JP2011042682A - Thickener for aqueous preparation - Google Patents
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- JP2011042682A JP2011042682A JP2010242734A JP2010242734A JP2011042682A JP 2011042682 A JP2011042682 A JP 2011042682A JP 2010242734 A JP2010242734 A JP 2010242734A JP 2010242734 A JP2010242734 A JP 2010242734A JP 2011042682 A JP2011042682 A JP 2011042682A
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- hyaluronic acid
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- boric acid
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Abstract
Description
本発明はヒアルロン酸を溶解含有する水性製剤の増粘剤、増粘方法および増粘されたヒアルロン酸含有水性製剤の製造法に関する。 The present invention relates to a thickener for an aqueous preparation containing dissolved hyaluronic acid, a thickening method, and a method for producing a thickened hyaluronic acid-containing aqueous preparation.
ヒアルロン酸は哺乳動物の結合組織に広く存在する高分子多糖で、N−アセチルグルコサミンとグルクロン酸が交互直鎖状に結合した構造を有し、水溶液は強い粘性を示すので、この性質を利用して白内障や緑内障の治療、角膜移植等の眼手術、変形性関節症、火傷等の処置に注入剤、注射剤や外用剤として用いられている。また眼組織表面の損傷、眼乾燥症候群の処置に点眼剤としても用いられている。ヒアルロン酸水溶液の粘性を利用するには該水溶液の粘度をできるだけ高くするのが望ましく、その目的でヒアルロン酸塩をグリセリンやグルコースのような非電解質で等張化した水に溶解した製剤が提案されている(特開昭58−57319号)。 Hyaluronic acid is a high-molecular polysaccharide widely present in mammalian connective tissues. It has a structure in which N-acetylglucosamine and glucuronic acid are linked in an alternating linear form, and aqueous solutions exhibit strong viscosity. It is used as an injection, injection or external preparation for the treatment of cataracts and glaucoma, eye surgery such as corneal transplantation, osteoarthritis, and burns. It is also used as eye drops for the treatment of eye tissue surface damage and dry eye syndrome. In order to utilize the viscosity of an aqueous solution of hyaluronic acid, it is desirable to increase the viscosity of the aqueous solution as much as possible. For this purpose, a formulation in which hyaluronic acid salt is dissolved in non-electrolyte water such as glycerin and glucose is proposed. (Japanese Patent Laid-Open No. 58-57319).
しかしながら、この製剤は食塩などの電解質を含有する製剤の場合には適用できず、実地の応用面における制約を免れない。本発明はそのような制約を受けることなく高粘度化されたヒアルロン酸水溶液を提供しようとするものである。 However, this preparation cannot be applied in the case of a preparation containing an electrolyte such as sodium chloride, and is unavoidable in practical application. The present invention seeks to provide a hyaluronic acid aqueous solution having a high viscosity without being subject to such restrictions.
本発明者らはヒアルロン酸ナトリウムに塩化ナトリウム及びホウ酸を種々の割合で配合して等張水溶液を調製する場合ホウ酸の濃度を高くすると調製時の粘度が高くなることを発見した。 The present inventors have found that when preparing an isotonic aqueous solution by mixing sodium hyaluronate with sodium chloride and boric acid in various proportions, increasing the concentration of boric acid increases the viscosity at the time of preparation.
本発明はこの知見に基づくもので、ホウ酸よりなるヒアルロン酸を溶解含有する水性製剤の増粘剤、ホウ酸を配合することを特徴とするヒアルロン酸を溶解含有する水性製剤の増粘方法、及びヒアルロン酸を溶解含有する水性製剤にホウ酸を配合することを特徴とする粘度を増加したヒアルロン酸含有水性製剤の製造法に関する。 The present invention is based on this finding, a thickener for an aqueous preparation containing dissolved hyaluronic acid composed of boric acid, a method for increasing the viscosity of an aqueous preparation containing dissolved hyaluronic acid, characterized by containing boric acid, The present invention also relates to a method for producing a hyaluronic acid-containing aqueous preparation with increased viscosity, characterized in that boric acid is added to an aqueous preparation containing dissolved hyaluronic acid.
