JP4126405B2 - Aqueous solution with improved solubility of aromatic carboxylic acids - Google Patents
Aqueous solution with improved solubility of aromatic carboxylic acids Download PDFInfo
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Description
【０００１】
【発明の属する技術分野】
この発明は、例えば医薬品等として使用されるアスピリン（アセチルサリチル酸）等の芳香族カルボン酸類の水に対する溶解度を向上化した芳香族カルボン酸類の水溶性化組成物及び溶解度向上化水溶液に関する。
【０００２】
【従来の技術】
一般的に、解熱剤や鎮痛剤等の医薬品等として広く使用されているアスピリン（アセチルサリチル酸）、安息香酸、サリチル酸等の芳香族カルボン酸類は、アルコール、エーテル、油脂類には易溶であるが、水には溶けにくい疎水性の化合物である。
【０００３】
そのため、この芳香族カルボン酸類を内用薬として使用する場合等には、粉末や錠剤の状態で水と共に服用するようにしている。
【０００４】
【発明が解決しようとする課題】
しかしながら、芳香族カルボン酸類を粉末や錠剤の状態で服用する場合には、服用しにくいと共に、吸収率が低く、体内滞留時間も短いという問題点がある。
【０００５】
この発明は、以上のような事情や問題点に鑑みてなされたものであり、芳香族カルボン酸類を内用薬として使用する場合等における服用の簡便化や吸収率の増加を図ることができると共に、体内滞留時間が長くて徐放性を有するように、水に対する溶解度を向上化した芳香族カルボン酸類の水溶性化組成物及び溶解度向上化水溶液を提供することを目的とする。
【０００６】
【課題を解決するための手段】
上記目的を達成するために、請求項１の芳香族カルボン酸類の溶解度向上化水溶液は、安息香酸、サリチル酸、アセチルサリチル酸、アントラニル酸、ｍ−トルイル酸、ベンジル酸、ｏ−トルイル酸の内から選択した１つの溶解度以上の芳香族カルボン酸類と、キトサンとをそれぞれ所定濃度で水に溶解させると共に、前記芳香族カルボン酸類の濃度が３．２ｇ／ｄＬ以下で、且つ、前記キトサンの濃度がこの芳香族カルボン酸類の濃度の１．３倍以下であることを特徴とすることを特徴としている。
【００１０】
【発明の実施の形態】
以下、この発明の実施形態について説明する。なお、第１実施形態では芳香族カルボン酸類の水溶性化組成物、第２実施形態では芳香族カルボン酸類の溶解度向上化水溶液についてそれぞれ説明する。
【００１１】
第１実施形態に係る芳香族カルボン酸類の水溶性化組成物は、芳香族カルボン酸類に所定量のキトサンを添加、混合したものである。
【００１２】
前記芳香族カルボン酸類としては、例えば、アスピリン（アセチルサリチル酸）、安息香酸、サリチル酸、アントラニル酸（ｏ−アミノ安息香酸）、ｍ−トルイル酸、ベンジル酸、ｏ−トルイル酸（ｏ−メチル安息香酸）やこれらのナトリウム塩等の塩、あるいは誘導体等が挙げられる。前記キトサンとしては、脱アセチル化度が８０％以上のものが望ましい。
【００１３】
前記水溶性化組成物を調製するには、適宜の芳香族カルボン酸類の粉末に所定量のキトサンの粉末を添加し、十分に混合すればよい。この水溶性化組成物を水に添加して所定時間攪拌すれば、単独では水に対してほとんど溶解しなかった芳香族カルボン酸類をより高濃度で溶解させることができ、その溶解度を向上できるという利点がある。これは、水溶液中における芳香族カルボン酸類とキトサンの相互作用の寄与によるものと考えられる。
【００１４】
