JPH0314808B2 - - Google Patents
Info
- Publication number
- JPH0314808B2 JPH0314808B2 JP62012184A JP1218487A JPH0314808B2 JP H0314808 B2 JPH0314808 B2 JP H0314808B2 JP 62012184 A JP62012184 A JP 62012184A JP 1218487 A JP1218487 A JP 1218487A JP H0314808 B2 JPH0314808 B2 JP H0314808B2
- Authority
- JP
- Japan
- Prior art keywords
- antihypertensive agent
- formula
- solution
- value
- agent according
- 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.)
- Expired - Lifetime
Links
- 239000000243 solution Substances 0.000 claims description 26
- 239000002220 antihypertensive agent Substances 0.000 claims description 18
- 229940030600 antihypertensive agent Drugs 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000010253 intravenous injection Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 6
- 239000004327 boric acid Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 claims description 4
- 150000001767 cationic compounds Chemical class 0.000 claims description 3
- 238000001802 infusion Methods 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 229910001411 inorganic cation Inorganic materials 0.000 claims description 3
- 150000002892 organic cations Chemical class 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- VWZUIIYOJGQRBR-UHFFFAOYSA-N 2-(3,4-dihydroxyanilino)-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)NC1=CC=C(O)C(O)=C1 VWZUIIYOJGQRBR-UHFFFAOYSA-N 0.000 claims 1
- 230000000996 additive effect Effects 0.000 claims 1
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 15
- 230000036772 blood pressure Effects 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- -1 for example Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000013522 chelant Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 210000001177 vas deferen Anatomy 0.000 description 2
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 206010005746 Blood pressure fluctuation Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 241000295146 Gallionellaceae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 210000000269 carotid artery external Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 239000011780 sodium chloride 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
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
（産業上の利用分野）
本発明は、活性剤としてのＬ−３，４−ジヒド
ロキシフエニル−α−メチルアラニン（略称、α
−メチルドーパ）なるキレート化合物からなる血
圧降下剤、およびその製造方法に関する。
本発明による血圧降下剤は、特に、注射若しく
は経口投与が好適である。
（従来の技術およびその問題点）
α−メチルドーパは、高血圧の治療に広く使用
される有用な血圧降下剤（米国特許第3344023号
明細書参照）である。
一般に、α−メチルドーパは、錠剤にして投与
されるが、場合によつては、経口投与するとか、
