JPH09176020A - Stable solution containing sodium hyaluronate - Google Patents
Stable solution containing sodium hyaluronateInfo
- Publication number
- JPH09176020A JPH09176020A JP7352138A JP35213895A JPH09176020A JP H09176020 A JPH09176020 A JP H09176020A JP 7352138 A JP7352138 A JP 7352138A JP 35213895 A JP35213895 A JP 35213895A JP H09176020 A JPH09176020 A JP H09176020A
- Authority
- JP
- Japan
- Prior art keywords
- sodium hyaluronate
- sodium
- solution
- molecular weight
- injection
- 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.)
- Pending
Links
- 229920002385 Sodium hyaluronate Polymers 0.000 title claims abstract description 42
- 229940010747 sodium hyaluronate Drugs 0.000 title claims abstract description 42
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 title claims abstract description 42
- 239000000243 solution Substances 0.000 claims abstract description 33
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 28
- 235000011187 glycerol Nutrition 0.000 claims description 11
- 238000010999 medical injection Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 4
- 238000002347 injection Methods 0.000 abstract description 4
- 239000007924 injection Substances 0.000 abstract description 4
- 241001465754 Metazoa Species 0.000 abstract description 3
- 241000282414 Homo sapiens Species 0.000 abstract description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000008215 water for injection Substances 0.000 description 9
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 7
- 229910000397 disodium phosphate Inorganic materials 0.000 description 7
- 235000019800 disodium phosphate Nutrition 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 7
- 235000019799 monosodium phosphate Nutrition 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 7
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 4
- 229920002674 hyaluronan Polymers 0.000 description 4
- 229960003160 hyaluronic acid Drugs 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 4
- 230000000087 stabilizing effect Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 206010048873 Traumatic arthritis Diseases 0.000 description 2
- 239000007864 aqueous solution Chemical group 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 210000003127 knee Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 1
- 241001573881 Corolla Species 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010023201 Joint contracture Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000000035 biogenic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000003009 skin protective agent Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Polymers & Plastics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、安定なヒアルロン酸ナ
トリウム含有溶液、詳しくは、特に医療用注射剤として
好適なグリセリンが添加された安定なヒアルロン酸ナト
リウム含有溶液に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stable sodium hyaluronate-containing solution, and more particularly to a stable sodium hyaluronate-containing solution containing glycerin, which is particularly suitable as a medical injection.
【０００２】[0002]
【従来の技術】ヒアルロン酸は、１９３４年にMeyerとP
almerによってウシ眼球のガラス体から見出された生体
成分物質である。その基本構造は、Ｄ−グルクロン酸と
Ｎ−アセチル−Ｄ−グルコサミンの２糖が、直鎖状に交
互に結合した構造を有し、分子量の大きいムコ多糖類に
属する。一般には生体からグルクロン酸のカルボキシル
基の水素がナトリウムに置き換えられたナトリウム塩の
形で分離精製され、その水溶液は非常に粘度が高い。そ
の後多くの研究者によって、動物の種々の組織、すなわ
ち関節液、鶏冠、臍帯、胎盤、皮膚、靭帯、腱、大動
脈、心臓弁、骨、軟骨、脳血清、腫瘍液などからも見出
されている。2. Description of the Related Art Hyaluronic acid was introduced by Meyer and P. in 1934.
It is a biogenic substance found in the glass body of bovine eyes by almer. Its basic structure has a structure in which disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine are alternately linked in a linear form, and belongs to a mucopolysaccharide having a large molecular weight. Generally, it is separated and purified from a living body in the form of a sodium salt in which hydrogen of the carboxyl group of glucuronic acid is replaced with sodium, and its aqueous solution has a very high viscosity. After that, it was also found by many researchers in various animal tissues, such as synovial fluid, corolla, umbilical cord, placenta, skin, ligaments, tendons, aortas, heart valves, bones, cartilage, cerebral serum, tumor fluids, etc. There is.
