JP3694868B2 - Sodium hyaluronate injection composition - Google Patents
Sodium hyaluronate injection composition Download PDFInfo
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- JP3694868B2 JP3694868B2 JP27545794A JP27545794A JP3694868B2 JP 3694868 B2 JP3694868 B2 JP 3694868B2 JP 27545794 A JP27545794 A JP 27545794A JP 27545794 A JP27545794 A JP 27545794A JP 3694868 B2 JP3694868 B2 JP 3694868B2
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- sodium hyaluronate
- citrate
- injection composition
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Description
【０００１】
【技術分野】
本発明は、人および動物の医療分野で使用されるヒアルロン酸ナトリウム注射液組成物に関する。
【０００２】
【背景技術】
１９４２年、Ｂａｌａｚｓは関節疾患治療薬としてヒアルロン酸を外傷性関節炎、変形性関節症、関節切開術後切開などのパンヌス形成の抑制、関節拘縮の進行防止などに使用することを提案した（Ｂａｌａｚｓ，Ｅ．Ａ．ｅｔ ａｌ．：Ｔｈｅｓｉｓ，Ｕｎｉｖｅｒｓｉｔｙ ｏｆ Ｂｕｔａｐｅｓｔ，Ｆａｃｕｌｔｙ ｏｆ ｍｅｄｉｃｉｎｅ，１９４２）。
【０００３】
その後の研究によりヒアルロン酸もしくはその塩はヒトの変性性関節症その他の関節疾患をはじめ、競争馬の外傷性関節炎などに試用され、最近、国内でも変形性関節症や肩関節周囲炎の治療薬として使用されるようになってきた。
近年、鶏冠由来のヒアルロン酸ナトリウム注射液が、膝及び肩の関節炎の治療に用いられ、その効果が高く評価され、多くの患者の苦痛をやわらげ、生活の質を高めている。
【０００４】
ところで、ヒアルロン酸は、それ自体では不安定な物質であるため、そのナトリウム塩の形で製剤化して適用されているが、ヒアルロン酸ナトリウムさえも水溶液の状態においては安定性に欠けている。また、ヒアルロン酸は、分子量が大きくなるほど安定性が悪くなるという性質を有する。
ヒアルロン酸ナトリウムの溶液は、ｐＨによってその安定性が左右され、中性付近においては比較的安定なものであるが、中性に保つために使用する緩衝液の種類によって安定性に差があるため安定性に優れた取扱い易い製剤の開発が強く要望されていた。
【０００５】
本発明者らは、このような状況のもとでヒアルロン酸ナトリウムの注射液の安定化につき鋭意研究を進めた結果、クエン酸またはクエン酸塩をヒアルロン酸ナトリウム溶液に添加することによってより安定性が増すことを見出した。本発明は、かかる知見にもとづいてなされたものである。
【０００６】
【発明の開示】
本発明は、ヒアルロン酸ナトリウム溶液にクエン酸および／またはクエン酸塩が添加され、溶液のｐＨが７〜７．５である、ヒアルロン酸ナトリウム注射液組成物を提供するものである。
【０００７】
以下、本発明を詳細に説明する。
本発明は、ヒアルロン酸ナトリウム溶液に対し、クエン酸またはクエン酸塩をヒアルロン酸ナトリウム１重量部に対して、好ましくは０．１〜２重量部の量で配合して添加することにより、ヒアルロン酸ナトリウム溶液の安定性を高めるものである。
【０００８】
本発明に用いられるヒアルロン酸ナトリウムは、その由来は限定されるものではなく、鶏冠由来および微生物由来のいずれも用いることができる。
本発明において、ヒアルロン酸ナトリウムとしては、その分子量は特定されず、特に、不安定な物質である高分子量のヒアルロン酸ナトリウム（分子量１９０万以上）についても顕著な安定化が認められる。
使用するクエン酸およびクエン酸塩は、人および動物に対して生理的に許容される物質であり、具体的には、クエン酸、クエン酸ナトリウム、クエン酸カリウム、クエン酸カルシウム、クエン酸リチウム、クエン酸アンモニウム、クエン酸水素カリウム、クエン酸鉄、クエン酸銅などがあげられる。
【０００９】
以下に本発明の実施例を試験例、比較例と共に示し、本発明を更に具体的に説明する。
なお、各実施例および比較例においては、分子量約１００万および約２００万の２種のヒアルロン酸ナトリウムを使用したが、本発明の実施にあたっては、これら実施例の記載に限定されるものではない。
【００１０】
【実施例】
実施例１
調製法
上記処方中のヒアルロン酸ナトリウムを除き他の処方成分すべてを９００ｍｌの注射用水に溶解させた。この溶液にヒアルロン酸ナトリウムを少量ずつ加えた後、注射用水で全量を１０００ｍｌとした。この処方液をバイアルに充填密封後、常法により滅菌した。調製した溶液は、比較例３、４、５および６以外は、ヒアルロン酸ナトリウムが比較的安定な領域とされるｐＨ７から７．５の範囲となるように調整した。
以下の、実施例および比較例においては、各実施例および比較例に記載の処方で実施例１記載の調製法に準じて調製した。
【００１２】
実施例２
実施例３
実施例４
実施例５
実施例６
実施例７
実施例８
実施例９
【比較例】
比較例１
比較例２
比較例３
比較例４
比較例５
比較例６
試験方法
各実施例、比較例により得られた各製剤および市販品（分子量約８０万）をバイアルに密封後、６０℃で保存（遮光）し、２週間後および１０日後の極限粘度を測定し、その測定結果からLaurentの式により平均分子量の不変化率を求めた。また、実施例５、実施例９、比較例２により得られた各製剤および市販品については、さらに、４０℃で保存し、１箇月後の平均分子量の不変化率も測定した。
その結果を表１および表２に示す。
【００２７】
【表１】
【表２】
以上の実験結果に示されているとおり、本発明に係るヒアルロン酸ナトリウム注射液組成物は、クエン酸および／またはクエン酸の塩が添加されていることによって、その分子量が約１００万および約２００万のいずれについても著しく向上した安定性が認められた。したがって、本発明によりヒアルロン酸ナトリウム注射液の取扱い上、著しい利点をもたらし、人および動物用の医療用注射液に対し極めて有用なものである。[0001]
【Technical field】
The present invention relates to a sodium hyaluronate injection composition used in the medical field of humans and animals.
