JP2003146890A - Aqueous colloid dispersion - Google Patents
Aqueous colloid dispersionInfo
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- JP2003146890A JP2003146890A JP2001342771A JP2001342771A JP2003146890A JP 2003146890 A JP2003146890 A JP 2003146890A JP 2001342771 A JP2001342771 A JP 2001342771A JP 2001342771 A JP2001342771 A JP 2001342771A JP 2003146890 A JP2003146890 A JP 2003146890A
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- aqueous
- added
- solution
- aqueous solution
- sulfate
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- Colloid Chemistry (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Emulsifying, Dispersing, Foam-Producing Or Wetting Agents (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は高カロリー輸液用の
微量元素製剤として有用な、鉄を含有する水性コロイド
分散液及びその製造法に関する。TECHNICAL FIELD The present invention relates to an aqueous colloidal dispersion containing iron, which is useful as a trace element preparation for high-calorie infusion, and a method for producing the same.
【０００２】[0002]
【従来の技術】高カロリー輸液療法に用いられている微
量元素製剤は、我国において高カロリー輸液療法が開始
され、それによる亜鉛欠乏症が発見された結果、まず亜
鉛の補給を目的として開発された。以来、種々の医療機
関におけるその他の微量元素を含めた院内処方の検討お
よびその使用を経て、１９９２年に塩化第二鉄９．４６
ｍｇ、塩化マンガン３．９５８ｍｇ、硫酸亜鉛１７．２
５ｍｇ、硫酸銅１．２４８ｍｇおよびヨウ化カリウム
０．１６６ｍｇを含有する２ｍＬ容量の製剤が上市され
た。その後塩化マンガン量が０．１９７９ｍｇとされ、
更に、２００１年にマンガンを含有しない製剤が上市さ
れている。2. Description of the Related Art A trace element preparation used for high calorie infusion therapy was first developed for the purpose of zinc supplementation as a result of the initiation of high calorie infusion therapy in Japan and the discovery of zinc deficiency. Since then, after studying and using in-hospital prescriptions including other trace elements in various medical institutions, ferric chloride 9.46 was found in 1992.
mg, manganese chloride 3.958 mg, zinc sulfate 17.2
A 2 mL volume formulation containing 5 mg, 1.248 mg copper sulfate and 0.166 mg potassium iodide was launched. After that, the amount of manganese chloride was set to 0.1979 mg,
Furthermore, a manganese-free preparation was put on the market in 2001.
【０００３】これらの製剤は、経口・経腸管栄養補給が
不能又は不十分で高カロリー静脈栄養に頼らざるを得な
い場合の微量元素、例えば亜鉛、鉄、銅、マンガン、ヨ
ウ素等の補給を目的とするもので、高カロリー静脈栄養
輸液に添加して点滴静注して使用されている。These preparations are intended to supplement trace elements such as zinc, iron, copper, manganese and iodine when oral / enteral nutritional supplementation is impossible or insufficient and high calorie parenteral nutrition must be relied upon. It is used as an intravenous drip infusion added to a high calorie parenteral nutrition infusion.
【０００４】当該製剤は微量元素として鉄を含有すると
ころから、水酸化第二鉄の沈澱を防止するために鉄をコ
ロイドとして、安定的に分散させる操作が必要であり、
従来から院内処方により取得された経験から、ウシ由来
のコンドロイチン硫酸ナトリウムによる処方が行われて
きた。Since the preparation contains iron as a trace element, it is necessary to stably disperse iron as a colloid in order to prevent the precipitation of ferric hydroxide.
From the experience obtained by in-hospital prescribing, bovine-derived sodium chondroitin sulfate has been prescribing.
【０００５】コンドロイチン硫酸ナトリウムの起源とし
ては、ウシの他サメが知られているが、この物質は種々
の分子量域を有すると共に、いくつかの異性体を含む混
合物であり、その８０％をコンドロイチン−４−硫酸ナ
トリウムとコンドロイチン−６−硫酸ナトリウムが占め
る少なくとも５種類の異性体のあることが確認されてい
る。As a source of sodium chondroitin sulfate, other sharks of bovine are known, but this substance has a variety of molecular weight ranges and is a mixture containing several isomers, of which 80% is chondroitin- It has been confirmed that there are at least five isomers occupied by sodium 4-sulfate and chondroitin-6-sodium sulfate.
【０００６】また当該微量元素製剤の調製方法として
は、「まず塩化第二鉄を注射用蒸留水で溶解（約pH１で
鉄は溶解する）させ、他の元素試薬を加え、コンドロイ
チン硫酸ナトリウム水溶液中に攪拌冷却下０．１ｍｏｌ
／Ｌ水酸化ナトリウム溶液と交互に添加してpH６．０に
調整する。０．４５μｍメンブランフィルターでろ過
後、１２１℃・２０分高圧蒸気滅菌して製剤化する（医
薬ジャーナル Ｖｏｌ．２８，Ｎｏ．５，１９９２／
ｐ．９７８）。」方法が知られている。As a method for preparing the trace element preparation, "First, ferric chloride is dissolved in distilled water for injection (iron is dissolved at about pH 1), other elemental reagents are added, and the solution is added to an aqueous sodium chondroitin sulfate solution. 0.1 mol under stirring and cooling
Alternately add / L sodium hydroxide solution to adjust to pH 6.0. After filtering with a 0.45 μm membrane filter, it is sterilized by high pressure steam at 121 ° C. for 20 minutes to prepare a drug product (Pharmaceutical Journal Vol. 28, No. 5, 1992 /
p. 978). The method is known.
【０００７】[0007]
【発明が解決しようとする課題】従来の方法に従って微
量元素製剤を製造すると、塩化第二鉄、塩化マンガン、
硫酸亜鉛、硫酸銅及びヨウ化カリウム等の微量元素を混
合した場合、この混合液のpHが非常に低い状態に置かれ
ることになる（約pH２前後）ため、例えば配合したヨウ
素が遊離することにより薬液中からヨウ素が放出され、
ヨウ素の定量値が低下するなど、製剤の品質が非常に不
安定になり、更に調製した微量元素製剤の水性コロイド
分散液自体の安定性が、期待される水準に至らず保存中
にコロイド（ゾル）から沈澱状物質（ゲル）を生じる傾
向があった。従って本発明の目的は、調製時の微量元素
の定量値の低下がなく、かつ長期保存安定性の良好な無
機質含有水性コロイド分散液及びその製造法を提供する
ことにある。When a trace element preparation is produced according to the conventional method, ferric chloride, manganese chloride,
When trace elements such as zinc sulphate, copper sulphate and potassium iodide are mixed, the pH of this mixture will be kept very low (around pH 2). Iodine is released from the drug solution,
The quality of the formulation became very unstable, such as the decrease in the quantitative value of iodine, and the stability of the aqueous colloidal dispersion itself of the prepared trace element formulation did not reach the expected level, and the colloid (sol From 1) to a precipitate (gel). Therefore, an object of the present invention is to provide an inorganic-containing aqueous colloidal dispersion liquid which does not lower the quantitative value of trace elements during preparation and has good long-term storage stability, and a method for producing the same.