【０００３】１９４２年Balazsらは、ヒアルロン酸を関
節疾患治療薬として外傷性関節炎、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
行防止などの治療に使用することを提案した（Balazs,
E.A, et al. : Thesis, University of Butapest, Facu
lty of medicine, 1942)。さらに、その後の研究により
ヒアルロン酸製剤は、競争馬の外傷性関節炎などの治療
に試みられ、最近、医薬品としては、ヒトの関節（膝、
肩、股、顎等）炎、変形性関節症、慢性関節リューマチ
症などの整形外科領域、皮膚用保護剤として皮膚科領域
あるいは眼科領域での手術の際の眼内注射剤等として使
用されている。1942 Balazs et al. Used hyaluronic acid as a therapeutic agent for joint diseases in the treatment of traumatic arthritis, osteoarthritis, suppression of pannus formation such as incision after joint dissection, and prevention of progression of joint contracture. I proposed that (Balazs,
EA, et al .: Thesis, University of Butapest, Facu
lty of medicine, 1942). Furthermore, in subsequent studies, hyaluronic acid preparations were tried to treat traumatic arthritis of competitive horses, and recently, as a medicine, human joints (knee,
Shoulder, crotch, jaw etc.), orthopedic field such as osteoarthritis, rheumatoid arthritis, etc., used as an intraocular injection during surgery in the dermatological field or ophthalmic field as a skin protective agent. There is.
【０００４】中でも、変形性膝関節症・肩関節周囲炎の
治療に、鶏冠から抽出・精製した平均分子量が約８０万
〜９０万のヒアルロン酸ナトリウム溶液（濃度１W/V
％）からなる注射剤は、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。最近、微生物醗酵法由
来のヒアルロン酸ナトリウムが製造されるようになり、
平均分子量も１６０万〜２５０万のものが治療に用いら
れようとしている。ヒアルロン酸ナトリウム溶液は、不
安定なヒアルロン酸をナトリウム塩とする事で安定性を
高めている。しかし、ナトリウム塩も水溶液の状態では
必ずしも安定ではない。また、ヒアルロン酸の分子量が
大きくなるほど安定性が悪くなる。Among them, for the treatment of osteoarthritis of the knee and periarthritis of the shoulder, a sodium hyaluronate solution having an average molecular weight of about 800,000 to 900,000 extracted and purified from chicken cob (concentration 1 W / V
%) Is used for the treatment of arthritis of the knees and shoulders, and its effect is highly evaluated, and it relieves the pain of many patients and enhances the quality of life. Recently, sodium hyaluronate derived from microbial fermentation has come to be produced,
Those having an average molecular weight of 1.6 to 2.5 million are about to be used for treatment. The sodium hyaluronate solution has improved stability by using unstable sodium hyaluronate as a sodium salt. However, sodium salt is not always stable in an aqueous solution. In addition, the higher the molecular weight of hyaluronic acid, the worse the stability.
【０００５】一般的に、ヒアルロン酸ナトリウム溶液
は、ｐＨによってその安定性が左右され、中性付近にお
いては比較的安定であるが、溶液を中性に保つために添
加される緩衝液の種類によって安定性に差があることが
知られていた。また、ピロ亜硫酸ナトリウム、亜硫酸水
素ナトリウム等の従来用いられている安定化剤では、十
分安定な溶液を得ることができず、したがって、安定な
ヒアルロン酸ナトリウム含有液剤が望まれていた。Generally, the stability of sodium hyaluronate solution depends on pH and is relatively stable in the vicinity of neutrality, but it depends on the type of buffer added to keep the solution neutral. It was known that there were differences in stability. Further, with the conventionally used stabilizers such as sodium pyrosulfite and sodium bisulfite, a sufficiently stable solution cannot be obtained. Therefore, a stable sodium hyaluronate-containing liquid preparation has been desired.