ヒアルロン酸およびホウ酸は遊離酸もしくは塩の形態で水に溶解し、水溶液中ではpHに従って相互に移行しうるので、本発明においては特記しない限りヒアルロン酸もしくはホウ酸として遊離酸型と塩型を総称するものとする。ヒアルロン酸としては分子量10万〜300万を有するものが一般に用いられる。 Since hyaluronic acid and boric acid are dissolved in water in the form of free acid or salt and can be transferred to each other according to pH in an aqueous solution, unless otherwise specified in the present invention, free acid form and salt form are designated as hyaluronic acid or boric acid. It shall be named generically. As hyaluronic acid, those having a molecular weight of 100,000 to 3,000,000 are generally used.
ヒアルロン酸水溶液の粘度は経日的に次第に低下する傾向を示すが、ホウ酸を配合した場合は配合しない場合に比べ、溶液調製当初の粘度が増加するのみならず、経日後の粘度も、経日的な低下にもかかわらず著しい高粘度を保たせることができる。 The viscosity of the aqueous hyaluronic acid solution tends to gradually decrease over time, but when boric acid is blended, not only does the viscosity increase at the beginning of the solution preparation, but also the viscosity after the passage of time passes. A remarkable high viscosity can be maintained despite the daily decline.
配合されるホウ酸の水溶液中における濃度は0.1〜3%、好ましくは0.5〜3%、より好ましくは1.5〜2.5%である。水性製剤には上記の成分のほかに、本発明の目的を達し得る限り他の薬効成分、等張化剤、緩衝剤、pH調整剤を含有させることができる。他の薬効成分としては、たとえば抗菌剤、キレート剤、抗炎症剤、抗アレルギー剤、抗生物質、鎮痛剤、眼圧降下剤、免疫調節剤等があげられる。等張化剤としては、たとえば塩化ナトリウム、塩化カリウム、糖類、多価アルコール類等があり、緩衝剤としては、たとえば酢酸ナトリウム、ホウ酸ナトリウム、クエン酸ナトリウム等、あるいはこれらの塩と対応する酸とが併用される。ホウ酸ナトリウムなどのホウ酸塩は緩衝剤としてのみならず増粘剤として作用させることもできる。 The density | concentration in the aqueous solution of the boric acid mix | blended is 0.1 to 3%, Preferably it is 0.5 to 3%, More preferably, it is 1.5 to 2.5%. In addition to the components described above, the aqueous preparation can contain other medicinal ingredients, isotonic agents, buffers, and pH adjusters as long as the object of the present invention can be achieved. Examples of other medicinal ingredients include antibacterial agents, chelating agents, anti-inflammatory agents, antiallergic agents, antibiotics, analgesics, intraocular pressure-lowering agents, immunomodulators and the like. Examples of tonicity agents include sodium chloride, potassium chloride, sugars, polyhydric alcohols, and the like, and examples of buffering agents include sodium acetate, sodium borate, sodium citrate, etc., or acids corresponding to these salts. And are used together. Borates such as sodium borate can act as a thickener as well as a buffer.
本発明は、以下を提供する。
(項目1)
ホウ酸よりなるヒアルロン酸を含有する水性製剤の増粘剤。
(項目2)
ヒアルロン酸がナトリウム塩である上記項目1記載の増粘剤。
(項目3)
水性製剤がヒアルロン酸を0.001〜0.5重量%含有する上記項目1記載の増粘剤。
(項目4)
水性製剤のpHが5〜7.5である上記項目1記載の増粘剤。
(項目5)
ホウ酸を配合することを特徴とするヒアルロン酸を含有する水性製剤の増粘方法。
(項目6)
水性製剤がヒアルロン酸を0.001〜0.5重量%含有する上記項目5記載の方法。
(項目7)
ホウ酸が遊離酸として0.1〜5重量%配合される上記項目5記載の方法。
(項目8)
ホウ酸が遊離酸として0.5〜2重量%配合される上記項目6記載の方法。
(項目9)
ヒアルロン酸がナトリウム塩である上記項目5記載の方法。
(項目10)
水性製剤のpHが5〜7.5である上記項目5記載の方法。
(項目11)
ヒアルロン酸を含有する水性製剤にホウ酸を配合することを特徴とする粘度を増加したヒアルロン酸含有水性製剤の製造法。
(項目12)
ヒアルロン酸がナトリウム塩である上記項目11記載の製造法。
(項目13)
水性製剤のpHが5〜7.5である上記項目11記載の製造法。
The present invention provides the following.