【０００８】[0008]
【課題を解決するための手段】そこで本発明者らは、コ
ロイド形成剤であるコンドロイチン硫酸ナトリウムの起
源、性状、分子量、硫酸基の含有率などの異なる原料を
用いて種々検討した結果、サメ由来で、イオウ含有率
が、３〜６．５質量％のコンドロイチン硫酸ナトリウム
を用いると生成する鉄のコロイドが安定化し、他の元素
を配合しても沈澱を生じず、長期安定性の良好な水性コ
ロイド分散液が得られることを見出した。また、当該コ
ンドロイチン硫酸ナトリウム水溶液への微量元素の添加
条件を特定のpHで行うことにより、安定な水性コロイド
分散液が得られることを見出し、本発明を完成するに至
った。[Means for Solving the Problems] Therefore, the present inventors have conducted various studies using different raw materials such as the origin, properties, molecular weight, and content of sulfate groups of sodium chondroitin sulfate, which is a colloid-forming agent, and as a result, derived from sharks. In addition, when sodium chondroitin sulfate having a sulfur content of 3 to 6.5% by mass is used, the generated iron colloid is stabilized, no precipitation occurs even if other elements are added, and the aqueous solution has good long-term stability. It has been found that a colloidal dispersion can be obtained. Further, they have found that a stable aqueous colloidal dispersion can be obtained by adding trace elements to the aqueous solution of sodium chondroitin sulfate at a specific pH, and completed the present invention.
【０００９】すなわち、本発明は、鉄、及びサメ由来で
かつイオウの含有率が３〜６．５質量％であるコンドロ
イチン硫酸ナトリウムを含有する水性コロイド分散液を
提供するものである。また、本発明は、サメ由来でかつ
イオウの含有率が３〜６．５質量％であるコンドロイチ
ン硫酸ナトリウムの水溶液に、水酸化ナトリウム水溶液
と塩化第二鉄水溶液を、pH３．６から１２．６の条件で
添加することを特徴とする水性コロイド分散液の製造方
法を提供するものである。That is, the present invention provides an aqueous colloidal dispersion containing iron and sodium chondroitin sulfate derived from a shark and having a sulfur content of 3 to 6.5% by mass. Further, in the present invention, an aqueous sodium hydroxide solution and an aqueous ferric chloride solution are added to an aqueous solution of sodium chondroitin sulfate having a sulfur content of 3 to 6.5% by mass, which is derived from a shark and has a pH of 3.6 to 12.6. The present invention provides a method for producing an aqueous colloidal dispersion, which is characterized in that it is added under the conditions of
【００１０】[0010]
【発明の実施の形態】本発明に用いられるコンドロイチ
ン硫酸ナトリウムは、サメ由来でかつイオウの含有率が
３〜６．５質量％のものである。またイオウ含有率が
６．５質量％を超えるコンドロイチン硫酸ナトリウムを
用いるとコロイドの安定性が悪く、ゲル化する。本発明
の水性コロイド分散液を医療用とするにはコンドロイチ
ン硫酸ナトリウムは、イオウ含有率が５．５〜６．５質
量％のものを用いるのが好ましい。BEST MODE FOR CARRYING OUT THE INVENTION The sodium chondroitin sulfate used in the present invention is derived from a shark and has a sulfur content of 3 to 6.5% by mass. When sodium chondroitin sulfate having a sulfur content of more than 6.5% by mass is used, the colloid is poor in stability and gels. In order to use the aqueous colloidal dispersion of the present invention for medical purposes, it is preferable to use sodium chondroitin sulfate having a sulfur content of 5.5 to 6.5% by mass.
【００１１】鉄としては塩化第二鉄を用いるのが好まし
い。Ferric chloride is preferably used as iron.
【００１２】本発明の水性コロイド分散液には、さらに
亜鉛、銅、マンガン及びヨウ素から選ばれる一種又は二
種以上を配合できる。これらの元素のうち、亜鉛、銅及
びヨウ素の組み合せを配合するか、マンガン、亜鉛、銅
及びヨウ素の組み合せを配合するのが好ましい。ここ
で、マンガンは塩化マンガンとして、亜鉛は硫酸亜鉛と
して、銅は硫酸銅として、ヨウ素はヨウ化カリウムとし
て配合するのが好ましい。The aqueous colloidal dispersion of the present invention may further contain one or more selected from zinc, copper, manganese and iodine. Of these elements, it is preferable to add a combination of zinc, copper and iodine or a combination of manganese, zinc, copper and iodine. Here, it is preferable to mix manganese as manganese chloride, zinc as zinc sulfate, copper as copper sulfate, and iodine as potassium iodide.
【００１３】本発明の水性コロイド分散液は、サメ由来
でかつイオウの含有率が３〜６．５質量％であるコンド
ロイチン硫酸ナトリウムの水溶液に、水酸化ナトリウム
水溶液と塩化第二鉄水溶液を、pH３．６〜１２．６の条
件で添加することにより製造される。pH３．６未満の条
件では、後に添加するヨウ素の定量値が低下する傾向に
あり、また、pH１２．６を超えると、付可逆的な沈澱が
生じ分散が困難となる。pHを３．６〜１２．６に維持す
るには、水酸化ナトリウム水溶液と塩化第二鉄水溶液の
添加を、少なくとも３回、特に３〜５回に分割して行う
のが好ましい。この分割添加は、時間的にも、また液の
pHを変化させずに安定な水性コロイド分散液を得るうえ
でも重要である。The aqueous colloidal dispersion of the present invention comprises a shark-derived aqueous solution of sodium chondroitin sulfate having a sulfur content of 3 to 6.5% by mass, an aqueous sodium hydroxide solution and an aqueous ferric chloride solution, and a pH of 3 It is manufactured by adding it under the conditions of 0.6 to 12.6. When the pH is less than 3.6, the quantitative value of iodine added later tends to decrease, and when the pH exceeds 12.6, reversible precipitation occurs and dispersion becomes difficult. In order to maintain the pH at 3.6 to 12.6, it is preferable to add the sodium hydroxide aqueous solution and the ferric chloride aqueous solution at least 3 times, particularly 3 to 5 times. This divided addition can
It is also important for obtaining a stable aqueous colloidal dispersion without changing the pH.
【００１４】用いられるコンドロイチン硫酸ナトリウム
水溶液の濃度は７〜８０ｍｇ／ｍＬ、特に８〜６０ｍｇ
／ｍＬが好ましい。また水酸化ナトリウム水溶液の濃度
は０．１〜１ｍｏｌ／Ｌが好ましく、塩化第二鉄水溶液
の濃度は５〜１００ｍｇ／ｍＬ、特に８〜６０ｍｇ／ｍ
Ｌが好ましい。コンドロイチン硫酸ナトリウムの濃度と
水酸化ナトリウムの濃度は一方が高い時に他方を低くす
るのがコロイド分散液の安定化のうえで好ましい。The concentration of the sodium chondroitin sulfate aqueous solution used is 7 to 80 mg / mL, especially 8 to 60 mg.
/ ML is preferred. The concentration of the sodium hydroxide aqueous solution is preferably 0.1 to 1 mol / L, and the concentration of the ferric chloride aqueous solution is 5 to 100 mg / mL, particularly 8 to 60 mg / m.
L is preferred. It is preferable that the concentration of sodium chondroitin sulfate and the concentration of sodium hydroxide be low when one is high in order to stabilize the colloidal dispersion.
【００１５】本発明の水性コロイド含有液に、さらに亜
鉛、銅及びヨウ素を配合する場合は、次の方法により製
造するのが好ましい。すなわち、サメ由来でかつイオウ
の含有率が３〜６．５質量％であるコンドロイチン硫酸
ナトリウムの水溶液に、水酸化ナトリウム水溶液と塩化
第二鉄水溶液を、pH３．６から１２．６の条件で添加し
た後、硫酸亜鉛、硫酸銅およびヨウ化カリウムの水溶液
を加える方法；又はサメ由来でかつイオウの含有率が３
〜６．５質量％であるコンドロイチン硫酸ナトリウムの
水溶液に、水酸化ナトリウム水溶液と塩化第二鉄水溶液
を、pH３．６から１２．６の条件で添加した後、硫酸亜
鉛および硫酸銅の水溶液を加え、次いでヨウ化カリウム
水溶液を加える方法である。When zinc, copper and iodine are further added to the aqueous colloid-containing liquid of the present invention, it is preferably produced by the following method. That is, an aqueous solution of sodium hydroxide and an aqueous solution of ferric chloride are added to an aqueous solution of sodium chondroitin sulfate having a sulfur content of 3 to 6.5% by mass under the conditions of pH 3.6 to 12.6. And then adding an aqueous solution of zinc sulfate, copper sulfate and potassium iodide; or from a shark and having a sulfur content of 3
~ 6.5 wt% sodium chondroitin sulfate aqueous solution, after adding the sodium hydroxide aqueous solution and ferric chloride aqueous solution under the conditions of pH 3.6 to 12.6, then add the zinc sulfate and copper sulfate aqueous solution , And then an aqueous solution of potassium iodide is added.