【０００６】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含有溶液の安定化について種々検
討を行いその結果、先にクエン酸またはクエン酸からな
る塩をヒアルロン酸ナトリウム溶液に添加することによ
りなる安定な注射用液を提案した（特願平６−２７５４
５７号）。本発明者らは、さらに検討を行った結果、グ
リセリンをヒアルロン酸ナトリウム含有溶液に添加する
ことによりさらに安定な溶液となることを見出した。本
発明は、かかる知見に基づくものである。すなわち、本
発明は、ヒアルロン酸ナトリウム含有溶液にグリセリン
を添加せしめたことを特徴とする安定なヒアルロン酸ナ
トリウム含有溶液を提供するものであり、特に医療用注
射剤として好適なヒアルロン酸ナトリウム含有溶液を提
供するものである。Under the circumstances, the present inventors have conducted various studies on the stabilization of the sodium hyaluronate-containing solution, and as a result, as a result, first added citric acid or a salt of citric acid to the sodium hyaluronate solution. A stable injectable solution was proposed (Japanese Patent Application No. 6-2754).
No. 57). As a result of further studies, the present inventors have found that adding glycerin to a sodium hyaluronate-containing solution results in a more stable solution. The present invention is based on such findings. That is, the present invention provides a stable sodium hyaluronate-containing solution, which is characterized by adding glycerin to a sodium hyaluronate-containing solution, and in particular, a sodium hyaluronate-containing solution suitable as a medical injection is provided. It is provided.
【０００７】以下、本発明を詳細に説明する。本発明に
係るヒアルロン酸ナトリウム含有溶液の好ましい態様
は、ヒアルロン酸ナトリウム含有溶液にグリセリンをヒ
アルロン酸ナトリウム１重量部に対して、０.１〜２重
量部、好ましくは０.１〜１重量部の量割合で添加され
る。２重量部以上を添加してもそれ以上の安定化効果は
期待できない。また、０.１重量部以下では、期待する
充分な安定化効果は得られない。Hereinafter, the present invention will be described in detail. A preferred embodiment of the sodium hyaluronate-containing solution according to the present invention is 0.1 to 2 parts by weight, preferably 0.1 to 1 part by weight of glycerin in the sodium hyaluronate-containing solution per 1 part by weight of sodium hyaluronate. It is added in a volume ratio. Even if 2 parts by weight or more is added, no further stabilizing effect can be expected. If the amount is less than 0.1 parts by weight, the expected sufficient stabilizing effect cannot be obtained.
【０００８】本発明において用いられるヒアルロン酸ナ
トリウムは、その由来を限定するものではなく、通常人
および動物の治療用に用いられているものであり、一般
に多くは鶏冠からの抽出・精製由来のものあるいは微生
物醗酵法由来のヒアルロン酸ナトリウムである。またヒ
アルロン酸ナトリウムの分子量は特に限定されるもので
はないが、より高分子量のヒアルロン酸ナトリウム、例
えば本発明においては、平均分子量８０万のものより平
均分子量１９０万のものにおいて顕著な安定化効果が得
られた。The source of the sodium hyaluronate used in the present invention is not limited, and it is usually used for treating humans and animals, and generally, it is generally derived from extraction / purification from a chicken cob. Alternatively, it is sodium hyaluronate derived from a microbial fermentation method. Further, the molecular weight of sodium hyaluronate is not particularly limited, but higher molecular weight sodium hyaluronate, for example, in the present invention, a remarkable stabilizing effect is obtained with an average molecular weight of 1.9 million rather than an average molecular weight of 800,000. Was obtained.
【０００９】また、本発明に用いられるグリセリンは一
般に入手出来るものであれば良いが、医療用のものとし
ては局方グリセリンが用いられる。次に本発明の実施例
を比較例と共に示し、本発明を更に具体的に説明する
が、本発明は、これらの実施例により限定されるもので
はない。The glycerin used in the present invention may be any glycerin that is generally available, but pharmacologically, glycerin is used. Next, the present invention will be described more specifically by showing Examples of the present invention together with Comparative Examples, but the present invention is not limited to these Examples.