静脈内注射で使用できる薬剤が必要になる。
α−メチルドーパの安定な水懸濁液は、米国特
許第3526698号明細書に開示されている。この懸
濁液は、患者に対して静脈内注射することができ
ず、また経口投与しても、吸収が悪い。
活性剤としてのα−メチルドーパのエチルエス
テルの塩酸塩からなる溶液は、米国特許第
3230153号明細書に開示されている。この薬剤は、
生体に投与してから加水分解を受け、α−メチル
ドーパになる。この薬剤は、静脈内注射により投
与されるが、相当希釈しなければならない。
静脈内注射でも、また経口的にも投与しうるα
−メチルドーパ水溶液は、ハンガリー国特許第
189796号明細書に開示されている。
この溶液は、１〜５％のα−メチルドーパ、17
〜75％の可溶化剤、20〜80％の水、および0.1〜
10％の添加剤を含み、かつ３〜５のPH値を有して
いる。可溶化剤として、ポリビニルピロリドンま
たはグリセロールが用いられる。
しかし、かかる組成物は、PH値が相当に低いた
め、静脈内注射用に不適当である。
本発明の目的は、殆ど中性のα−メチルドーパ
血圧降下剤を提供することである。
（問題点を解決するための手段）
上記の目的は、式
または、式
（式中、X+は、水素イオン、または有機若し
くは無機の陽イオンを表わす。）
で示される化合物と、水とを含み、かつPH値が７
〜8.5の血圧降下剤によつて達成しうる。
本発明は、α−メチルドーパはホウ酸と反応
し、水中で高い溶解度を有する錯化合物を形成す
るという認識に基づいている。
式（）および式（）で示されるキレート化
合物は、それぞれ、次の反応式(A)(B)によつて生成
される。
等モル量のホウ酸の存在下で、式（）で示さ
れる化合物は生成される。低い量のホウ酸を用い
ると、式（）で示される化合物か、または両方
のキレート化合物からなる混合物が得られる。
本発明者の経験によれば、式（）および
（）（式中、X+は水素イオンを表わす。）で示さ
れる化合物は、適切な強さの酸であり、その塩は
分離でき（これは、本発明に関しては不要であ
る。）、また水中で、速やかに溶ける。水溶液中で
は勿論、キレート化合物、ホウ酸、およびα−メ
チルドーパの間で平衡状態が保たれ、従つて、各
化合物は、同時に存在できる。
本発明による血圧降下剤中、式（）および
（）で示される化合物の総量は、約1.2〜24％で
ある。
本発明による血圧降下剤のPH値は、7.2〜7.6の
範囲が好ましい。
本発明による血圧降下剤は、静脈内注射か、滅
菌式点滴により投与される。また、経口的にも投
与できる。
本発明による血圧降下剤は、体重約70Kgの成人
の患者に対し、100〜6000mgの量で投与される。
本発明による血圧降下剤は、0.2〜6.0重量％の
ホウ酸、１〜20重量％のα−メチルドーパ、およ
び0.01〜２重量％の添加剤からなる水溶液を混
ぜ、塩基を加えてPH値を７〜8.5の範囲に調整し、
更に溶媒を、その量が72〜98.76重量％になるま
で選択的に加えて得られる溶液を、好ましくは、
静脈内注射用、または注入投与若しくは経口投与
用として使用しうる液体状薬剤に変換する。
PH調整用塩基は、無機若しくは有機の塩基を使
用できる。水中で高い溶解度を有し、かつ生理的
に使用しうる、例えば、水酸化ナトリウムまたは
水酸化カリウムのような塩基を用いるのが好まし
い。
添加剤として、例えば、亜硫酸ナトリウム、亜
硫酸水素ナトリウム、ピロ亜硫酸ナトリウムなど
のような酸化防止剤、メチル−ｐ−ヒドロキシベ
ンゾアート、エチル−ｐ−ヒドロキシベンゾアー
トなどのような抗細菌剤、塩化ナトリウムのよう
な無機塩などが使用される。
溶媒として、水、生理的食塩水、または水と混
和しうる生理的に使用可能な有機溶媒が使用され
る。１種類以上の溶媒が使用できる。
静脈内注射用溶液の場合、溶媒は、水か、生理
的食塩水が好ましく、かつ溶液のPHは、7.0〜7.6
の範囲に調整される。
経口投与用溶液の場合、一般に溶媒は、水、エ
タノール、グリセロール、または水と混和しうる
無毒性有機溶媒が使用される。
また、組成物の味をよくするため、ソルビトー
ル水溶液を、溶媒としてか、若しくはその一部と
して使用できる。そのPH値は、７〜8.5の範囲に
調整される。
経口投与用溶液のPHは、静脈注射用のものほど
微妙ではないので、PH領域を８〜8.5の範囲とし
てもよい。
本発明による血圧降下剤を調整する際、添加剤
は、PHの調整後でも加えることができる。１種類
以上の溶剤を加える場合、PHを制御し、必要に応
じて、再び調整できる。
静脈内注射により投与する際、PH値が7.0〜7.6
の範囲になつている溶液を、あらゆる公知の方
法、例えば、微小孔濾過または熱殺菌法により、
滅菌処理する。滅菌溶液は、密閉容器に入れ、使
用するまで保管される。
実施例２に記載の方法により調製した注射液の
急性毒性を、体重18〜22ｇの白二十日ねずみ
（CFLP）を使つて決定した。それぞれ５匹の雄
と雌の個体からなるグループに対し、静脈内注射
により各種の量を投与した。
処置後、標準飼料と任意量の水を与えながら、
14日間、個体を観察した。生理的食塩水を用いて
調製した１％のα−メチルドーパ溶液を、基準と
して使用した。（注意すべきことは、結晶性α−
メチルドーパから１％水溶液を調製できるが、つ
くられる溶液は、不安定で、かつ１〜２時間で分
解してしまう。しかし、新しい溶液はテストしう
る。）
得られたLD50値を、表１に示す。
(Industrial Application Field) The present invention provides L-3,4-dihydroxyphenyl-α-methylalanine (abbreviation: α-methylalanine) as an activator.