[0002]
[Background]
In 1942, Balazs proposed the use of hyaluronic acid as a treatment for joint diseases in the prevention of pannus formation such as traumatic arthritis, osteoarthritis, and post-incision incision, and prevention of joint contracture progression (Balazs). , EA et al .: Thesis, University of Butapest, Facility of medicine, 1942).
[0003]
Subsequent research has shown that hyaluronic acid or its salts have been used in human degenerative arthritis and other joint diseases, as well as traumatic arthritis in competitive horses. Recently, it has been used in Japan to treat osteoarthritis and shoulder periarthritis. Has come to be used as.
In recent years, sodium hyaluronate injections derived from chicken crown have been used for the treatment of knee and shoulder arthritis, and their effects have been highly evaluated, relieving the suffering of many patients and improving the quality of life.
[0004]
By the way, since hyaluronic acid is an unstable substance by itself, it is formulated and applied in the form of its sodium salt, but even sodium hyaluronate lacks stability in the state of an aqueous solution. Further, hyaluronic acid has a property that its stability decreases as the molecular weight increases.
The stability of sodium hyaluronate solution is affected by the pH and is relatively stable near neutrality, but the stability varies depending on the type of buffer used to maintain neutrality. There has been a strong demand for the development of an easy-to-handle preparation with excellent stability.
[0005]
As a result of diligent research on the stabilization of an injection solution of sodium hyaluronate under these circumstances, the present inventors have made it more stable by adding citric acid or citrate to the sodium hyaluronate solution. Has been found to increase. The present invention has been made based on such knowledge.
[0006]
DISCLOSURE OF THE INVENTION
The present invention provides a sodium hyaluronate injection composition in which citric acid and / or citrate is added to a sodium hyaluronate solution, and the pH of the solution is 7 to 7.5 .
[0007]
Hereinafter, the present invention will be described in detail.
In the present invention, hyaluronic acid is added to sodium hyaluronate solution by adding citric acid or citrate in an amount of preferably 0.1 to 2 parts by weight to 1 part by weight of sodium hyaluronate. This increases the stability of the sodium solution.
[0008]
The origin of the sodium hyaluronate used in the present invention is not limited, and any of those derived from a chicken crown and a microorganism can be used.
In the present invention, the molecular weight of sodium hyaluronate is not specified. In particular, significant stabilization is also observed for high molecular weight sodium hyaluronate (molecular weight of 1.9 million or more), which is an unstable substance.