そのため、前記芳香族カルボン酸類を内用薬として使用する場合等には、前記水溶性化組成物を水に溶解させれば十分な量の芳香族カルボン酸類が溶解していると共に、水溶液として服用できるので、服用の簡便化や吸収率の増加を図ることができる。また、水溶液として服用した場合には、体内滞留時間が長くて徐放性があるという利点がある。更に、芳香族カルボン酸類とキトサンとを混合した水溶性化組成物をあらかじめ調製しておけば、これを必要に応じて水に溶解させるだけであるので、便利であるという利点がある。
【００１５】
ここで、前記キトサンの添加量が、前記芳香族カルボン酸類の重量の１．３倍以下である場合には、前記水溶性化組成物が水に溶解し易いという利点がある。
【００１６】
第２実施形態に係る芳香族カルボン酸類の溶解度向上化水溶液は、水に芳香族カルボン酸類とキトサンとをそれぞれ所定濃度で溶解させたものである。
【００１７】
この溶解度向上化水溶液を調製するには、第１実施形態の水溶性化組成物を水に溶解させるか、あるいは混合していない芳香族カルボン酸類とキトサンとを同時に又は別々に水に溶解させればよい。このように、芳香族カルボン酸類に加えてキトサンを溶解させているので、第１実施形態と同様に、より高濃度の芳香族カルボン酸類が溶解しているという利点がある。そのため、この溶解度向上化水溶液をあらかじめ調製しておけば、前記水溶性化組成物等を溶解させる手間を省けると共に、内用薬等としてそのまますぐに利用できるという利点がある。
【００１８】
ここで、前記芳香族カルボン酸類の濃度が３．２ｇ／ｄＬ以下で、且つ、前記キトサンの濃度がこの芳香族カルボン酸類の濃度の１．３倍以下である場合には、芳香族カルボン酸類の溶け残りがほとんど又は全くないという利点がある。
【００１９】
【実施例】
次に、この発明を実施例により更に詳細に説明するが、この発明は係る実施例に限定されるものではない。
【００２０】
〔実施例１〕
芳香族カルボン酸類として、市販のフェノキシ酢酸、ＤＬ−マンデル酸、ｍ−アミノ安息香酸、ｐ−アミノ安息香酸、無水フタル酸、無水トリメリット酸、プロトカテク酸、５−スルホサリチル酸二水和物、アスピリン（＝アセチルサリチル酸）、安息香酸、サリチル酸、アントラニル酸（＝ｏ−アミノ安息香酸）、ｍ−トルイル酸、ベンジル酸、ｏ−トルイル酸（＝ｏ−メチル安息香酸）、テレフタル酸、イソフタル酸、１−ナフタレン酢酸（＝α−ナフチル酸）、１−ナフトエ酸、チオサリチル酸、ｐ−ニトロ安息香酸、ｐ−tert−ブチル安息香酸、テレフタル酸ジメチル、及び５−ヒドロキシイソフタル酸を、それぞれ０．５ｇ／ｄＬの割合で所定量の水に添加し、室温（約２５℃）で約１２時間攪拌した後、溶解性状を観察し、下記の評価基準に基づいてそれぞれ評価を行った。その結果を表１に示す。
【００２１】
〔評価基準〕
◎：完全溶解
○：少量の不溶解分を認める。
△：不溶解分は多いが、粘性がある。
×：不溶
【００２２】
【表１】
また、上記の溶液又は懸濁液にキトサン（商品名「ＳＫ−１０」，甲陽ケミカル社製，脱アセチル化度：８０％）を０．５ｇ／ｄＬの割合で添加し、室温（約２５℃）で更に約１２時間攪拌した後、溶解性状を観察し、上記の評価基準に基づいて評価を行った。その結果も表１に示す。
【００２４】
〔実施例２〕
芳香族カルボン酸類として市販のアスピリン（アセチルサリチル酸）を使用し、このアスピリンと実施例１と同じキトサンとを同時に水に加え、室温（約２５℃）で約２４時間攪拌した。この操作をキトサン−アスピリンの比率及び添加量を変えてそれぞれ行い、溶解性状を実施例１と同様にして観察した。その結果を表２に示す。
【００２５】
【表２】
〔実施例３〕
実施例２と同じキトサンとアスピリンとをそれぞれの濃度が１．０ｇ／ｄＬとなるようにして水に溶解させた後、その水溶液をエバポレーターで濃縮乾固し、更に５０℃で一晩乾燥させて、赤外吸収スペクトルの測定サンプル（サンプルａ）とした。