The present invention relates to an antihypertensive agent comprising a chelate compound (-methyldopa) and a method for producing the same. The antihypertensive agent according to the present invention is particularly suitable for injection or oral administration. BACKGROUND OF THE INVENTION Alpha-methyldopa is a useful antihypertensive agent widely used in the treatment of hypertension (see US Pat. No. 3,344,023). Generally, α-methyldopa is administered in the form of tablets, but in some cases it may be administered orally or
You will need a drug that can be administered intravenously. Stable aqueous suspensions of α-methyldopa are disclosed in US Pat. No. 3,526,698. This suspension cannot be injected intravenously into patients and is poorly absorbed even when administered orally. A solution consisting of the hydrochloride of the ethyl ester of α-methyldopa as an activator is described in U.S. Pat.
It is disclosed in the specification of No. 3230153. This drug is
After being administered to a living body, it undergoes hydrolysis and becomes α-methyldopa. This drug is administered by intravenous injection and must be diluted considerably. α that can be administered either intravenously or orally
- Methyldopa aqueous solution has a Hungarian patent
It is disclosed in the specification of No. 189796. This solution contains 1-5% α-methyldopa, 17
~75% solubilizer, 20-80% water, and 0.1~
Contains 10% additives and has a PH value of 3-5. Polyvinylpyrrolidone or glycerol is used as a solubilizer. However, such compositions have rather low PH values, making them unsuitable for intravenous injection. It is an object of the present invention to provide a nearly neutral alpha-methyldopa hypotensive agent. (Means for solving the problem) The purpose of the above is to Or, the expression (In the formula, X + represents a hydrogen ion or an organic or inorganic cation.) Contains a compound represented by the formula and water, and has a PH value of 7.
~8.5 can be achieved by antihypertensive agents. The invention is based on the recognition that alpha-methyldopa reacts with boric acid to form complex compounds with high solubility in water. The chelate compounds represented by formula () and formula () are produced by the following reaction formulas (A) and (B), respectively. In the presence of equimolar amounts of boric acid, a compound of formula () is produced. With lower amounts of boric acid, compounds of formula () or a mixture of both chelates are obtained. According to the inventor's experience, the compounds of formulas () and () (wherein X + represents a hydrogen ion) are acids of suitable strength and their salts can be separated (this are not necessary for the present invention), and are rapidly soluble in water. In the aqueous solution, of course, an equilibrium is maintained between the chelate compound, boric acid, and α-methyldopa, so each compound can exist simultaneously. In the antihypertensive agent according to the present invention, the total amount of compounds represented by formulas () and () is about 1.2-24%. The PH value of the antihypertensive agent according to the present invention is preferably in the range of 7.2 to 7.6. The antihypertensive agent according to the present invention is administered by intravenous injection or sterile infusion. It can also be administered orally. The antihypertensive agent according to the present invention is administered in an amount of 100 to 6000 mg to an adult patient weighing approximately 70 kg. The antihypertensive agent according to the present invention is prepared by mixing an aqueous solution consisting of 0.2-6.0% by weight of boric acid, 1-20% by weight of α-methyldopa, and 0.01-2% by weight of additives, and adding a base to adjust the pH value to 7. Adjust to a range of ~8.5,
Further, a solution obtained by selectively adding a solvent until the amount becomes 72 to 98.76% by weight, preferably,
It is converted into a liquid drug that can be used for intravenous injection or for infusion or oral administration. As the base for adjusting pH, an inorganic or organic base can be used. Preference is given to using bases which have high solubility in water and are physiologically usable, such as, for example, sodium hydroxide or potassium hydroxide. As additives, for example, antioxidants such as sodium sulfite, sodium bisulfite, sodium pyrosulfite, etc., antibacterial agents such as methyl-p-hydroxybenzoate, ethyl-p-hydroxybenzoate, etc., sodium chloride. Inorganic salts such as As solvent, water, physiological saline, or physiologically usable organic solvents which are miscible with water are used. More than one type of solvent can be used. In the case of solutions for intravenous injection, the solvent is preferably water or physiological saline, and the pH of the solution is 7.0 to 7.6.
is adjusted to the range of For solutions for oral administration, the solvent generally used is water, ethanol, glycerol, or a non-toxic organic solvent that is miscible with water. Also, to improve the taste of the composition, an aqueous sorbitol solution can be used as a solvent or as part thereof. Its PH value is adjusted to a range of 7-8.5. Since the PH of solutions for oral administration is not as sensitive as that for intravenous injection, the PH range may be within the range of 8 to 8.5. When preparing the antihypertensive agent according to the invention, additives can be added even after adjusting the PH. If one or more solvents are added, the PH can be controlled and readjusted if necessary. When administered by intravenous injection, the PH value is 7.0-7.6
of the solution by any known method, such as microporous filtration or heat sterilization.