(Item 1)
A thickener for aqueous preparations containing hyaluronic acid consisting of boric acid.
(Item 2)
The thickener according to item 1, wherein the hyaluronic acid is a sodium salt.
(Item 3)
The thickener according to item 1, wherein the aqueous preparation contains 0.001 to 0.5% by weight of hyaluronic acid.
(Item 4)
The thickener according to item 1, wherein the pH of the aqueous preparation is 5 to 7.5.
(Item 5)
A method for increasing the viscosity of an aqueous preparation containing hyaluronic acid, comprising boric acid.
(Item 6)
6. The method according to item 5 above, wherein the aqueous preparation contains 0.001 to 0.5% by weight of hyaluronic acid.
(Item 7)
6. The method according to item 5, wherein boric acid is blended in an amount of 0.1 to 5% by weight as a free acid.
(Item 8)
7. The method according to item 6 above, wherein boric acid is added as a free acid in an amount of 0.5 to 2% by weight.
(Item 9)
6. The method according to item 5 above, wherein the hyaluronic acid is a sodium salt.
(Item 10)
6. The method according to item 5 above, wherein the pH of the aqueous preparation is 5 to 7.5.
(Item 11)
A method for producing a hyaluronic acid-containing aqueous preparation with increased viscosity, characterized in that boric acid is added to an aqueous preparation containing hyaluronic acid.
(Item 12)
Item 12. The method according to Item 11, wherein the hyaluronic acid is a sodium salt.
(Item 13)
12. The production method according to item 11, wherein the pH of the aqueous preparation is 5 to 7.5.
本発明によればヒアルロン酸水溶液にホウ酸を配合することにより簡易に溶液の粘度を上昇させることができ、経日後もなお高い粘度を保たせることができ、また必要に応じて電解質を加えることにより、粘度の調節も可能であるため、たとえば眼科手術時に用いる水性製剤に有利に用いられる。 According to the present invention, the viscosity of the solution can be easily increased by adding boric acid to the hyaluronic acid aqueous solution, and the high viscosity can be maintained even after aging, and an electrolyte is added as necessary. Thus, the viscosity can be adjusted, so that it is advantageously used in an aqueous preparation used at the time of ophthalmic surgery, for example.
以下に実験例および実施例を挙げて本発明をさらに説明する。 The present invention will be further described below with reference to experimental examples and examples.
実験例1
表1および表2の処方に従って水溶液を調製し、その粘度を経日的に測定した。結果を表3および表4に示す。
Experimental example 1
Aqueous solutions were prepared according to the formulations in Tables 1 and 2, and their viscosities were measured over time. The results are shown in Table 3 and Table 4.
(表1と2のヒアルロン酸ナトリウムは分子量200万(株)資生堂製) (The sodium hyaluronate in Tables 1 and 2 has a molecular weight of 2 million manufactured by Shiseido Co., Ltd.)
以下の表3、表4および表7、表8において、
In Table 3, Table 4, Table 7, and Table 8 below,
表1、表2および表3、表4から明らかなようにホウ酸の配合量が増加するにつれて調製当初の粘度は増加し、経日後もその傾向は保持された。またグルコン酸クロルヘキシジンの併用でも上記の傾向は変わらなかった。 As apparent from Table 1, Table 2, Table 3, and Table 4, the viscosity at the beginning of the preparation increased as the amount of boric acid increased, and this tendency was maintained even after aging. In addition, the above tendency was not changed even when chlorhexidine gluconate was used in combination.
実験例2
表5および表6の処方に従って水溶液を調製し、その粘度を経日的に測定した。結果を表7および表8に示す。
Experimental example 2
Aqueous solutions were prepared according to the formulations in Tables 5 and 6, and their viscosities were measured over time. The results are shown in Table 7 and Table 8.
