JPS6216929B2 - - Google Patents
Info
- Publication number
- JPS6216929B2 JPS6216929B2 JP60185230A JP18523085A JPS6216929B2 JP S6216929 B2 JPS6216929 B2 JP S6216929B2 JP 60185230 A JP60185230 A JP 60185230A JP 18523085 A JP18523085 A JP 18523085A JP S6216929 B2 JPS6216929 B2 JP S6216929B2
- Authority
- JP
- Japan
- Prior art keywords
- prostaglandin
- pge
- solution
- freeze
- stable
- 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
Links
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims description 20
- 239000001913 cellulose Substances 0.000 claims description 6
- 229920002678 cellulose Polymers 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000654 additive Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- IMPVDANDCDGWFM-SLESNMHTSA-N (z)-7-[(1r,2r,3r)-3-hydroxy-2-[(e,3s)-3-hydroxy-4-methyloct-1-enyl]-5-oxocyclopentyl]hept-5-enoic acid Chemical compound CCCCC(C)[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O IMPVDANDCDGWFM-SLESNMHTSA-N 0.000 description 1
- KEJJEEMSWMJCHB-BDKFZLQASA-N (z)-7-[(1r,2r,3r)-3-hydroxy-2-[(e,3s,4s)-3-hydroxy-8-methoxy-4-methyloct-1-enyl]-5-oxocyclopentyl]hept-5-enoic acid Chemical compound COCCCC[C@H](C)[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O KEJJEEMSWMJCHB-BDKFZLQASA-N 0.000 description 1
- OBUOTEZRDMDNCG-ULXDGKDISA-N CCCCC[C@](C)(O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(=O)OC Chemical compound CCCCC[C@](C)(O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(=O)OC OBUOTEZRDMDNCG-ULXDGKDISA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- CBOMORHDRONZRN-QLOYDKTKSA-N prostaglandin E3 Chemical compound CC\C=C/C[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O CBOMORHDRONZRN-QLOYDKTKSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明はプロスタグランジンE類にセルロース
誘導体である高分子化合物を添加し、凍結乾燥す
ることを特徴とする安定なプロスタグランジンE
類製剤の製法に関する。
本発明に於てプロスタグランジンE類とはプロ
スタグランジンE1(PGE1)、プロスタグランジ
ンE2(PGE2)、プロスタグランジンE3(PGE3)
の他、これらの化合物の側鎖における誘導体を意
味しており、具体的には例えばPGE2について挙
げるならば16−メチル−PGE2、3−メチル−
PGE2、3・16(R)−ジメチル−PGE2、17−オ
キソ−15−エピ−PGE2、16(R)−ヒドロキシ−
PGE2、15(R)−メチル−PGE2−メチルエステ
ル、15(S)−メチル−PGE2−メチルエステル、
16・16−ジメチル−PGE2−メチルエステル、4
(R)・16(R)−ジメチル−PGE2、4(R)・16
(S)−ジメチル−PGE2、4(S)・16(R)−ジ
メチル−PGE2、4(S)・16(S)−ジメチル−
PGE2及び16(R・S)−メチル−20−メトキシ−
PGE2等である。
プロスタグランジンE類は、微量で子宮収縮力
の調節、降圧作用、消化器潰瘍の治療と予防、脱
質代謝の調節、気管支拡張作用等広範な薬理作用
を有する医薬であるが、非常に不安定で分解され
易く溶液状態のみならず結晶状態でも分解される
ので、通常は−20℃の冷凍庫中に結晶又はエタノ
ール溶液として保存されている。
従来、プロスタグランジンE類を安定化する方
法としては、含水量0.1%以下のN・N−ジメチ
ルアセトアミド等の有機溶媒に溶解する方法が知
られている(ベルギー特許第790840号)。
しかしながら医薬を人体に直接投与特に注射剤
として投与する場合、安定性、溶解度等の点で水
溶液とするとが出来ない時は有機溶媒溶液又はこ
れを水で希釈して投与することもあるが通常は水
溶液として投与することが好ましいとされている
〔Dispensing of Medication、976、7th Ed.、
Mackpublishing Company1971〕。
即ち、プロスタグランジンE類を安定な形で保
存することが出来、且つ注射剤として投与する場
合には水溶液として投与出来る安定なプロスタグ
ランジンE類の製剤が要望されていた。
本発明者等はかかる技術水準下に種々研究した
結果、プロスタグランジンE類にセルロース誘導
体である高分子化合物を添加し凍結乾燥して得ら
れたプロスタグランジンE類の製剤が、安定で室
温で長期間保存しても分解され難く、且つ注射剤
として投与する場合は水溶液として投与出来るこ
とを見出し、本発明を完成した。
本発明に於てセルロース誘導体である高分子化
合物としては、ヒドロキシエチルセルロース、ヒ
ドロキシプロピルセルロース、ヒドロキシプロピ
ルメチルセルロース、カルボキシメチルセルロー
ス、メチルセルロース等が挙げられる。
本発明方法の実施はプロスタグランジンE類に
水及びセルロース誘導体である高分子化合物を添
加して水溶液となし、液性の調節、無菌過等常
法の操作を施した後、バイアルに分注し、次いで
常法に従つて凍結乾燥することによつて行われ
る。
なお、プロスタグランジンE類は水溶性である
が、その結晶を水に溶解させるのに長時間要する
ので、結晶を用いる時には予めエタノール、酢酸
エチル等の有機溶媒に溶解し次いで有機溶媒を留
去して無晶型の固体となし、水との接触面積を拡
大させておくことが好ましい。
本発明に於て添加されるセルロース誘導体であ
る高分子化合物の添加量は、薬効を呈しない量で
あるが、1バイアル当りの好ましい添加量は、5
〜250mgである。
かくして得られた安定なプロスタグランジンE
類は必要に応じて更に等張化剤、防腐剤、賦形
剤、無痛化剤等を添加しても良い。
次に、本発明方法によつて得られるプロスタグ
ランジンE類が室温で長期間保存しても安定であ
ることを以下の実施例で示す。
実施例 1〜3
2の溶器に下表1で示される各種プロスタグ
ランジンE類50mgをエタノール1mlに溶解した溶
液を入れ、その器壁をその溶液で湿潤し、減圧或
いは窒素ガスを通気してエタノールを留去する。
次いで下表1に示される添加剤及び蒸留水1500ml
を加えて添加剤を溶解し、水酸化ナトリウム水溶
液を加えてPH6.5に調整し、かきまぜてプロスタ
グランジンE類を溶解した後、蒸留水を加えて全
量2000mlとする。以下常法に従つて無菌過した
後1mlずつバイアルに充填し凍結乾燥した後密封
する。