Sterilize. Sterile solutions are stored in closed containers until use. The acute toxicity of the injection solution prepared by the method described in Example 2 was determined using 20-day white rats (CFLP) weighing 18-22 g. Groups of 5 male and 5 female individuals each were administered various doses by intravenous injection. After treatment, give standard feed and ad libitum amount of water.
Individuals were observed for 14 days. A 1% α-methyldopa solution prepared using physiological saline was used as a standard. (It should be noted that crystalline α-
Although a 1% aqueous solution can be prepared from methyldopa, the resulting solution is unstable and decomposes within 1-2 hours. However, new solutions can be tested. ) The obtained LD 50 values are shown in Table 1.
【表】
表１から明らかなように、本発明による薬剤の
毒性は、調製したばかりのα−メチルドーパ溶液
のものと同じてある。観察された毒性は、文献に
よる値（1700mg／Kg）と一致している。
実施例２による注射液の血圧降下作用を、体重
が200〜250ｇで、麻酔をかけたウイスター
（Wistar）ラツトを用いて決定した。動脈血圧
を、電気マノメータにより頚動脈に結合されるポ
リエチレンカニユーレによつて測定した。
20mg／Kgの被検溶液を、外部頚動脈に挿着した
カニユーレを通して投与した。
血圧を、直前、処置してから５分後、15分後、
30分後、および60分後にはかつた。基準としての
作成したばかりの１％α−メチルドーパ溶液に関
しても、血圧降下をはかつた。
血圧値、この血圧値と処理直前にはかつた血圧
値との変化、および有意性を表わすｐ値を、表２
に示す。
測定して得た血圧値の平均値と、血圧変化量と
は、標準偏差とともに示してある。Table 1 As can be seen from Table 1, the toxicity of the drug according to the invention is the same as that of the freshly prepared α-methyldopa solution. The observed toxicity is consistent with literature values (1700 mg/Kg). The hypotensive effect of the injection solution according to Example 2 was determined using anesthetized Wistar rats weighing 200-250 g. Arterial blood pressure was measured by a polyethylene cannula connected to the carotid artery by an electromanometer. 20 mg/Kg of the test solution was administered through a cannula inserted into the external carotid artery. Blood pressure immediately before, 5 minutes after treatment, 15 minutes after treatment,
After 30 minutes and 60 minutes. The freshly prepared 1% α-methyldopa solution as a standard also lowered blood pressure. The blood pressure value, the change between this blood pressure value and the blood pressure value that existed immediately before the treatment, and the p value representing significance are shown in Table 2.
Shown below. The average value of the measured blood pressure values and the amount of change in blood pressure are shown together with the standard deviation.
【表】
表２から明らかなように、本発明による溶液
は、処置後５分で、麻酔をかけられたラツトの血
圧を相当に下げることができた。その効果は、テ
ストの60分間にわたつて安定した。
注目すべきは、本発明による溶液を用いると、
基準溶液より短時間に、血圧が大幅に下降した。
250mg／Kgのα−メチルドーパ、即ち静脈内注
射による投与量の12.5倍のものを経口投与するこ
とによつて、同じ血圧降下量が得られた。
実施例２による溶液、および前述の基準溶液の
アドレナリン性受容体作用を調べるため、電気刺
激によるラツトの分離精管に対するテストを行な
つた。
ブリテイツシユ・ジヤーナル・オブ・フアーマ
シー（Br.J.Pharm.）46巻、764〜766ページ
（1972）に掲載のヘンダーソン（Henderson）等
による方法、および同66巻、361〜363ページ
（1979）に掲載のハート（Hart）等による方法を
用いて、体重140〜180ｇのラツトから精管を分離
した。
器管に対する浴として、クレブス（Krebs）溶
液を37℃で用いた。0.5ｇの予負荷を与えて、ア
イソメトリツク・レジストレーシヨンを用いた。
器官を、容量が４mlの容器に吊るし、かつブリ
テイツシユ・ジヤーナル・オブ・フイーマシー
（Br.J.Pharm.）50巻、453ページ（1974）に掲載
されているベネツト（Benett）およびストツク
リー（Stockley）の方法に基づき、電圧：50V、
周波数：0.1Hz、間隔：1msという特性を有する
電気的衝撃を用いて、連続的に刺激した。
電気的刺激による収縮の生長に、もはや変化が
起きなかつた際、実施例２による溶液、および基
準としての１％α−メチルドーパ溶液を用いての
累積投与量に対する作用をプロツトした。
テストされるべき溶液を添加する直前に測定し
た収縮に基づき、抑制値を計算した。
このようにして、50％の抑制（IC50）をもたら
す濃度を、両方の溶液に対して決定した。