【００２７】
また、キトサンとアスピリンとを粉体のまま１：１の割合でよく混合し、赤外吸収スペクトルの測定サンプル（サンプルｂ）とした。
【００２８】
上記のサンプルａとサンプルｂについて、赤外吸収スペクトルをそれぞれ測定した（分解：４ｃｍ-1，アポダイゼーション：Cosine，積算回数：２００）。その結果を図１乃至図３に示す。なお、図３は、サンプルａとサンプルｂの両方のスペクトルを同じチャートに表示したものである。また、図４及び図５に示すように、キトサンとアスピリンのそれぞれ単独の赤外吸収スペクトルも測定した。
【００２９】
〔実施例４〕
ラット８頭を用い、４頭には市販のアスピリン（添加量３．２ｇ／ｄＬ）のＣＭＣ（カルボキシメチルセルロース，添加量３．２ｇ／ｄＬ）懸濁液を１０ｍｇ／ｋｇの割合で経口投与し（対照群）、他の４頭には実施例２と同様にして調製したキトサン−アスピリン水溶液（各添加量は３．２ｇ／ｄＬ）を１０ｍｇ／ｋｇの割合で経口投与した（試験群）。
【００３０】
ラットは、実験前日の夜は絶食させ、絶食の間は生理食塩水を自由に飲ませた。上記の薬物を投与した後、１、３、６、９時間後にそれぞれ採血し、血漿中のアスピリンの濃度変化を高速液体クロマトグラフィー（ＨＰＬＣ）により調べた。この間は、絶食絶水させた。そして、Ｃmax （最高血漿中濃度）、ＡＵＣ（０〜９ｈ，吸収されたアスピリン量の比例定数）、ＭＲＴ（平均体内滞留時間）をそれぞれ測定した。その結果を表３に示す。なお、Ｔmax （最高血漿中濃度到達時間）は、各採血時間の測定値から読み取った。
【００３１】
【表３】
〔比較例〕
前記キトサンの代わりに、その構成単位であるグルコサミンの塩酸塩を使用した以外は実施例２と同様の操作を行い、溶解性状を観察した。その結果を表４に示す。
【００３３】
【表４】
【発明の効果】
以上のように、請求項１の発明によれば、芳香族カルボン酸類に加えてキトサンを水に溶解させているので、単独の場合と比較してより高濃度の芳香族カルボン酸類が溶解しているという利点がある。そのため、この溶解度向上化水溶液をあらかじめ調製しておけば、前記水溶性化組成物等を溶解させる手間を省けると共に、内用薬等としてそのまますぐに利用できるという利点がある。また、前記芳香族カルボン酸類の濃度が３．２ｇ／ｄＬ以下で、且つ、前記キトサンの濃度がこの芳香族カルボン酸類の濃度の１．３倍以下であるので、芳香族カルボン酸類の溶け残りがほとんど又は全くないという利点がある。
【図面の簡単な説明】
【図１】キトサン−アスピリン水溶液の乾燥物（サンプルａ）の赤外吸収スペクトルチャート。
【図２】キトサンとアスピリンの混合物（サンプルｂ）の赤外吸収スペクトルチャート。
【図３】キトサン−アスピリン水溶液の乾燥物（サンプルａ）と、キトサンとアスピリンの混合物（サンプルｂ）の両方の赤外吸収スペクトルを表示したチャート。
【図４】キトサンの赤外吸収スペクトルチャート。
【図５】アスピリンの赤外吸収スペクトルチャート。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a water-solubilizing composition for an aromatic carboxylic acid and an aqueous solution for improving the solubility of an aromatic carboxylic acid having improved solubility in water of an aromatic carboxylic acid such as aspirin (acetylsalicylic acid) used as a pharmaceutical product, for example.