【００１６】また、本発明の水性コロイド分散液に、さ
らにマンガン、亜鉛、銅及びヨウ素を配合する場合は、
次の方法により製造するのが好ましい。すなわち、サメ
由来でかつイオウの含有率が３〜６．５質量％であるコ
ンドロイチン硫酸ナトリウムの水溶液に、水酸化ナトリ
ウム水溶液と塩化第二鉄水溶液を、pH３．６から１２．
６の条件で添加した後、塩化マンガン、硫酸亜鉛、硫酸
銅およびヨウ化カリウムの水溶液を加える方法；又はサ
メ由来でかつイオウの含有率が３〜６．５質量％である
コンドロイチン硫酸ナトリウムの水溶液に、水酸化ナト
リウム水溶液と塩化第二鉄水溶液を、pH３．６から１
２．６の条件で添加した後、塩化マンガン、硫酸亜鉛お
よび硫酸銅の水溶液を加え、次いでヨウ化カリウムの水
溶液を加える方法である。When manganese, zinc, copper and iodine are further added to the aqueous colloidal dispersion of the present invention,
It is preferably produced by the following method. That is, an aqueous sodium hydroxide solution and an aqueous ferric chloride solution were added to an aqueous solution of sodium chondroitin sulfate having a sulfur content of 3 to 6.5% by mass, which was derived from a shark and had a pH of 3.6 to 12.
Method of adding manganese chloride, zinc sulfate, copper sulfate and potassium iodide solution after addition under the conditions of 6; or an aqueous solution of sodium chondroitin sulfate derived from shark and having a sulfur content of 3 to 6.5 mass%. Then, add an aqueous sodium hydroxide solution and an aqueous ferric chloride solution to a pH of 3.6 to 1
After adding under the conditions of 2.6, an aqueous solution of manganese chloride, zinc sulfate and copper sulfate is added, and then an aqueous solution of potassium iodide is added.
【００１７】これらの方法において水酸化ナトリウム水
溶液と塩化第二鉄水溶液の添加までは前記の方法と同様
である。In these methods, the steps up to the addition of the aqueous sodium hydroxide solution and the aqueous ferric chloride solution are the same as those described above.
【００１８】上記の方法に用いる水溶液中の塩化マンガ
ン、硫酸亜鉛、硫酸銅及びヨウ化カリウムの濃度は目的
とする製剤に応じて調整することができる。The concentrations of manganese chloride, zinc sulfate, copper sulfate and potassium iodide in the aqueous solution used in the above method can be adjusted according to the intended preparation.
【００１９】これらの方法のうち、ヨウ化カリウム水溶
液を最後に添加するのが定量性の点で好ましい。なお、
ヨウ化カリウム添加後の液のpHは２．５以上、さらに
２．５〜６．５に保たれていることが分散液の安定性の
点で特に好ましい。Of these methods, it is preferable to add the potassium iodide aqueous solution lastly in terms of quantitativeness. In addition,
It is particularly preferable that the pH of the liquid after addition of potassium iodide is 2.5 or more, and more preferably 2.5 to 6.5 from the viewpoint of stability of the dispersion liquid.
【００２０】また、本発明の水性コロイド分散液には、
上記成分の他、緩衝液等を配合することもできる。The aqueous colloidal dispersion of the present invention also comprises
In addition to the above components, a buffer solution or the like may be added.
【００２１】[0021]
【実施例】次に実施例を挙げて本発明を更に詳細に説明
するが、本発明はこれら実施例に何ら限定されるもので
はない。The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
【００２２】実施例で使用したコンドロイチン硫酸ナト
リウムは、サメ由来であり、水及び薬品は全て医薬品用
の規格のものを用いた。The sodium chondroitin sulfate used in the examples was derived from sharks, and the water and chemicals used were all those specified for pharmaceuticals.
【００２３】イオウの測定方法は「日本薬局方外医薬品
規格1997」におけるコンドロイチン硫酸ナトリウムのイ
オウの定量法に準じるが、略記すれば以下の通りであ
る。本品を乾燥し、その約０．０５ｇを精密に量り、過
酸化水素試液 ２０ｍＬを吸収液とし、酸素フラスコ燃
焼法（日本薬局方、一般試験法、22）により試験を行
う。ただし当該試験法の（２）燃焼法中、時々振り混ぜ
ながら３０分間放置した後、吸収液を他のフラスコに移
し、メタノール１５ｍＬの代わりに水１５ｍＬを用い、
フラスコの栓（Ｃ）、白金の籠（Ｂ）及び三角フラスコ
（Ａ）の内壁を洗い、洗液は吸収液と合わせ、水を加え
て正確に５０ｍＬとし、試料溶液とする。別に試料を用
いないで同様に操作し、空試験液を調製する。試料溶液
１０ｍＬを正確に量り、０．０１ｍｏｌ／Ｌ塩化バリウ
ム液５ｍＬを正確に加え、水浴中で２５分間加熱する。
冷後、０．１ｍｏｌ／Ｌ水酸化ナトリウム液を加えて中
和し、０．０１ｍｏｌ／Ｌエチレンジアミン四酢酸二ナ
トリウム液で滴定し、その値をａｍＬとする（指示薬：
液状ユニバーサルＢＴ０．３ｍＬ）。ただし、滴定の終
点は、液の赤紫色が青色に変わるときとする。別に試料
溶液１０ｍＬ正確に量り、０．０１ｍｏｌ／Ｌ塩化バリ
ウムの代わりに水５ｍＬを加え、同様に操作し、その値
をｂｍＬとする。空試験につき同様に操作し、それぞれ
の値をＡｍＬ及びＢｍＬとする。The method for measuring sulfur is in accordance with the method for quantifying sulfur in sodium chondroitin sulfate in "Japanese Pharmacopoeia Standard 1997", but it is as follows. This product is dried, about 0.05 g of it is precisely weighed, and 20 mL of hydrogen peroxide test solution is used as an absorbent, and the test is carried out by the oxygen flask combustion method (Japanese Pharmacopoeia, General test method, 22). However, during the (2) combustion method of the test method, after leaving for 30 minutes with occasional shaking, the absorption liquid was transferred to another flask, and 15 mL of water was used instead of 15 mL of methanol,
The inner wall of the flask stopper (C), the platinum basket (B) and the Erlenmeyer flask (A) is washed, the washing liquid is combined with the absorbing liquid, and water is added to make exactly 50 mL to obtain a sample solution. A blank test solution is prepared in the same manner without using a sample. Accurately measure 10 mL of the sample solution, add exactly 5 mL of 0.01 mol / L barium chloride solution, and heat in a water bath for 25 minutes.
After cooling, the solution was neutralized by adding a 0.1 mol / L sodium hydroxide solution and titrated with a 0.01 mol / L disodium ethylenediaminetetraacetate solution, and the value was taken as amL (indicator:
Liquid universal BT 0.3 mL). However, the end point of the titration is when the red-purple color of the liquid changes to blue. Separately, accurately measure 10 mL of the sample solution, add 5 mL of water instead of 0.01 mol / L barium chloride, and perform the same operation to set the value as b mL. Perform the same operation for the blank test, and set the respective values as AmL and BmL.