【００１０】[0010]
実施例１ 処方 ヒアルロン酸ナトリウム(平均分子量１９０万) １０.０ｇ 塩化ナトリウム ６.３ｇ リン酸水素ナトリウム １.８ｇ 結晶リン酸二水素ナトリウム ０.２ｇ クエン酸ナトリウム ４.０ｇ グリセリン ３.１ｇ 注射用水 適量 全 量 １０００ml ｐＨ：７.３ 浸透圧比：１.０１Example 1 Formulation Sodium hyaluronate (average molecular weight 1.9 million) 10.0 g Sodium chloride 6.3 g Sodium hydrogen phosphate 1.8 g Crystalline sodium dihydrogen phosphate 0.2 g Sodium citrate 4.0 g Glycerin 3.1 g Water for injection qs. Total volume 1000 ml pH: 7.3 Osmolarity ratio: 1.01
【００１１】調製法 ヒアルロン酸ナトリウムを除く全てを９００mlの注射用
水に溶解させた。溶解後、ヒアルロン酸ナトリウムを少
量ずつ溶解液に加えた。その後、注射用水を加えて全量
を１０００mlとし、ヒアルロン酸ナトリウムを撹拌溶解
させた。このヒアルロン酸ナトリウム含有溶液をバイア
ルに充填し、密封した後、常法により滅菌した。溶解液
は、ヒアルロン酸ナトリウムが従来比較的安定といわれ
るｐＨ７.０から７.５の範囲に調整した。以下の実施例
２及び各比較例に記載の調製液についても、本法に準じ
た操作で調製した。Preparation method All except sodium hyaluronate were dissolved in 900 ml of water for injection. After dissolution, sodium hyaluronate was added to the solution little by little. Then, water for injection was added to make the total amount 1000 ml, and sodium hyaluronate was dissolved with stirring. This solution containing sodium hyaluronate was filled in a vial, sealed, and then sterilized by a conventional method. The solution was adjusted to a pH range of 7.0 to 7.5 where sodium hyaluronate was conventionally said to be relatively stable. The preparation liquids described in Example 2 and each comparative example below were also prepared by an operation according to this method.
【００１２】実施例２ 処方 ヒアルロン酸ナトリウム(平均分子量８０万) １０.０ｇ 塩化ナトリウム ６.３ｇ リン酸水素ナトリウム １.８ｇ 結晶リン酸二水素ナトリウム ０.２ｇ クエン酸ナトリウム ４.０ｇ グリセリン ３.１ｇ 注射用水 適量 全 量 １０００ml ｐＨ：７.３ 浸透圧比：１.０１Example 2 Formulation Sodium hyaluronate (average molecular weight 800,000) 10.0 g Sodium chloride 6.3 g Sodium hydrogen phosphate 1.8 g Crystalline sodium dihydrogen phosphate 0.2 g Sodium citrate 4.0 g Glycerin 3.1 g Water for injection Appropriate amount Total amount 1000 ml pH: 7.3 Osmolarity ratio: 1.01
【００１３】比較例１ 処方 ヒアルロン酸ナトリウム(平均分子量１９０万) １０.０ｇ 塩化ナトリウム ８.５ｇ リン酸水素ナトリウム ０.６ｇ 結晶リン酸二水素ナトリウム ０.０２ｇ 注射用水 適量 全 量 １０００ml ｐＨ：７.４ 浸透圧比：１.０１Comparative Example 1 Formulation Sodium hyaluronate (average molecular weight of 1.9 million) 10.0 g Sodium chloride 8.5 g Sodium hydrogen phosphate 0.6 g Crystalline sodium dihydrogen phosphate 0.02 g Water for injection Total amount 1000 ml pH: 7.0 4 Osmotic pressure ratio: 1.01