得られた結果を表３に示す。Table 2 As is evident from Table 2, the solution according to the invention was able to significantly lower the blood pressure in anesthetized rats 5 minutes after the treatment. The effect remained stable over the 60 minutes of testing. Of note, with the solution according to the invention:
Blood pressure decreased significantly in a shorter time than with the reference solution. The same amount of blood pressure reduction was obtained by oral administration of 250 mg/Kg of α-methyldopa, 12.5 times the dose administered by intravenous injection. In order to examine the adrenergic receptor effects of the solution according to Example 2 and the reference solution described above, tests were carried out on isolated rat vas deferens by electrical stimulation. The method by Henderson et al. published in British Journal of Pharmacy (Br.J.Pharm.), Vol. 46, pp. 764-766 (1972), and published in Br.J.Pharm., Vol. 66, pp. 361-363 (1979). Vas deferens were isolated from rats weighing 140-180 g using the method of Hart et al. Krebs solution was used at 37°C as a bath for the vessels. Isometric registration was used with a preload of 0.5 g. The organ was suspended in a container with a capacity of 4 ml, and the organ was suspended in a container with a capacity of 4 ml and placed in a container as described by Bennett and Stockley in Br.J.Pharm., vol. 50, p. 453 (1974). Based on the method, voltage: 50V,
Electric impulses with a frequency of 0.1 Hz and an interval of 1 ms were used for continuous stimulation. When no further changes occurred in the growth of contractions due to electrical stimulation, the effect on cumulative doses was plotted using the solution according to Example 2 and the 1% α-methyldopa solution as reference. The inhibition value was calculated based on the contraction measured immediately before adding the solution to be tested. In this way, the concentration resulting in 50% inhibition (IC 50 ) was determined for both solutions. The results obtained are shown in Table 3.
【表】
ルドーパ
[Table] Ludopa
Claims (1)
くは無機の陽イオンを表わす。） で示される化合物と、水とを含み、かつPH値が７
〜8.5であることを特徴とする血圧降下剤。 ２ 式（）および（）で示される化合物の全
量が、1.2〜2.4％であることを特徴とする特許請
求の範囲第１項に記載の血圧降下剤。 ３ PH値が、7.2〜7.6の範囲であることを特徴と
する特許請求の範囲第１項または第２項に記載の
血圧降下剤。 ４ 式 または、式 （式中、X+は、水素イオン、または有機若し
くは無機の陽イオンを表わす。） で示される化合物と、水とを含み、かつPH値が７
〜8.5の血圧降下剤を製造する方法であつて、 0.2〜6.0重量％のホウ酸、１〜20重量％のＬ−
３，４−ジヒドロキシフエニル−α−メチルアラ
ニン、および0.01〜２重量％の添加剤からなる水
溶液を混合する段階と、 塩基を加えて、PH値を７〜8.5に調整する段階
と、 溶媒を更に、その量が72〜98.79重量％になる
まで選択的に加える段階と、 溶液を、好ましくは、静脈内注射用、または注
入投与若しくは経口投与用として使用しうる液体
状薬剤に変換する段階 とからなることを特徴とする血圧降下剤の製造方
法。 ５ 塩基が、無機塩基であることを特徴とする特
許請求の範囲第４項に記載の血圧降下剤の製造方
法。 ６ 無機塩基が、好ましくは水溶液としての水酸
化ナトリウムであることを特徴とする特許請求の
範囲第５項に記載の血圧降下剤の製造方法。[Claims] 1 formula Or, the expression (In the formula, X + represents a hydrogen ion or an organic or inorganic cation.) Contains a compound represented by the formula and water, and has a PH value of 7.
An antihypertensive agent characterized in that it is ~8.5. 2. The antihypertensive agent according to claim 1, wherein the total amount of the compounds represented by formulas () and () is 1.2 to 2.4%. 3. The antihypertensive agent according to claim 1 or 2, which has a PH value in the range of 7.2 to 7.6. 4 formula Or, the expression (In the formula, X + represents a hydrogen ion or an organic or inorganic cation.) Contains a compound represented by the formula and water, and has a PH value of 7.