【００２４】[0024]
【数１】 [Equation 1]
【００２５】なお、本試験は日本薬局方一般試験法 ２
２．酸素フラスコ燃焼法に準じて実施する。This test is based on the Japanese Pharmacopoeia General Test Method 2
2. Carry out according to the oxygen flask combustion method.
【００２６】分子量の測定方法は以下の通りである。本
品約０．０５ｇを試験管にとり、水約５ｍＬを加えて溶
解し、試料溶液とする。試料溶液及び標準溶液Ａ，Ｂそ
れぞれ１０μＬにつき、次の条件で液体クロマトグラフ
法により試験を行い標準品の保持時間及び分子量より検
量線を作成し、試料の保持時間より分子量を求める。The method for measuring the molecular weight is as follows. Take about 0.05 g of this product into a test tube and add about 5 mL of water to dissolve it into a sample solution. For 10 μL each of the sample solution and the standard solutions A and B, a test is conducted by the liquid chromatography method under the following conditions, a calibration curve is prepared from the retention time and the molecular weight of the standard product, and the molecular weight is determined from the retention time of the sample.
【００２７】標準品Ａ：Ｐ−１０，Ｐ−３の各０．５％
水溶液
標準品Ｂ：Ｐ−５の各０．５％ 溶液
（Ｐ−３，Ｐ−５，Ｐ−１０は、いずれも市販分子量マ
ーカーのプルラン・昭和電工製）Standard product A: 0.5% for each of P-10 and P-3
Aqueous solution standard product B: 0.5% solution of P-5 (P-3, P-5, P-10 are all commercially available molecular weight markers Pullulan / Showa Denko)
【００２８】操作条件
カラム：ＳＢ−８０２．５ＨＱ×２＋ＳＢ−Ｇ（Ｓｈｏ
ｄｅｘ）
カラム温度：５０℃
移動相：水
流 量：０．８ｍＬ／ｍｉｎ
検出器：示差屈折率計（ＲＩ）Operating condition column: SB-802.5HQ × 2 + SB-G (Sho
dex) Column temperature: 50 ° C. Mobile phase: Water flow rate: 0.8 mL / min Detector: Differential refractometer (RI)
【００２９】実施例１
塩化第二鉄を０．９４６ｇとり、水を加えて溶解し１０
０ｍＬとした。別に塩化マンガン０．０９８９５ｇ、硫
酸亜鉛８．６２５ｇ及び硫酸銅０．６２４ｇをとり、同
一の容器で水を加え溶解して５０ｍＬとした。また別に
ヨウ化カリウム０．８３０ｇをとり、水を加え溶解し５
０ｍＬとした。イオウの含有率が６．４５質量％である
コンドロイチン硫酸ナトリウムを０．９７７４ｇとり、
水４０ｍＬを加えて溶解した。この液に１ｍｏｌ／Ｌの
水酸化ナトリウム水溶液を２ｍＬ攪拌下に加えたのち、
先に調製した塩化第二鉄水溶液２０ｍＬを同様に加え、
更に水酸化ナトリウム水溶液及び塩化第二鉄水溶液をそ
れぞれ前記と同量を交互に４回繰り返して添加した。こ
の液に先に調製した塩化マンガン、硫酸亜鉛及び硫酸銅
の混合水溶液を１０ｍＬ加え、更に同様に先に調製した
ヨウ化カリウム水溶液を１ｍＬ添加し混和して暗赤褐色
のコロイド分散液を得た。１ｍｏｌ／Ｌ水酸化ナトリウ
ム水溶液でpH６に調整後、水を加えて２００ｍＬとし、
０．４５μｍ及び０．２２μｍのメンブランフィルター
でろ過ののち、２ｍＬづつガラスアンプルに充填して微
量元素製剤とした。Example 1 0.946 g of ferric chloride was added and dissolved by adding water to 10
It was set to 0 mL. Separately, 0.09895 g of manganese chloride, 8.625 g of zinc sulfate and 0.624 g of copper sulfate were taken, and water was added and dissolved in the same container to make 50 mL. Separately, take 0.830 g of potassium iodide and add water to dissolve it.
It was set to 0 mL. Take 0.9774 g of sodium chondroitin sulfate having a sulfur content of 6.45% by mass,
40 mL of water was added and dissolved. To this solution was added 1 mol / L sodium hydroxide aqueous solution with stirring in 2 mL,
Similarly, add 20 mL of the aqueous ferric chloride solution prepared above,
Further, the sodium hydroxide aqueous solution and the ferric chloride aqueous solution were added in the same amount as the above alternately and repeatedly four times. To this solution was added 10 mL of the previously prepared mixed aqueous solution of manganese chloride, zinc sulfate and copper sulfate, and similarly 1 mL of the previously prepared aqueous solution of potassium iodide was added and mixed to obtain a dark reddish brown colloidal dispersion. After adjusting the pH to 6 with a 1 mol / L sodium hydroxide aqueous solution, add water to make 200 mL,
After filtering with 0.45 μm and 0.22 μm membrane filters, 2 mL each was filled in a glass ampoule to give a trace element preparation.
【００３０】実施例２
塩化第二鉄を０．９４６ｇとり、水を加えて溶解し１０
０ｍＬとした。別に塩化マンガン０．０９８９５ｇ、硫
酸亜鉛８．６２５ｇ及び硫酸銅０．６２４ｇをとり、同
一の容器で水を加え溶解して５０ｍＬとした。また別に
ヨウ化カリウム０．８３０ｇをとり、水を加え溶解し５
０ｍＬとした。イオウの含有率が６．０質量％であるコ
ンドロイチン硫酸ナトリウムを１．９５４８ｇとり、水
４０ｍＬを加えて溶解した。この液に１ｍｏｌ／Ｌの水
酸化ナトリウム水溶液を２．０ｍＬ攪拌下に加えたの
ち、先に調製した塩化第二鉄水溶液２０ｍＬを同様に加
え、更に水酸化ナトリウム水溶液及び塩化第二鉄水溶液
をそれぞれ前記と同量を交互に４回繰り返して添加し
た。この液に先に調製した塩化マンガン、硫酸亜鉛及び
硫酸銅の混合水溶液を１０ｍＬ加え、更に同様に先に調
製したヨウ化カリウム水溶液を１ｍＬ添加し混和して暗
赤褐色のコロイド分散液を得た。１ｍｏｌ／Ｌ水酸化ナ
トリウム水溶液でpH６に調整後、水を加えて２００ｍＬ
とし、０．４５μｍ及び０．２２μｍのメンブランフィ
ルターでろ過ののち、２ｍＬづつガラスアンプルに充填
して微量元素製剤とした。Example 2 0.946 g of ferric chloride was added and dissolved by adding water.
It was set to 0 mL. Separately, 0.09895 g of manganese chloride, 8.625 g of zinc sulfate and 0.624 g of copper sulfate were taken, and water was added and dissolved in the same container to make 50 mL. Separately, take 0.830 g of potassium iodide and add water to dissolve it.
It was set to 0 mL. 1.9548 g of sodium chondroitin sulfate having a sulfur content of 6.0 mass% was taken, and 40 mL of water was added and dissolved. To this solution was added a 1 mol / L sodium hydroxide aqueous solution with stirring (2.0 mL), then the previously prepared ferric chloride aqueous solution (20 mL) was added in the same manner, and a sodium hydroxide aqueous solution and a ferric chloride aqueous solution were respectively added. The same amount as described above was alternately added 4 times. To this solution was added 10 mL of the previously prepared mixed aqueous solution of manganese chloride, zinc sulfate and copper sulfate, and similarly 1 mL of the previously prepared aqueous solution of potassium iodide was added and mixed to obtain a dark reddish brown colloidal dispersion. After adjusting the pH to 6 with a 1 mol / L aqueous sodium hydroxide solution, add water and add 200 mL.