【００１４】比較例２ 処方 ヒアルロン酸ナトリウム(平均分子量１９０万) １０.０ｇ 塩化ナトリウム ３.０ｇ リン酸水素ナトリウム ３.６ｇ 結晶リン酸二水素ナトリウム ０.５ｇ クエン酸 １０.０ｇ 水酸化ナトリウム ６.０ｇ 注射用水 適量 全量 １０００ml ｐＨ：７.３ 浸透圧比：１.０１Comparative Example 2 Formulation Sodium hyaluronate (average molecular weight of 1.9 million) 10.0 g Sodium chloride 3.0 g Sodium hydrogen phosphate 3.6 g Crystalline sodium dihydrogen phosphate 0.5 g Citric acid 10.0 g Sodium hydroxide 6.0 0g Water for injection Suitable amount Total 1000ml pH: 7.3 Osmotic pressure ratio: 1.01
【００１５】比較例３ 処方 ヒアルロン酸ナトリウム(平均分子量１９０万) １０．０ｇ 塩化ナトリウム ７.５ｇ リン酸水素ナトリウム １.８ｇ 結晶リン酸二水素ナトリウム ０.２ｇ クエン酸ナトリウム ４.０ｇ 注射用水 適量 全 量 １０００ml ｐＨ：７.３ 浸透圧比：１.０１Comparative Example 3 Formulation Sodium hyaluronate (average molecular weight 1.9 million) 10.0 g Sodium chloride 7.5 g Sodium hydrogen phosphate 1.8 g Crystalline sodium dihydrogen phosphate 0.2 g Sodium citrate 4.0 g Water for injection Suitable amount Total Volume 1000 ml pH: 7.3 Osmolarity ratio: 1.01
【００１６】比較例４ 処方 ヒアルロン酸ナトリウム(平均分子量８０万) １０.０ｇ 塩化ナトリウム ８.５ｇ リン酸水素ナトリウム ０.６ｇ 結晶リン酸二水素ナトリウム ０.０２ｇ 注射用水 適量 全 量 １０００ml ｐＨ：７.３ 浸透圧比：１.０１Comparative Example 4 Formulation Sodium hyaluronate (average molecular weight 800,000) 10.0 g Sodium chloride 8.5 g Sodium hydrogen phosphate 0.6 g Crystalline sodium dihydrogen phosphate 0.02 g Water for injection Appropriate amount 1000 ml pH: 7.0 3 Osmotic pressure ratio: 1.01
【００１７】比較例５ 処方 ヒアルロン酸ナトリウム(平均分子量８０万) １０.０ｇ 塩化ナトリウム ７.７ｇ リン酸水素ナトリウム ０.６ｇ 結晶リン酸二水素ナトリウム ０.１ｇ クエン酸ナトリウム ３.０ｇ 注射用水 適量 全 量 １０００ml ｐＨ：７.３ 浸透圧比：１.０１Comparative Example 5 Formulation Sodium hyaluronate (average molecular weight 800,000) 10.0 g Sodium chloride 7.7 g Sodium hydrogen phosphate 0.6 g Crystalline sodium dihydrogen phosphate 0.1 g Sodium citrate 3.0 g Water for injection Suitable amount Total Volume 1000 ml pH: 7.3 Osmolarity ratio: 1.01
【００１８】[0018]
【試験方法】実施例１、実施例２、比較例１、比較例
２、比較例３、比較例４及び比較例５をバイアルに密封
後、４０℃で保存（遮光）し、６箇月後までの平均分子
量変化率を観た。他に、比較対照として市販品（平均分
子量約８０万）についても同様の試験を行った。それら
の結果を表１に示す。[Test Method] Example 1, Example 2, Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4, and Comparative Example 5 were sealed in vials and then stored at 40 ° C. (shielded) for up to 6 months. The average molecular weight change rate of was observed. In addition, the same test was performed on a commercial product (average molecular weight of about 800,000) as a comparative control. Table 1 shows the results.