[0002]
[Prior art]
In general, aromatic carboxylic acids such as aspirin (acetylsalicylic acid), benzoic acid and salicylic acid, which are widely used as pharmaceuticals such as antipyretics and analgesics, are readily soluble in alcohols, ethers and fats, It is a hydrophobic compound that is difficult to dissolve in water.
[0003]
Therefore, when this aromatic carboxylic acid is used as an internal medicine, it is taken with water in the form of a powder or a tablet.
[0004]
[Problems to be solved by the invention]
However, when taking aromatic carboxylic acids in the form of a powder or a tablet, there are problems that they are difficult to take, have a low absorption rate, and have a short residence time in the body.
[0005]
The present invention has been made in view of the circumstances and problems as described above, and can simplify the dosage and increase the absorption rate when using aromatic carboxylic acids as internal medicines. An object of the present invention is to provide a water-solubilizing composition of an aromatic carboxylic acid and an aqueous solution with improved solubility so that the solubility in water is improved so that the residence time in the body is long and it has sustained release properties.
[0006]
[Means for Solving the Problems]
To achieve the above object , the aqueous solution for improving the solubility of aromatic carboxylic acids according to
[0010]
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the present invention will be described below. In the first embodiment, a water-solubilizing composition of aromatic carboxylic acids will be described, and in the second embodiment, an aqueous solution for improving the solubility of aromatic carboxylic acids will be described.
[0011]
The water-solubilizing composition for aromatic carboxylic acids according to the first embodiment is obtained by adding and mixing a predetermined amount of chitosan to aromatic carboxylic acids.
[0012]
Examples of the aromatic carboxylic acids include aspirin (acetylsalicylic acid), benzoic acid, salicylic acid, anthranilic acid (o-aminobenzoic acid), m-toluic acid, benzylic acid, o-toluic acid (o-methylbenzoic acid). And salts such as sodium salts or derivatives thereof. The chitosan preferably has a deacetylation degree of 80% or more.
[0013]
In order to prepare the water-solubilizing composition, a predetermined amount of chitosan powder may be added to an appropriate aromatic carboxylic acid powder and mixed thoroughly. If this water-solubilized composition is added to water and stirred for a predetermined time, aromatic carboxylic acids that have hardly dissolved in water alone can be dissolved at a higher concentration, and the solubility can be improved. There are advantages. This is considered to be due to the contribution of the interaction between the aromatic carboxylic acids and chitosan in the aqueous solution.
[0014]
Therefore, when the aromatic carboxylic acid is used as an internal medicine, a sufficient amount of the aromatic carboxylic acid is dissolved as long as the water-solubilizing composition is dissolved in water. Therefore, it is possible to simplify the dose and increase the absorption rate. In addition, when taken as an aqueous solution, there is an advantage that the residence time in the body is long and there is sustained release. Furthermore, if a water-solubilizing composition prepared by mixing aromatic carboxylic acids and chitosan is prepared in advance, it can be simply dissolved in water as necessary, and thus there is an advantage that it is convenient.
[0015]
Here, when the addition amount of the chitosan is 1.3 times or less of the weight of the aromatic carboxylic acids, there is an advantage that the water-soluble composition is easily dissolved in water.
[0016]
The aqueous solution for improving the solubility of aromatic carboxylic acids according to the second embodiment is obtained by dissolving aromatic carboxylic acids and chitosan at a predetermined concentration in water.
[0017]
In order to prepare this aqueous solution with improved solubility, the water-solubilizing composition of the first embodiment can be dissolved in water, or the aromatic carboxylic acids and chitosan not mixed can be dissolved in water simultaneously or separately. That's fine. Thus, since chitosan is dissolved in addition to aromatic carboxylic acids, there is an advantage that higher concentrations of aromatic carboxylic acids are dissolved as in the first embodiment. Therefore, if this solubility-improved aqueous solution is prepared in advance, there is an advantage that it is possible to save the trouble of dissolving the water-solubilized composition and the like and to use it as it is as an internal medicine.