(ヒアルロン酸ナトリウムは分子量200万(株)資生堂製) (Sodium hyaluronate has a molecular weight of 2 million manufactured by Shiseido Co., Ltd.)
〔ヒアルロン酸ナトリウムは分子量60〜120万(平均95.55万)、 (株)資生堂製〕 [Sodium hyaluronate has a molecular weight of 60 to 1,200,000 (average 95.550,000), manufactured by Shiseido Co., Ltd.]
表5の処方においては表1の処方に比べ、ヒアルロン酸ナトリウムが2倍に増量されているので、表7に示されるように水溶液の粘度も高くなっているが、ホウ酸の配合量が増加するにつれて調製当初の粘度は増加し経日後もその傾向は保持された。表6および表8から明らかなように、ヒアルロン酸ナトリウムの分子量が表5の場合の200万に比べ約半分に低下してもホウ酸の配合量が増加するにつれて上記の傾向は変わらなかった。また、pH5およびpH7.5についてもホウ酸の配合により当初粘度は増加した。 In the formulation of Table 5, sodium hyaluronate is increased twice as much as the formulation of Table 1, so the viscosity of the aqueous solution is high as shown in Table 7, but the amount of boric acid is increased. As a result, the viscosity at the beginning of the preparation increased and the tendency was maintained even after the lapse of time. As is clear from Tables 6 and 8, even though the molecular weight of sodium hyaluronate was reduced to about half compared to 2 million in Table 5, the above tendency did not change as the amount of boric acid increased. In addition, with respect to pH 5 and pH 7.5, the initial viscosity increased due to the incorporation of boric acid.
100 mL中
ヒアルロン酸ナトリウム 0.01g
塩酸ナファゾリン 0.005g
マレイン酸クロルフェニラミン 0.05g
ホウ酸 1.5g
パラオキシ安息香酸メチル 0.02g
パラオキシ安息香酸プロピル 0.01g
塩酸 適量
滅菌精製水 適量(pH5.0)
0.01 g sodium hyaluronate in 100 mL
Naphazoline hydrochloride 0.005g
Chlorpheniramine maleate 0.05g
Boric acid 1.5g
Methyl paraoxybenzoate 0.02g
0.01 g propyl paraoxybenzoate
Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount (pH 5.0)
100 mL中
ヒアルロン酸ナトリウム 0.01g
アラントイン 0.005g
メチル硫酸ネオスチグミン 0.005g
フラビンアデニンジヌムレオチド 0.01g
イプシロンアミノカプロン 0.1g
ホウ酸 2.0g
水酸化ナトリウム 適量
滅菌精製水 適量(pH7.5)
0.01 g sodium hyaluronate in 100 mL
Allantoin 0.005g
Methyl sulfate neostigmine 0.005g
Flavin adenine dinumreotide 0.01g
Epsilon aminocapron 0.1g
Boric acid 2.0g
Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount (pH 7.5)
100 mL中
ヒアルロン酸ナトリウム 0.005g
塩化ナトリウム 0.5g
塩化カリウム 0.2g
ホウ酸 1.2g
乾燥炭酸ナトリウム 0.05g
水酸化ナトリウム 適量
滅菌精製水 適量(pH7.0)
0.005 g sodium hyaluronate in 100 mL
Sodium chloride 0.5g
Potassium chloride 0.2g
Boric acid 1.2g
0.05g dry sodium carbonate
Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount (pH 7.0)
100 mL中
ヒアルロン酸ナトリウム 0.005g
パルミチン酸レチノール 100,000I.U.
ポリソルベート 80 0.2g
濃グリセリン 0.5g
ホウ酸 1.5g
エデト酸ナトリウム 0.05g
ホウ砂 適量
滅菌精製水 適量(pH7.0)
In 100 mL
Sodium hyaluronate 0.005g
Retinol palmitate 100,000 I.I. U.