After filtering with 0.45 μm and 0.22 μm membrane filters, 2 mL each was filled in a glass ampoule to give a trace element preparation.
【００３１】実施例３
塩化第二鉄を０．９４６ｇとり、水を加えて溶解し１０
０ｍＬとした。別に塩化マンガン０．０９８９５ｇ、硫
酸亜鉛８．６２５ｇ及び硫酸銅０．６２４ｇをとり、同
一の容器で水を加え溶解して５０ｍＬとした。また別に
ヨウ化カリウム０．８３０ｇをとり、水を加え溶解し５
０ｍＬとした。イオウの含有率が６．０質量％であるコ
ンドロイチン硫酸ナトリウムを０．４８８７ｇとり、水
４０ｍＬを加えて溶解した。この液に１ｍｏｌ／Ｌの水
酸化ナトリウム水溶液を２ｍＬ攪拌下に加えたのち、先
に調製した塩化第二鉄水溶液２０ｍＬを同様に加え、更
に水酸化ナトリウム水溶液及び塩化第二鉄水溶液をそれ
ぞれ前記と同量を交互に４回繰り返して添加した。この
液に先に調製した塩化マンガン、硫酸亜鉛及び硫酸銅の
混合水溶液を１０ｍＬ加え、更に同様に先に調製したヨ
ウ化カリウム水溶液を１ｍＬ添加し混和して暗赤褐色の
コロイド分散液を得た。１ｍｏｌ／Ｌ水酸化ナトリウム
水溶液でpH６に調整後、水を加えて２００ｍＬとし、
０．４５μｍ及び０．２２μｍのメンブランフィルター
でろ過ののち、２ｍＬづつガラスアンプルに充填して微
量元素製剤とした。Example 3 0.946 g of ferric chloride was taken, and water was added to dissolve it.
It was set to 0 mL. Separately, 0.09895 g of manganese chloride, 8.625 g of zinc sulfate and 0.624 g of copper sulfate were taken, and water was added and dissolved in the same container to make 50 mL. Separately, take 0.830 g of potassium iodide and add water to dissolve it.
It was set to 0 mL. 0.4887 g of sodium chondroitin sulfate having a sulfur content of 6.0 mass% was taken, and 40 mL of water was added and dissolved. After adding 2 mL of a 1 mol / L sodium hydroxide aqueous solution to this solution while stirring, 20 mL of the ferric chloride aqueous solution prepared above was added in the same manner, and a sodium hydroxide aqueous solution and a ferric chloride aqueous solution were respectively added as described above. The same amount was alternately and repeatedly added 4 times. To this solution was added 10 mL of the previously prepared mixed aqueous solution of manganese chloride, zinc sulfate and copper sulfate, and similarly 1 mL of the previously prepared aqueous solution of potassium iodide was added and mixed to obtain a dark reddish brown colloidal dispersion. After adjusting the pH to 6 with a 1 mol / L sodium hydroxide aqueous solution, add water to make 200 mL,
After filtering with 0.45 μm and 0.22 μm membrane filters, 2 mL each was filled in a glass ampoule to give a trace element preparation.
【００３２】実施例４
塩化第二鉄を０．９４６ｇとり、水を加えて溶解し１０
０ｍＬとした。別に硫酸亜鉛８．６２５ｇ及び硫酸銅
０．６２４ｇをとり、同一の容器で水を加え溶解して５
０ｍＬとした。また別にヨウ化カリウム０．８３０ｇを
とり、水を加え溶解し５０ｍＬとした。イオウの含有率
が６．０質量％であるコンドロイチン硫酸ナトリウムを
０．９７７４ｇとり、水４０ｍＬを加えて溶解した。こ
の液に１ｍｏｌ／Ｌの水酸化ナトリウム水溶液を２ｍＬ
攪拌下に加えたのち、先に調製した塩化第二鉄水溶液２
０ｍＬを同様に加え、更に水酸化ナトリウム水溶液及び
塩化第二鉄水溶液をそれぞれ前記と同量を交互に４回繰
り返して添加した。この液に先に調製した硫酸亜鉛及び
硫酸銅の混合水溶液を１０ｍＬ加え、更に同様に先に調
製したヨウ化カリウム水溶液を１ｍＬ添加し混和して暗
赤褐色のコロイド分散液を得た。１ｍｏｌ／Ｌ水酸化ナ
トリウム水溶液でpH６に調整後、水を加えて２００ｍＬ
とし、０．４５μｍ及び０．２２μｍのメンブランフィ
ルターでろ過ののち、２ｍＬづつガラスアンプルに充填
して微量元素製剤とした。Example 4 0.946 g of ferric chloride was taken and dissolved by adding water.
It was set to 0 mL. Separately, take 8.625 g of zinc sulfate and 0.624 g of copper sulfate, and add water in the same container to dissolve it.
It was set to 0 mL. Separately, 0.830 g of potassium iodide was taken and water was added to dissolve it to make 50 mL. 0.9774 g of sodium chondroitin sulfate having a sulfur content of 6.0% by mass was taken, and 40 mL of water was added and dissolved. 2 mL of 1 mol / L aqueous sodium hydroxide solution
After adding with stirring, the ferric chloride aqueous solution prepared above 2
0 mL was added in the same manner, and a sodium hydroxide aqueous solution and a ferric chloride aqueous solution were each added in the same amount as the above alternately and repeatedly 4 times. To this solution was added 10 mL of the previously prepared mixed aqueous solution of zinc sulfate and copper sulfate, and similarly, 1 mL of the previously prepared aqueous solution of potassium iodide was added and mixed to obtain a dark reddish brown colloidal dispersion. After adjusting the pH to 6 with a 1 mol / L aqueous sodium hydroxide solution, add water and add 200 mL.
After filtering with 0.45 μm and 0.22 μm membrane filters, 2 mL each was filled in a glass ampoule to give a trace element preparation.
【００３３】実施例５
塩化第二鉄を０．９４６ｇとり、水を加えて溶解し１０
０ｍＬとした。別に塩化マンガン０．０９８９５ｇ、硫
酸亜鉛８．６２５ｇ及び硫酸銅０．６２４ｇをとり、同
一の容器で水を加え溶解して５０ｍＬとした。また別に
ヨウ化カリウム０．８３０ｇをとり、水を加え溶解し５
０ｍＬとした。イオウの含有率が６．０質量％であるコ
ンドロイチン硫酸ナトリウムを０．９７７４ｇとり、水
４０ｍＬを加えて溶解した。この液に１ｍｏｌ／Ｌの水
酸化ナトリウム水溶液を３．３ｍＬ攪拌下に加えたの
ち、先に調製した塩化第二鉄水溶液３３ｍＬを同様に加
え、更に水酸化ナトリウム水溶液及び塩化第二鉄水溶液
をそれぞれ前記と同量を交互に２回繰り返して添加し
た。この液に先に調製した塩化マンガン、硫酸亜鉛及び
硫酸銅の混合水溶液を１０ｍＬ加え、更に同様に先に調
製したヨウ化カリウム水溶液を１ｍＬ添加し混和して暗
赤褐色のコロイド分散液を得た。１ｍｏｌ／Ｌ水酸化ナ
トリウム水溶液でpH６に調整後、水を加えて２００ｍＬ
とし、０．４５μｍ及び０．２２μｍのメンブランフィ
ルターでろ過ののち、２ｍＬづつガラスアンプルに充填
して微量元素製剤とした。Example 5 0.946 g of ferric chloride was taken, and water was added to dissolve it.