[0018]
Here, when the concentration of the aromatic carboxylic acids is 3.2 g / dL or less and the concentration of the chitosan is 1.3 times or less of the concentration of the aromatic carboxylic acids, There is an advantage that there is little or no unmelted residue.
[0019]
【Example】
EXAMPLES Next, although an Example demonstrates this invention still in detail, this invention is not limited to the Example which concerns.
[0020]
[Example 1]
As aromatic carboxylic acids, commercially available phenoxyacetic acid, DL-mandelic acid, m-aminobenzoic acid, p-aminobenzoic acid, phthalic anhydride, trimellitic anhydride, protocatechuic acid, 5-sulfosalicylic acid dihydrate, aspirin (= Acetylsalicylic acid), benzoic acid, salicylic acid, anthranilic acid (= o-aminobenzoic acid), m-toluic acid, benzylic acid, o-toluic acid (= o-methylbenzoic acid), terephthalic acid, isophthalic acid, 1 -Naphthalene acetic acid (= α-naphthylic acid), 1-naphthoic acid, thiosalicylic acid, p-nitrobenzoic acid, p-tert-butylbenzoic acid, dimethyl terephthalate, and 5-hydroxyisophthalic acid, 0.5 g / After adding to a predetermined amount of water at a ratio of dL and stirring at room temperature (about 25 ° C.) for about 12 hours, the dissolution properties were observed and Each was evaluated on the basis of the value criteria. The results are shown in Table 1.
[0021]
〔Evaluation criteria〕
A: Complete dissolution O: A small amount of insoluble component is observed.
(Triangle | delta): Although there is much insoluble matter, it is viscous.
×: Insoluble [0022]
[Table 1]
Further, chitosan (trade name “SK-10”, manufactured by Koyo Chemical Co., Ltd., degree of deacetylation: 80%) was added to the above solution or suspension at a rate of 0.5 g / dL, and room temperature (about 25 ° C.) was added. ) Was further stirred for about 12 hours, and then the dissolution properties were observed and evaluated based on the above evaluation criteria. The results are also shown in Table 1.
[0024]
[Example 2]
Commercially available aspirin (acetylsalicylic acid) was used as the aromatic carboxylic acid, and this aspirin and chitosan as in Example 1 were simultaneously added to water and stirred at room temperature (about 25 ° C.) for about 24 hours. This operation was performed while changing the ratio of chitosan-aspirin and the amount added, and the dissolution properties were observed in the same manner as in Example 1. The results are shown in Table 2.
[0025]
[Table 2]
Example 3
The same chitosan and aspirin as in Example 2 were dissolved in water so that each concentration was 1.0 g / dL, then the aqueous solution was concentrated to dryness with an evaporator, and further dried at 50 ° C. overnight. A sample for measuring an infrared absorption spectrum (sample a) was used.
[0027]
Moreover, chitosan and aspirin were mixed well in a ratio of 1: 1 as a powder to obtain a measurement sample (sample b) of an infrared absorption spectrum.
[0028]
The infrared absorption spectrum was measured for each of the samples a and b (decomposition: 4 cm −1 , apodization: Cosine, integration number: 200). The results are shown in FIGS. In addition, FIG. 3 displays the spectrum of both the sample a and the sample b on the same chart. Moreover, as shown in FIG.4 and FIG.5, each infrared absorption spectrum of chitosan and aspirin was also measured.
[0029]
Example 4
Eight rats were used, and four rats were orally administered a suspension of commercially available aspirin (addition amount 3.2 g / dL) in CMC (carboxymethylcellulose, addition amount 3.2 g / dL) at a rate of 10 mg / kg ( The control group) and the other 4 animals were orally administered with a chitosan-aspirin aqueous solution prepared in the same manner as in Example 2 (each added amount was 3.2 g / dL) at a rate of 10 mg / kg (test group).