The present invention provides stable prostaglandin E, which is characterized by adding a polymer compound, which is a cellulose derivative, to prostaglandin E, and freeze-drying the mixture.
Concerning the manufacturing method of similar preparations. In the present invention, prostaglandin E includes prostaglandin E 1 (PGE 1 ), prostaglandin E 2 (PGE 2 ), and prostaglandin E 3 (PGE 3 ).
In addition, it refers to derivatives in the side chains of these compounds; specifically, for example, in the case of PGE2 , 16-methyl- PGE2 , 3-methyl-
PGE 2 , 3·16(R)-dimethyl-PGE 2 , 17-oxo-15-epi-PGE 2 , 16(R)-hydroxy-
PGE2 , 15(R)-methyl- PGE2 -methyl ester, 15(S)-methyl- PGE2 -methyl ester,
16・16-dimethyl-PGE 2 -methyl ester, 4
(R)・16(R)-dimethyl-PGE 2 , 4(R)・16
(S)-dimethyl-PGE 2 , 4(S)・16(R)-dimethyl-PGE 2 , 4(S)・16(S)-dimethyl-
PGE 2 and 16 (R S)-methyl-20-methoxy-
PGE 2nd grade. Prostaglandin E is a drug that has a wide range of pharmacological effects such as regulating uterine contractility, antihypertensive action, treatment and prevention of gastrointestinal ulcers, regulating detoxification metabolism, and bronchodilatory action in minute amounts, but it is extremely rare. It is stable and easily decomposed, and is decomposed not only in a solution state but also in a crystalline state, so it is usually stored as a crystal or an ethanol solution in a -20°C freezer. Conventionally, a known method for stabilizing prostaglandin E is to dissolve it in an organic solvent such as N·N-dimethylacetamide with a water content of 0.1% or less (Belgium Patent No. 790840). However, when administering drugs directly to the human body, particularly as injections, if it is not possible to make an aqueous solution due to stability, solubility, etc., an organic solvent solution or diluting this with water may be used, but usually It is said that it is preferable to administer it as an aqueous solution [Dispensing of Medication, 976, 7th Ed.,
Mackpublishing Company1971]. That is, there has been a need for a stable preparation of prostaglandin E that can be stored in a stable form and that can be administered as an aqueous solution when administered as an injection. As a result of various studies based on the above state of the art, the present inventors have found that a preparation of prostaglandin E obtained by adding a polymer compound, which is a cellulose derivative, to prostaglandin E and freeze-drying is stable at room temperature. The present invention was completed based on the discovery that it is resistant to decomposition even when stored for a long period of time, and that it can be administered as an aqueous solution when administered as an injection. In the present invention, examples of polymer compounds that are cellulose derivatives include hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and methylcellulose. The method of the present invention is carried out by adding water and a polymeric compound, which is a cellulose derivative, to prostaglandin E to form an aqueous solution, adjusting the liquid properties, and subjecting it to sterile routine procedures, and then dispensing it into vials. and then freeze-drying according to a conventional method. Although prostaglandin E is water-soluble, it takes a long time to dissolve its crystals in water, so when using the crystals, it is necessary to first dissolve them in an organic solvent such as ethanol or ethyl acetate, and then distill off the organic solvent. It is preferable to form an amorphous solid by expanding the contact area with water. The amount of the polymer compound that is a cellulose derivative added in the present invention is an amount that does not exhibit medicinal efficacy, but the preferable amount added per vial is 5.