The citric acid and citrate used are substances that are physiologically acceptable to humans and animals, specifically citric acid, sodium citrate, potassium citrate, calcium citrate, lithium citrate, Examples include ammonium citrate, potassium hydrogen citrate, iron citrate, and copper citrate.
[0009]
Examples of the present invention are shown below together with test examples and comparative examples, and the present invention will be described more specifically.
In each example and comparative example, two types of sodium hyaluronate having a molecular weight of about 1 million and about 2 million were used. However, the present invention is not limited to the description of these examples. .
[0010]
【Example】
Example 1
Preparation Method Except for sodium hyaluronate in the above formulation, all other formulation components were dissolved in 900 ml of water for injection. Sodium hyaluronate was added to this solution little by little, and the total volume was made up to 1000 ml with water for injection. The formulation solution was filled and sealed in a vial and then sterilized by a conventional method. Except for Comparative Examples 3, 4, 5 and 6, the prepared solution was adjusted to a pH range of 7 to 7.5 in which sodium hyaluronate is a relatively stable region.
In the following Examples and Comparative Examples, the preparations described in Examples 1 and 1 were prepared according to the preparation method described in Example 1.
[0012]
Example 2
Example 3
Example 4
Example 5
Example 6
Example 7
Example 8
Example 9
[Comparative example]
Comparative Example 1
Comparative Example 2
Comparative Example 3
Comparative Example 4
Comparative Example 5
Comparative Example 6
Test methods Each preparation and commercial product (molecular weight of about 800,000) obtained in each Example and Comparative Example were sealed in a vial, stored at 60 ° C. (light-shielded), and measured for intrinsic viscosity after 2 weeks and 10 days From the measurement results, the rate of change in average molecular weight was determined by the Laurent equation. Moreover, about each formulation obtained by Example 5, Example 9, and the comparative example 2, and a commercial item, it preserve | saved further at 40 degreeC and measured the invariable rate of the average molecular weight after one month.
The results are shown in Tables 1 and 2.
[0027]
[Table 1]
[Table 2]
As shown in the above experimental results, the sodium hyaluronate injection composition according to the present invention has a molecular weight of about 1 million and about 200 by adding citric acid and / or a salt of citric acid. Significantly improved stability was observed for all ten thousand. Therefore, the present invention provides significant advantages in handling sodium hyaluronate injection solutions and is extremely useful for medical injection solutions for humans and animals.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27545794A JP3694868B2 (en) | 1994-10-04 | 1994-10-04 | Sodium hyaluronate injection composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27545794A JP3694868B2 (en) | 1994-10-04 | 1994-10-04 | Sodium hyaluronate injection composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH08104642A JPH08104642A (en) | 1996-04-23 |
| JP3694868B2 true JP3694868B2 (en) | 2005-09-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27545794A Expired - Fee Related JP3694868B2 (en) | 1994-10-04 | 1994-10-04 | Sodium hyaluronate injection composition |
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| Country | Link |
|---|---|
| JP (1) | JP3694868B2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2496121C (en) | 2002-08-16 | 2010-03-30 | Yoshiaki Miyata | Stable formulations of hyaluronic acid for use in the therapeutic treatment of arthropathy |
| JP5957440B2 (en) * | 2011-03-02 | 2016-07-27 | デンカ株式会社 | An aqueous solution containing hyaluronic acid or a salt thereof |
| WO2012118194A1 (en) * | 2011-03-02 | 2012-09-07 | 電気化学工業株式会社 | Pre-filled syringe filling syringe having resin barrel with aqueous solution containing hyaluronic acid or salt thereof |
| WO2018061884A1 (en) * | 2016-09-29 | 2018-04-05 | カーリットホールディングス株式会社 | Menthol derivative-containing composition |
| EP3919047A1 (en) * | 2020-06-03 | 2021-12-08 | AZAD Pharma AG | Microemulsion for the treatment of dry eye syndrome |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55153711A (en) * | 1979-05-19 | 1980-11-29 | Pola Chem Ind Inc | Cosmetic lotion |
| JP2951681B2 (en) * | 1990-02-23 | 1999-09-20 | 株式会社資生堂 | Pharmaceutical composition for transmucosal administration |
| JPH06192110A (en) * | 1992-12-24 | 1994-07-12 | Takada Seiyaku Kk | Injection of sodium hyaluronate solution |
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1994
- 1994-10-04 JP JP27545794A patent/JP3694868B2/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| JPH08104642A (en) | 1996-04-23 |
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