It was set to 0 mL. Separately, 0.09895 g of manganese chloride, 8.625 g of zinc sulfate and 0.624 g of copper sulfate were taken, and water was added and dissolved in the same container to make 50 mL. Separately, take 0.830 g of potassium iodide and add water to dissolve it.
It was set to 0 mL. 0.9774 g of sodium chondroitin sulfate having a sulfur content of 6.0% by mass was taken, and 40 mL of water was added and dissolved. To this liquid, 1 mol / L sodium hydroxide aqueous solution was added with stirring (3.3 mL), and then the previously prepared ferric chloride aqueous solution (33 mL) was added in the same manner, and further sodium hydroxide aqueous solution and ferric chloride aqueous solution were respectively added. The same amount as the above was alternately added twice. To this solution was added 10 mL of the previously prepared mixed aqueous solution of manganese chloride, zinc sulfate and copper sulfate, and similarly 1 mL of the previously prepared aqueous solution of potassium iodide was added and mixed to obtain a dark reddish brown colloidal dispersion. After adjusting the pH to 6 with a 1 mol / L aqueous sodium hydroxide solution, add water and add 200 mL.
After filtering with 0.45 μm and 0.22 μm membrane filters, 2 mL each was filled in a glass ampoule to give a trace element preparation.
【００３４】実施例６
塩化第二鉄を０．９４６ｇとり、水を加えて溶解し１０
０ｍＬとした。別に塩化マンガン０．０９８９５ｇ、硫
酸亜鉛８．６２５ｇ及び硫酸銅０．６２４ｇをとり、同
一の容器で水を加え溶解して５０ｍＬとした。また別に
ヨウ化カリウム０．８３０ｇをとり、水を加え溶解し５
０ｍＬとした。イオウの含有率が６．４５質量％である
コンドロイチン硫酸ナトリウムを０．９７７４ｇとり、
水４０ｍＬを加えて溶解した。この液に１ｍｏｌ／Ｌの
水酸化ナトリウム水溶液を０．４ｍＬ攪拌下に加えたの
ち、先に調製した塩化第二鉄水溶液４ｍＬを同様に加
え、更に水酸化ナトリウム水溶液及び塩化第二鉄水溶液
をそれぞれ前記と同量を交互に２４回繰り返して添加し
た。この液に先に調製した塩化マンガン、硫酸亜鉛及び
硫酸銅の混合水溶液を１０ｍＬ加え、更に同様に先に調
製したヨウ化カリウム水溶液を１ｍＬ添加し混和して暗
赤褐色のコロイド分散液を得た。１ｍｏｌ／Ｌ水酸化ナ
トリウム水溶液でpH６に調整後、水を加えて２００ｍＬ
とし、０．４５μｍ及び０．２２μｍのメンブランフィ
ルターでろ過ののち、２ｍＬづつガラスアンプルに充填
して微量元素製剤とした。Example 6 0.946 g of ferric chloride was taken, and water was added to dissolve it.
It was set to 0 mL. Separately, 0.09895 g of manganese chloride, 8.625 g of zinc sulfate and 0.624 g of copper sulfate were taken, and water was added and dissolved in the same container to make 50 mL. Separately, take 0.830 g of potassium iodide and add water to dissolve it.
It was set to 0 mL. Take 0.9774 g of sodium chondroitin sulfate having a sulfur content of 6.45% by mass,
40 mL of water was added and dissolved. After adding 1 mL / L of sodium hydroxide aqueous solution to this solution under stirring of 0.4 mL, the previously prepared ferric chloride aqueous solution 4 mL was similarly added, and further sodium hydroxide aqueous solution and ferric chloride aqueous solution were respectively added. The same amount as above was alternately added 24 times. To this solution was added 10 mL of the previously prepared mixed aqueous solution of manganese chloride, zinc sulfate and copper sulfate, and 1 mL of the previously prepared aqueous solution of potassium iodide was similarly added and mixed to obtain a dark reddish brown colloidal dispersion. After adjusting the pH to 6 with a 1 mol / L aqueous sodium hydroxide solution, add water and add 200 mL.
After filtering with 0.45 μm and 0.22 μm membrane filters, 2 mL each was filled in a glass ampoule to give a trace element preparation.
【００３５】対照例１
塩化第二鉄を０．９４６ｇとり、水を加えて溶解し１０
０ｍＬとした。別に塩化マンガン０．０９８９５ｇ、硫
酸亜鉛８．６２５ｇ及び硫酸銅０．６２４ｇをとり、同
一の容器で水を加え溶解して５０ｍＬとした。また別に
ヨウ化カリウム０．８３０ｇをとり、水を加え溶解し５
０ｍＬとした。イオウの含有率が６．０質量％であるコ
ンドロイチン硫酸ナトリウムを０．９７７４ｇとり、水
４０ｍＬを加えて溶解した。この液に１ｍｏｌ／Ｌの水
酸化ナトリウム水溶液を１０ｍＬ攪拌下に加えた。この
処方は以降の操作を行う前に白色の濁りが出現の後、沈
澱が生じ良好なコロイド分散液を製造することができな
かった。当該対照例と類似する製造方法で製造したコン
ドロイチン硫酸ナトリウム水溶液への塩化第二鉄水溶液
の添加過程でpHが１２．７を越えたもの、及び２．５を
下回ったものは、白色の沈澱が生じ良好なコロイド分散
液が得られなかった。Control Example 1 0.946 g of ferric chloride was taken, and water was added to dissolve it.
It was set to 0 mL. Separately, 0.09895 g of manganese chloride, 8.625 g of zinc sulfate and 0.624 g of copper sulfate were taken, and water was added and dissolved in the same container to make 50 mL. Separately, take 0.830 g of potassium iodide and add water to dissolve it.
It was set to 0 mL. 0.9774 g of sodium chondroitin sulfate having a sulfur content of 6.0% by mass was taken, and 40 mL of water was added and dissolved. A 1 mol / L aqueous sodium hydroxide solution was added to this solution with stirring (10 mL). In this formulation, after the appearance of white turbidity before the subsequent operations, precipitation occurred and a good colloidal dispersion could not be manufactured. When the pH of the ferric chloride aqueous solution added to the sodium chondroitin sulfate aqueous solution produced by the production method similar to that of the control example exceeded 12.7 and dropped below 2.5, a white precipitate was observed. A good colloidal dispersion was not obtained.