[0030]
Rats were fasted the night before the experiment and were given free saline during the fasting period. After administration of the above drug, blood was collected 1, 3, 6, and 9 hours later, and the change in the concentration of aspirin in plasma was examined by high performance liquid chromatography (HPLC). During this time, I was fasting fast. Cmax (maximum plasma concentration), AUC (0 to 9 h, proportional constant of the amount of aspirin absorbed), and MRT (average residence time) were measured. The results are shown in Table 3. In addition, Tmax (maximum plasma concentration arrival time) was read from the measured value of each blood collection time.
[0031]
[Table 3]
[Comparative Example]
Instead of the chitosan, the same operation as in Example 2 was carried out except that glucosamine hydrochloride, which is the structural unit, was used, and the dissolution properties were observed. The results are shown in Table 4.
[0033]
[Table 4]
【The invention's effect】
As described above, according to the invention of
[Brief description of the drawings]
FIG. 1 is an infrared absorption spectrum chart of a dried product (sample a) of an aqueous chitosan-aspirin solution.
FIG. 2 is an infrared absorption spectrum chart of a mixture of chitosan and aspirin (sample b).
FIG. 3 is a chart showing infrared absorption spectra of both a dried product of chitosan-aspirin aqueous solution (sample a) and a mixture of chitosan and aspirin (sample b).
FIG. 4 is an infrared absorption spectrum chart of chitosan.
FIG. 5 is an infrared absorption spectrum chart of aspirin.
Claims (1)
前記芳香族カルボン酸類の濃度が３．２ｇ／ｄＬ以下で、且つ、前記キトサンの濃度がこの芳香族カルボン酸類の濃度の１．３倍以下であることを特徴とする芳香族カルボン酸類の溶解度向上化水溶液。 Aromatic carboxylic acids having at least one solubility selected from benzoic acid, salicylic acid, acetylsalicylic acid, anthranilic acid, m-toluic acid, benzylic acid, and o-toluic acid, and chitosan are dissolved in water at predetermined concentrations, respectively. With
The concentration of the the aromatic carboxylic acids or less 3.2 g / dL, and, in Fang aromatic acids you, wherein the concentration of the chitosan is less than 1.3 times the concentration of the aromatic carboxylic acids An aqueous solution with improved solubility.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP02080098A JP4126405B2 (en) | 1998-02-02 | 1998-02-02 | Aqueous solution with improved solubility of aromatic carboxylic acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP02080098A JP4126405B2 (en) | 1998-02-02 | 1998-02-02 | Aqueous solution with improved solubility of aromatic carboxylic acids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH11222457A JPH11222457A (en) | 1999-08-17 |
| JP4126405B2 true JP4126405B2 (en) | 2008-07-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP02080098A Expired - Fee Related JP4126405B2 (en) | 1998-02-02 | 1998-02-02 | Aqueous solution with improved solubility of aromatic carboxylic acids |
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| JP (1) | JP4126405B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101591470B1 (en) * | 2014-11-19 | 2016-02-03 | 제너럴바이오(주) | A composition for chitosan solution thereof |
| NZ749230A (en) * | 2016-06-28 | 2023-05-26 | Asamedic As | Two-component composition |
| EP3501522A1 (en) | 2017-12-22 | 2019-06-26 | Asamedic AS | Compositions comprising acetylsalicylic acid and a phosphate salt |
| EP3501523A1 (en) | 2017-12-22 | 2019-06-26 | Asamedic AS | Two-component compositions comprising acetyl salicylic acid and a carbonate salt |
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1998
- 1998-02-02 JP JP02080098A patent/JP4126405B2/en not_active Expired - Fee Related
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| Publication number | Publication date |
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| JPH11222457A (en) | 1999-08-17 |
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