result, the fluidity of the granulated products of Examples 1-2 was better than that of Comparative Examples 1-4.
試験例２：造粒物の製造機械への付着性の評価
造粒物の製造機械への付着性を評価した。
その結果、実施例１〜２で得られた二次造粒物の製造機械への付着は、僅かしか認められなかった。
また、比較例１〜４で得られた造粒物の製造機械への付着も、実施例１〜２と同様に僅かしか認められなかった。
Test Example 2: Evaluation of Adhesiveness of Granulated Product to Manufacturing Machine The adhesiveness of the granulated product to the manufacturing machine was evaluated.
As a result, the adhesion of the secondary granulated product obtained in Examples 1 and 2 to the production machine was only slightly recognized.
Moreover, the adhesion to the manufacturing machine of the granulated material obtained by Comparative Examples 1-4 was also recognized only slightly similarly to Examples 1-2.
試験例３：変色性・安定性の評価
前記実施例１〜２及び比較例１〜４で得られた造粒物をガラス瓶に充填し密栓した。これを４０℃に保存したときの４週間、８週間、１２週間後の色差を目視で評価した。
Test Example 3: Evaluation of Discoloration and Stability Granules obtained in Examples 1-2 and Comparative Examples 1-4 were filled into glass bottles and sealed. The color difference after 4 weeks, 8 weeks and 12 weeks when stored at 40 ° C. was visually evaluated.
その結果、前記実施例１〜２のショ糖パルミチン酸エステルを用い、本発明方法により調製した造粒物は、比較例１〜４により調製した造粒物と比べると格段に変色しにくいものであり、その安定性において優れたものであることが判明した。 As a result, the granulated product prepared by the method of the present invention using the sucrose palmitate of Examples 1 and 2 was much less likely to be discolored than the granulated product prepared by Comparative Examples 1 to 4. And it has been found to be excellent in stability.
試験例４：「ままこ」発生の評価
前記実施例１〜２で得られた造粒物１０ｇを容器中の水又は温水１００ｇ中に、好ましくは温水１００ｇ中へ添加後又は添加しながら撹拌することにより、「ままこ」が生成することなく、速やかに均一な溶解液とすることができた。また、予め容器に必要量の造粒物を添加したのち水又は温水で、好ましくは温水を注ぎ込んだ後又は注ぎながら撹拌することにより速やかに均一な溶解液とすることができた。また、同一の条件下で比較例１〜４の造粒物を試験した。ままこの発生は目視で確認した。
その結果を表２に示した。
Test Example 4: Evaluation of “Mamako” Occurrence 10 g of the granulated product obtained in Examples 1 and 2 above was added to 100 g of water or warm water in a container, preferably 100 g of hot water, or stirred while being added. As a result, “Mamako” was not generated, and a uniform solution could be quickly formed. Further, after adding a necessary amount of granulated material to the container in advance, it was possible to quickly obtain a uniform solution by stirring with water or warm water, preferably after pouring or warm water. Moreover, the granulated material of Comparative Examples 1-4 was tested on the same conditions. This occurrence was confirmed visually.
The results are shown in Table 2.
本発明により、従来品に比べて比容積が小さく、流動性の良い、かつ有効成分の不快味を軽減させ、服用、調剤ならびに携帯に便利であって、そのままでも、あるいは水、温湯等に溶解させることにより、容易に服用することができるビタミンＥ類を含有する用時溶解型造粒物が提供される。
本発明が提供する用時溶解型ビタミン剤は、服用時に、水又は温水等に添加したときに固形のビタミンＥ類が「ままこ」にならず、均一に懸濁／溶解し得るものであり、産業上有用である。
According to the present invention, the specific volume is smaller than that of conventional products, the fluidity is good, and the unpleasant taste of the active ingredient is reduced. It is convenient for taking, dispensing and carrying, and can be used as it is or dissolved in water, hot water, etc. Thus, a use-dissolving granulated product containing vitamin E that can be easily taken is provided.
The use-dissolvable vitamin preparation provided by the present invention is a solid vitamin E compound that does not become “remaining” when added to water or warm water at the time of taking, and can be suspended / dissolved uniformly. , Industrially useful.
Claims (5)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10298074A (en) * | 1997-04-25 | 1998-11-10 | Grelan Pharmaceut Co Ltd | Composition containing vitamins |
| JP2006143613A (en) * | 2004-11-17 | 2006-06-08 | Shionogi & Co Ltd | Vitamin composition |
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| JPH10298074A (en) * | 1997-04-25 | 1998-11-10 | Grelan Pharmaceut Co Ltd | Composition containing vitamins |
| JP2006143613A (en) * | 2004-11-17 | 2006-06-08 | Shionogi & Co Ltd | Vitamin composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104799302A (en) * | 2014-01-25 | 2015-07-29 | 天津中瑞药业股份有限公司 | Inositol nicotinate nutrition fortification capsule preparation metho |
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