~8.5 A method for producing an antihypertensive agent, comprising: 0.2 to 6.0% by weight of boric acid, 1 to 20% by weight of L-
A step of mixing an aqueous solution consisting of 3,4-dihydroxyphenyl-α-methylalanine and 0.01 to 2% by weight of an additive, a step of adding a base to adjust the pH value to 7 to 8.5, and a step of adding a solvent to the solution. and converting the solution into a liquid medicament that can preferably be used for intravenous injection or for infusion or oral administration. A method for producing an antihypertensive agent, comprising: 5. The method for producing an antihypertensive agent according to claim 4, wherein the base is an inorganic base. 6. The method for producing an antihypertensive agent according to claim 5, wherein the inorganic base is preferably sodium hydroxide in the form of an aqueous solution.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU86268A HU195424B (en) | 1986-01-21 | 1986-01-21 | Process for the production of medical solutions containing l-3,4-dihydroxi-phenil-alpha-methil-alanine |
| HU2251/268/86 | 1986-01-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62228013A JPS62228013A (en) | 1987-10-06 |
| JPH0314808B2 true JPH0314808B2 (en) | 1991-02-27 |
Family
ID=10948826
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62012184A Granted JPS62228013A (en) | 1986-01-21 | 1987-01-21 | Drug and manufacture |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS62228013A (en) |
| AT (1) | AT389227B (en) |
| DE (1) | DE3701461A1 (en) |
| FR (1) | FR2597341B1 (en) |
| GB (1) | GB2185975B (en) |
| HU (1) | HU195424B (en) |
| IT (1) | IT1201174B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN119176768A (en) * | 2023-06-21 | 2024-12-24 | 海南大学 | Preparation method and application of catechol derivatives and administration and preparation device |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2115848A (en) * | 1934-12-29 | 1938-05-03 | Stanco Inc | Ephedrine composition |
| NL124121C (en) * | 1960-04-08 | |||
| NL125246C (en) * | 1963-06-13 | |||
| US3480670A (en) * | 1964-08-11 | 1969-11-25 | Merck & Co Inc | Resolution of racemic chemical compounds |
| US3526698A (en) * | 1968-04-11 | 1970-09-01 | Merck & Co Inc | Stabilization of levo-3-(3,4-dihydroxyphenyl)-2-methylalanine with sodium bisulfite and sorbitol |
| FR2113090A5 (en) * | 1970-10-21 | 1972-06-23 | Ajinomoto Kk | |
| CH552567A (en) * | 1970-10-30 | 1974-08-15 | Hoffmann La Roche | PROCESS FOR PRODUCING PHENYLALANINE DERIVATIVES. |
| CH545280A (en) * | 1970-10-30 | 1973-12-15 | Hoffmann La Roche | Process for the preparation of phenylalanine derivatives |
| JPS5518688B2 (en) * | 1972-12-02 | 1980-05-21 |
-
1986
- 1986-01-21 HU HU86268A patent/HU195424B/en not_active IP Right Cessation
-
1987
- 1987-01-20 DE DE19873701461 patent/DE3701461A1/en active Granted
- 1987-01-21 FR FR878700637A patent/FR2597341B1/en not_active Expired
- 1987-01-21 JP JP62012184A patent/JPS62228013A/en active Granted
- 1987-01-21 AT AT0010587A patent/AT389227B/en not_active IP Right Cessation
- 1987-01-21 GB GB8701281A patent/GB2185975B/en not_active Expired - Lifetime
- 1987-01-21 IT IT19118/87A patent/IT1201174B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| DE3701461A1 (en) | 1987-07-23 |
| IT1201174B (en) | 1989-01-27 |
| GB2185975B (en) | 1990-03-21 |
| HUT42947A (en) | 1987-09-28 |
| FR2597341B1 (en) | 1989-05-12 |
| JPS62228013A (en) | 1987-10-06 |
| GB2185975A (en) | 1987-08-05 |
| ATA10587A (en) | 1989-04-15 |
| HU195424B (en) | 1988-05-30 |
| FR2597341A1 (en) | 1987-10-23 |
| GB8701281D0 (en) | 1987-02-25 |
| IT8719118A0 (en) | 1987-01-21 |
| AT389227B (en) | 1989-11-10 |
| DE3701461C2 (en) | 1992-06-04 |
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