Polysorbate 80 0.2g
Concentrated glycerin 0.5g
Boric acid 1.5g
Sodium edetate 0.05g
Borax appropriate amount
Sterilized purified water appropriate amount (pH 7.0)
Claims (1)
Priority Applications (1)
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JP2010242734A JP2011042682A (en) | 1997-05-20 | 2010-10-28 | Thickener for aqueous preparation |
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JP14731597 | 1997-05-20 | ||
JP2010242734A JP2011042682A (en) | 1997-05-20 | 2010-10-28 | Thickener for aqueous preparation |
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JP12865898A Division JPH1143446A (en) | 1997-05-20 | 1998-05-12 | Viscosity-increasing agent for aqueous preparation |
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JP2013219722A Division JP5886260B2 (en) | 1997-05-20 | 2013-10-23 | Method for inhibiting thickening and viscosity reduction of hyaluronic acid containing aqueous preparation |
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JP2011042682A true JP2011042682A (en) | 2011-03-03 |
JP2011042682A5 JP2011042682A5 (en) | 2011-12-01 |
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JP2010242734A Pending JP2011042682A (en) | 1997-05-20 | 2010-10-28 | Thickener for aqueous preparation |
JP2013219722A Expired - Lifetime JP5886260B2 (en) | 1997-05-20 | 2013-10-23 | Method for inhibiting thickening and viscosity reduction of hyaluronic acid containing aqueous preparation |
JP2015192424A Pending JP2016014053A (en) | 1997-05-20 | 2015-09-30 | Thickened hyaluronic acid-containing aqueous formulation |
JP2016211210A Expired - Lifetime JP6156762B2 (en) | 1997-05-20 | 2016-10-28 | Thickening and viscosity reduction inhibitor for hyaluronic acid-containing aqueous preparations |
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JP2013219722A Expired - Lifetime JP5886260B2 (en) | 1997-05-20 | 2013-10-23 | Method for inhibiting thickening and viscosity reduction of hyaluronic acid containing aqueous preparation |
JP2015192424A Pending JP2016014053A (en) | 1997-05-20 | 2015-09-30 | Thickened hyaluronic acid-containing aqueous formulation |
JP2016211210A Expired - Lifetime JP6156762B2 (en) | 1997-05-20 | 2016-10-28 | Thickening and viscosity reduction inhibitor for hyaluronic acid-containing aqueous preparations |
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Cited By (1)
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JP2013112628A (en) * | 2011-11-28 | 2013-06-10 | Senju Pharmaceut Co Ltd | Ophthalmic composition for animal |
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JP6603785B2 (en) * | 2017-12-08 | 2019-11-06 | 千寿製薬株式会社 | Aqueous solution containing water-soluble polymer |
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JPS5857319A (en) * | 1981-09-30 | 1983-04-05 | Green Cross Corp:The | High-viscosity hyaluronic acid preparation |
JPH0296531A (en) * | 1988-08-04 | 1990-04-09 | Ciba Geigy Ag | Method and composition for preserving intraocular solution |
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2010
- 2010-10-28 JP JP2010242734A patent/JP2011042682A/en active Pending
-
2013
- 2013-10-23 JP JP2013219722A patent/JP5886260B2/en not_active Expired - Lifetime
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2015
- 2015-09-30 JP JP2015192424A patent/JP2016014053A/en active Pending
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- 2016-10-28 JP JP2016211210A patent/JP6156762B2/en not_active Expired - Lifetime
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JPH0296531A (en) * | 1988-08-04 | 1990-04-09 | Ciba Geigy Ag | Method and composition for preserving intraocular solution |
SU1623991A1 (en) * | 1989-05-06 | 1991-01-30 | Всесоюзный научно-исследовательский институт текстильно-галантерейной промышленности | Process for stabilization of gialuronic acid |
JPH0469342A (en) * | 1990-07-06 | 1992-03-04 | Senju Pharmaceut Co Ltd | Aqueous medicinal preparation |
JPH1025254A (en) * | 1996-07-12 | 1998-01-27 | Rohto Pharmaceut Co Ltd | Water-soluble preparation free from contraindication |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2013112628A (en) * | 2011-11-28 | 2013-06-10 | Senju Pharmaceut Co Ltd | Ophthalmic composition for animal |
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JP2016014053A (en) | 2016-01-28 |
JP6156762B2 (en) | 2017-07-05 |
JP5886260B2 (en) | 2016-03-16 |
JP2017019867A (en) | 2017-01-26 |
JP2014012743A (en) | 2014-01-23 |
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