【００３６】対照例２
塩化第二鉄を０．９４６ｇとり、水を３０ｍＬを加えて
溶解した。別に塩化マンガン０．０９８９５ｇ、硫酸亜
鉛８．６２５ｇ、硫酸銅０．６２４ｇをとり、同一の容
器で水を加え溶解して５０ｍＬとした。また別にヨウ化
カリウム０．８３０ｇをとり、水を加えて５０ｍＬとし
た。先の塩化第二鉄水溶液に塩化マンガン、硫酸亜鉛及
び硫酸銅の混合水溶液を１０ｍＬ加えた後、ヨウ化カリ
ウム水溶液の１ｍＬを加え、更に水を加えて５０ｍＬと
した。イオウの含有率が６．０であるコンドロイチン硫
酸ナトリウムを０．９７７４ｇとり、水４０ｍＬを加え
て溶解した。この液に０．１ｍｏｌ／Ｌの水酸化ナトリ
ウム水溶液２０ｍＬ攪拌下に加えたのち、先に調製した
塩化第二鉄、塩化マンガン、硫酸亜鉛、硫酸銅及びヨウ
化カリウムの混合水溶液の１０ｍＬを加えて混合し、更
に水酸化ナトリウム水溶液及び微量元素水溶液をそれぞ
れ前記と同量を交互に４回繰り返して添加し混和して黄
褐色のコロイド分散液を得た。１ｍｏｌ／Ｌ水酸化ナト
リウム水溶液でpH６に調整後、水を加えて２００ｍＬと
し、０．４５μｍ及び０．２２μｍのメンブランフィル
ターでろ過ののち、２ｍＬづつガラスアンプルに充填し
て微量元素製剤とした。この製剤は定量試験において、
ヨウ素の検出が充分ではなく製剤として不適当であっ
た。Control Example 2 0.946 g of ferric chloride was added, and 30 mL of water was added and dissolved. Separately, 0.09895 g of manganese chloride, 8.625 g of zinc sulfate and 0.624 g of copper sulfate were taken, and water was added and dissolved in the same container to make 50 mL. Separately, 0.830 g of potassium iodide was taken, and water was added to make 50 mL. After adding 10 mL of a mixed aqueous solution of manganese chloride, zinc sulfate and copper sulfate to the above ferric chloride aqueous solution, 1 mL of an aqueous potassium iodide solution was added, and water was further added to make 50 mL. 0.9774 g of sodium chondroitin sulfate having a sulfur content of 6.0 was taken, and 40 mL of water was added and dissolved. To this solution was added 20 mL of a 0.1 mol / L sodium hydroxide aqueous solution with stirring, and then 10 mL of the previously prepared mixed aqueous solution of ferric chloride, manganese chloride, zinc sulfate, copper sulfate and potassium iodide was added. The mixture was mixed, and the aqueous sodium hydroxide solution and the trace element aqueous solution were alternately added in the same amounts as described above four times, and mixed to obtain a yellowish brown colloidal dispersion. After adjusting the pH to 6 with a 1 mol / L sodium hydroxide aqueous solution, water was added to make 200 mL, and after filtering with a 0.45 μm and 0.22 μm membrane filter, 2 mL each was filled in a glass ampoule to give a trace element preparation. This formulation is
The detection of iodine was not sufficient and it was unsuitable as a formulation.
【００３７】対照例３
塩化第二鉄を０．９４６ｇとり、水を加えて溶解し１０
０ｍＬとした。別に塩化マンガン０．０９８９５ｇ、硫
酸亜鉛８．６２５ｇ及び硫酸銅０．６２４ｇをとり、同
一の容器で水を加え溶解して５０ｍＬとした。また別に
ヨウ化カリウム０．８３０ｇをとり、水を加え溶解し５
０ｍＬとした。イオウの含有率が６．７２質量％である
サメ由来のコンドロイチン硫酸ナトリウムを０．９７７
４ｇとり、水４０ｍＬを加えて溶解した。この液に１ｍ
ｏｌ／Ｌの水酸化ナトリウム水溶液を２ｍＬ攪拌下に加
えたのち、先に調製した塩化第二鉄水溶液２０ｍＬを同
様に加え、更に水酸化ナトリウム水溶液及び塩化第二鉄
水溶液をそれぞれ前記と同量を交互に４回繰り返して添
加した。この液に先に調製した塩化マンガン、硫酸亜鉛
及び硫酸銅の混合水溶液を１０ｍＬ加え、更に同様に先
に調製したヨウ化カリウム水溶液を１ｍＬ添加し混和し
てコロイド分散液を製造した。しかし、この分散液は塩
化第二鉄の分散が充分でなく沈澱が生じ、攪拌によって
も分散液は生成しなかった。Control Example 3 0.946 g of ferric chloride was added and dissolved by adding water to 10
It was set to 0 mL. Separately, 0.09895 g of manganese chloride, 8.625 g of zinc sulfate and 0.624 g of copper sulfate were taken, and water was added and dissolved in the same container to make 50 mL. Separately, take 0.830 g of potassium iodide and add water to dissolve it.
It was set to 0 mL. The shark-derived sodium chondroitin sulfate having a sulfur content of 6.72% by mass was added to 0.977.
4 g was taken and 40 mL of water was added and dissolved. 1m to this liquid
After adding 2 mL of an ol / L aqueous sodium hydroxide solution under stirring, 20 mL of the previously prepared aqueous ferric chloride solution was added in the same manner, and an aqueous sodium hydroxide solution and an aqueous ferric chloride solution were added in the same amounts as described above. Alternately repeated 4 times. To this solution, 10 mL of the previously prepared mixed aqueous solution of manganese chloride, zinc sulfate and copper sulfate was added, and similarly 1 mL of the previously prepared aqueous solution of potassium iodide was added and mixed to prepare a colloidal dispersion. However, in this dispersion, the dispersion of ferric chloride was not sufficient and precipitation occurred, and no dispersion was formed even by stirring.
【００３８】対照例４
塩化第二鉄を０．９４６ｇとり、水を加えて溶解し１０
０ｍＬとした。別に塩化マンガン０．０９８９５ｇ、硫
酸亜鉛８．６２５ｇ及び硫酸銅０．６２４ｇをとり、同
一の容器で水を加え溶解して５０ｍＬとした。また別に
ヨウ化カリウム０．８３０ｇをとり、水を加え溶解し５
０ｍＬとした。イオウの含有率が６．６６質量％である
サメ由来のコンドロイチン硫酸ナトリウムを０．９７７
４ｇとり、水４０ｍＬを加えて溶解した。この液に１ｍ
ｏｌ／Ｌの水酸化ナトリウム水溶液を２ｍＬ攪拌下に加
えたのち、先に調製した塩化第二鉄水溶液２０ｍＬを同
様に加え、更に水酸化ナトリウム水溶液及び塩化第二鉄
水溶液をそれぞれ前記と同量を交互に４回繰り返して添
加した。この液に先に調製した塩化マンガン、硫酸亜鉛
及び硫酸銅の混合水溶液を１０ｍＬ加え、更に同様に先
に調製したヨウ化カリウム水溶液を１ｍＬ添加し混和し
てコロイド分散液を製造した。しかし、この分散液は塩
化第二鉄の分散が充分でなく沈澱が生じ、攪拌によって
も分散液は生成しなかった。Control Example 4 0.946 g of ferric chloride was taken, and water was added to dissolve it.
It was set to 0 mL. Separately, 0.09895 g of manganese chloride, 8.625 g of zinc sulfate and 0.624 g of copper sulfate were taken, and water was added and dissolved in the same container to make 50 mL. Separately, take 0.830 g of potassium iodide and add water to dissolve it.
It was set to 0 mL. 0.977% of shark-derived sodium chondroitin sulfate having a sulfur content of 6.66% by mass.
4 g was taken and 40 mL of water was added and dissolved. 1m to this liquid
After adding 2 mL of an ol / L aqueous sodium hydroxide solution under stirring, 20 mL of the previously prepared aqueous ferric chloride solution was added in the same manner, and an aqueous sodium hydroxide solution and an aqueous ferric chloride solution were added in the same amounts as described above. Alternately repeated 4 times. To this solution, 10 mL of the previously prepared mixed aqueous solution of manganese chloride, zinc sulfate and copper sulfate was added, and similarly 1 mL of the previously prepared aqueous solution of potassium iodide was added and mixed to prepare a colloidal dispersion. However, in this dispersion, the dispersion of ferric chloride was not sufficient and precipitation occurred, and no dispersion was formed even by stirring.
【００３９】[0039]
【表１】 [Table 1]
【００４０】試験例１
実施例１及び２の微量元素製剤について、１００℃で苛
酷試験を行い、その安定性をpHの変動及び外観性状につ
いて比較した。その結果を表２に示した。Test Example 1 The trace element preparations of Examples 1 and 2 were subjected to a severe test at 100 ° C., and their stability was compared with respect to pH fluctuation and appearance. The results are shown in Table 2.
【００４１】pH測定装置 装置：pH ＭＥＴＥＲ Ｆ−１４ 堀場製作所PH measuring device Equipment: pH METER F-14 Horiba, Ltd.