【００１９】[0019]
【表１】 [Table 1]
【００２０】[0020]
【発明の効果】以上の説明から明らかなとおり、本発明
は、ヒアルロン酸ナトリウム含有溶液にグリセリンを添
加することにより、より安定なヒアルロン酸ナトリウム
含有溶液を提供するものであり、従って、当該溶液は、
特に注射剤等の医療用用途のものとして極めて有用であ
る。特にその安定化効果は、平均分子量の高いヒアルロ
ン酸ナトリウム溶液において優れていることが認められ
た。As is apparent from the above description, the present invention provides a more stable sodium hyaluronate-containing solution by adding glycerin to the sodium hyaluronate-containing solution. ,
In particular, it is extremely useful for medical purposes such as injections. In particular, it was confirmed that the stabilizing effect was excellent in a sodium hyaluronate solution having a high average molecular weight.
Claims (2)
セリンを添加せしめたことを特徴とする安定なヒアルロ
ン酸ナトリウム含有溶液。1. A stable sodium hyaluronate-containing solution, wherein glycerin is added to the sodium hyaluronate-containing solution.
記載のヒアルロン酸ナトリウム含有溶液。2. The solution is a medical injection solution.
A solution containing sodium hyaluronate as described.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7352138A JPH09176020A (en) | 1995-12-28 | 1995-12-28 | Stable solution containing sodium hyaluronate |
| PCT/JP1996/000850 WO1997024374A1 (en) | 1995-12-28 | 1996-03-29 | Stable solution containing sodium hyaluronate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7352138A JPH09176020A (en) | 1995-12-28 | 1995-12-28 | Stable solution containing sodium hyaluronate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH09176020A true JPH09176020A (en) | 1997-07-08 |
Family
ID=18422039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7352138A Pending JPH09176020A (en) | 1995-12-28 | 1995-12-28 | Stable solution containing sodium hyaluronate |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH09176020A (en) |
| WO (1) | WO1997024374A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8609634B2 (en) | 2007-05-16 | 2013-12-17 | Mcneil-Ppc, Inc. | Preserved compositions containing hyaluronic acid or a pharmaceutically-acceptable salt thereof and related methods |
| US10588977B2 (en) | 2007-05-16 | 2020-03-17 | Johnson & Johnson Consumer Inc. | Preserved compositions containing hyaluronic acid or a pharmaceutically-acceptable salt thereof and related methods |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8398611B2 (en) | 2010-12-28 | 2013-03-19 | Depuy Mitek, Inc. | Compositions and methods for treating joints |
| US8524662B2 (en) | 2010-12-28 | 2013-09-03 | Depuy Mitek, Llc | Compositions and methods for treating joints |
| US8455436B2 (en) | 2010-12-28 | 2013-06-04 | Depuy Mitek, Llc | Compositions and methods for treating joints |
| US8623839B2 (en) * | 2011-06-30 | 2014-01-07 | Depuy Mitek, Llc | Compositions and methods for stabilized polysaccharide formulations |
| US9682099B2 (en) | 2015-01-20 | 2017-06-20 | DePuy Synthes Products, Inc. | Compositions and methods for treating joints |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07241200A (en) * | 1991-04-10 | 1995-09-19 | Rooman Kogyo:Kk | Production of hyaluronic acid |
-
1995
- 1995-12-28 JP JP7352138A patent/JPH09176020A/en active Pending
-
1996
- 1996-03-29 WO PCT/JP1996/000850 patent/WO1997024374A1/en not_active Ceased
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8609634B2 (en) | 2007-05-16 | 2013-12-17 | Mcneil-Ppc, Inc. | Preserved compositions containing hyaluronic acid or a pharmaceutically-acceptable salt thereof and related methods |
| US10588977B2 (en) | 2007-05-16 | 2020-03-17 | Johnson & Johnson Consumer Inc. | Preserved compositions containing hyaluronic acid or a pharmaceutically-acceptable salt thereof and related methods |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997024374A1 (en) | 1997-07-10 |
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