【００４２】[0042]
【表２】 [Table 2]
【００４３】[0043]
【発明の効果】本発明により、良質で、かつ保存性の良
好な微量元素含有製剤の製造が可能となった。INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to produce a trace element-containing preparation of good quality and good storage stability.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｋ 33/34 Ａ６１Ｋ 33/34 47/02 47/02 47/36 47/36 Ａ６１Ｐ 3/02 Ａ６１Ｐ 3/02 Ｂ０１Ｆ 17/56 Ｂ０１Ｆ 17/56 Ｂ０１Ｊ 13/00 Ｂ０１Ｊ 13/00 Ｃ Ｃ０８Ｌ 5/08 Ｃ０８Ｌ 5/08 Ｆターム(参考） 4C076 AA16 BB17 DD22 EE30F FF43 FF63 GG45 4C086 AA01 HA01 HA03 HA09 HA11 HA24 MA06 MA17 MA66 NA03 ZC21 4D077 AA04 AB12 AC05 BA07 CA02 DC17X DC59X 4G065 AA01 AA05 AB06Y BA07 BB07 CA13 DA02 EA01 EA06 FA03 4J002 AB051 DD077 DD079 DD089 DE056 DG048 DG049 FD206 FD207 FD208 FD209 GB04 HA06 ─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 7 Identification code FI theme code (reference) A61K 33/34 A61K 33/34 47/02 47/02 47/36 47/36 A61P 3/02 A61P 3 / 02 B01F 17/56 B01F 17/56 B01J 13/00 B01J 13/00 C C08L 5/08 C08L 5/08 F Term (Reference) 4C076 AA16 BB17 DD22 EE30F FF43 FF63 GG45 4C086 AA01 HA01 HA03 HA09 HA11 HA24 MA06 MA17 MA17 MA17 MA17 MA66 ZC21 4D077 AA04 AB12 AC05 BA07 CA02 DC17X DC59X 4G065 AA01 AA05 AB06Y BA07 BB07 CA13 DA02 EA01 EA06 FA03 4J002 AB051 DD077 DD079 DD089 DE056 DG048 DG049 FD206 FD207 FD208 FD209 GB04 HA06
Claims (11)
が３〜６．５質量％であるコンドロイチン硫酸ナトリウ
ムを含有する水性コロイド分散液。1. An aqueous colloidal dispersion liquid containing iron and sodium chondroitin sulfate derived from a shark and having a sulfur content of 3 to 6.5% by mass.
のコンドロイチン硫酸ナトリウムを含有するものである
請求項１記載の水性コロイド分散液。2. The sulfur content is 5.5 to 6.5% by mass.
The aqueous colloidal dispersion according to claim 1, which contains the above chondroitin sulfate sodium salt.
ものである請求項１又は２記載の水性コロイド分散液。3. The aqueous colloidal dispersion according to claim 1, which further contains zinc, copper and iodine.
を含有するものである請求項１又は２記載の水性コロイ
ド分散液。4. The aqueous colloidal dispersion according to claim 1, further containing manganese, zinc, copper and iodine.
６．５質量％であるコンドロイチン硫酸ナトリウムの水
溶液に、水酸化ナトリウム水溶液と塩化第二鉄水溶液
を、pH３．６から１２．６の条件で添加することを特徴
とする水性コロイド分散液の製造方法。5. A shark-derived material having a sulfur content of 3 to
A method for producing an aqueous colloidal dispersion, which comprises adding an aqueous sodium hydroxide solution and an aqueous ferric chloride solution to a 6.5% by mass aqueous solution of sodium chondroitin sulfate under the conditions of pH 3.6 to 12.6. .
６．５質量％であるコンドロイチン硫酸ナトリウムの水
溶液に、水酸化ナトリウム水溶液と塩化第二鉄水溶液
を、pH３．６から１２．６の条件で添加した後、硫酸亜
鉛、硫酸銅およびヨウ化カリウムの水溶液を加えること
を特徴とする水性コロイド分散液の製造方法。6. A shark-derived sulfur content of 3 to
An aqueous sodium hydroxide solution and an aqueous ferric chloride solution were added to an aqueous solution of 6.5% by mass of sodium chondroitin sulfate under conditions of pH 3.6 to 12.6, and then zinc sulfate, copper sulfate and potassium iodide were added. A method for producing an aqueous colloidal dispersion, which comprises adding an aqueous solution.
６．５質量％であるコンドロイチン硫酸ナトリウムの水
溶液に、水酸化ナトリウム水溶液と塩化第二鉄水溶液
を、pH３．６から１２．６の条件で添加した後、硫酸亜
鉛および硫酸銅の水溶液を加え、次いでヨウ化カリウム
水溶液を加えることを特徴とする水性コロイド分散液の
製造方法。7. A shark-derived material having a sulfur content of 3 to
An aqueous sodium hydroxide solution and an aqueous ferric chloride solution were added to an aqueous solution of 6.5% by mass of sodium chondroitin sulfate under the conditions of pH 3.6 to 12.6, and then an aqueous solution of zinc sulfate and copper sulfate was added, Next, a method for producing an aqueous colloidal dispersion, which comprises adding an aqueous potassium iodide solution.
６．５質量％であるコンドロイチン硫酸ナトリウムの水
溶液に、水酸化ナトリウム水溶液と塩化第二鉄水溶液
を、pH３．６から１２．６の条件で添加した後、塩化マ
ンガン、硫酸亜鉛、硫酸銅およびヨウ化カリウムの水溶
液を加えることを特徴とする水性コロイド分散液の製造
方法。8. A shark-derived material having a sulfur content of 3 to
An aqueous sodium hydroxide solution and an aqueous ferric chloride solution were added to an aqueous solution of 6.5% by mass of sodium chondroitin sulfate under the conditions of pH 3.6 to 12.6, and then manganese chloride, zinc sulfate, copper sulfate and iodine were added. A method for producing an aqueous colloidal dispersion, which comprises adding an aqueous solution of potassium iodide.
６．５質量％であるコンドロイチン硫酸ナトリウムの水
溶液に、水酸化ナトリウム水溶液と塩化第二鉄水溶液
を、pH３．６から１２．６の条件で添加した後、塩化マ
ンガン、硫酸亜鉛および硫酸銅の水溶液を加え、次いで
ヨウ化カリウム水溶液を加えることを特徴とする水性コ
ロイド分散液の製造方法。9. A shark-derived sulfur content of 3 to
An aqueous solution of sodium hydroxide and an aqueous solution of ferric chloride were added to an aqueous solution of 6.5% by mass of sodium chondroitin sulfate under the conditions of pH 3.6 to 12.6, and then an aqueous solution of manganese chloride, zinc sulfate and copper sulfate. Is added, and then an aqueous potassium iodide solution is added, which is a method for producing an aqueous colloidal dispersion.
％のコンドロイチン硫酸ナトリウムを使用するものであ
る請求項５〜９のいずれか１項記載の製造方法。10. The method according to claim 5, wherein sodium chondroitin sulfate having a sulfur content of 5.5 to 6.5% by mass is used.
が、少なくとも３回に分割して添加する操作である請求
項５〜１０のいずれか１項記載の製造方法。11. The production method according to claim 5, wherein the operation of adjusting the pH to 3.6 to 12.6 is an operation of adding in three divided portions.
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| US9446067B2 (en) * | 2010-09-09 | 2016-09-20 | Bioregen Biomedical (Changzhou) Co. Ltd. | Mercapto-modified biocompatible macromolecule derivatives with low degree of mercapto-modification and the cross-linked materials and uses thereof |
| US10064889B2 (en) | 2010-09-09 | 2018-09-04 | Bioregen Biomedical (Changzhou) Co., Ltd. | Mercapto-modified biocompatible macromolecule derivatives with low degree of mercapto-modification and the cross-linked materials and uses thereof |
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