~250mg. The stable prostaglandin E thus obtained
If necessary, tonicity agents, preservatives, excipients, soothing agents, etc. may be added. Next, the following examples demonstrate that prostaglandin E obtained by the method of the present invention is stable even when stored at room temperature for a long period of time. Examples 1 to 3 A solution of 50 mg of various prostaglandin E shown in Table 1 below dissolved in 1 ml of ethanol was placed in the vessel of Examples 1 to 3, the walls of the vessel were moistened with the solution, and the vessel was vacuumed or nitrogen gas was bubbled through it. ethanol is distilled off.
Next, add the additives shown in Table 1 below and 1500 ml of distilled water.
to dissolve the additives, add an aqueous sodium hydroxide solution to adjust the pH to 6.5, stir to dissolve prostaglandin E, and then add distilled water to make a total volume of 2000 ml. After sterilization according to a conventional method, the mixture is filled into 1 ml vials, freeze-dried, and sealed.
【表】
つぎに、本発明によつて得られる凍結乾燥品の
安定性を調べるため、上記実施例1〜3で製造し
た製品1バイアルの夫々の含有量に対する50℃で
10日間保存した後の凍結乾燥品1バイアルの夫々
のプロスタグランジンE類の含有量を残存率とし
て次表2に示す。[Table] Next, in order to examine the stability of the freeze-dried product obtained by the present invention, the following results were shown at 50°C for each vial of the product produced in Examples 1 to 3 above.
The content of prostaglandin E in each vial of the freeze-dried product after storage for 10 days is shown in Table 2 below as a residual rate.
【表】
実施例 4〜5
2の溶器に16(S)−メチル−20−メトキシ
−プロスタグランジンE2()50mgをエタノー
ル1mlに溶解した液を入れ、その器壁をその溶液
で湿潤し、減圧或いは窒素ガスを通気してエタノ
ールを留去する。次いで下表3に表す添加剤及び
蒸留水1500mlを加えて添加剤を溶解し、水酸化ナ
トリウム水溶液を加えてPH5.6に調整し、かきま
ぜてプロスタグランジンE類を溶解した後、蒸留
水を加えて全量2000mlとする。以下常法に従つて
過した後、トレイに充填し凍結乾燥する。必要
ならば粉砕する。[Table] Examples 4 to 5 A solution prepared by dissolving 50 mg of 16(S)-methyl-20-methoxy-prostaglandin E 2 () in 1 ml of ethanol was placed in a 2-volume vessel, and the walls of the vessel were moistened with the solution. Then, ethanol is distilled off under reduced pressure or by blowing nitrogen gas. Next, add the additives shown in Table 3 below and 1500 ml of distilled water to dissolve the additives, add an aqueous sodium hydroxide solution to adjust the pH to 5.6, stir to dissolve prostaglandin E, and then add distilled water. In addition, the total volume is 2000ml. After filtering according to a conventional method, the mixture is packed in a tray and freeze-dried. Crush if necessary.
【表】【table】
【表】
実施例 6〜8
実施例4〜5で得られたプロスタグランジン含
有粉末(以下PG−powdと略す)を表下4に示す
組成で剤形化する。[Table] Examples 6 to 8 The prostaglandin-containing powders (hereinafter abbreviated as PG-powd) obtained in Examples 4 to 5 were formulated into a dosage form with the composition shown in Table 4 below.
Claims (1)
である高分子化合物を添加し、凍結乾燥すること
を特徴とする安定なプロスタグランジンE類製剤
の製造方法。1. A method for producing a stable prostaglandin E preparation, which comprises adding a polymer compound that is a cellulose derivative to prostaglandin E and freeze-drying the mixture.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP18523085A JPS61171421A (en) | 1985-08-23 | 1985-08-23 | Production of stable prostaglandin e preparation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP18523085A JPS61171421A (en) | 1985-08-23 | 1985-08-23 | Production of stable prostaglandin e preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS61171421A JPS61171421A (en) | 1986-08-02 |
JPS6216929B2 true JPS6216929B2 (en) | 1987-04-15 |
Family
ID=16167151
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP18523085A Granted JPS61171421A (en) | 1985-08-23 | 1985-08-23 | Production of stable prostaglandin e preparation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS61171421A (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7772220B2 (en) | 2004-10-15 | 2010-08-10 | Seo Hong Yoo | Methods and compositions for reducing toxicity of a pharmaceutical compound |
JP2005272458A (en) * | 2004-02-27 | 2005-10-06 | Ono Pharmaceut Co Ltd | Medical composition for oral administration |
JP2005314413A (en) * | 2004-04-02 | 2005-11-10 | Ono Pharmaceut Co Ltd | Medicine composition for oral administration |
BRPI0514725A (en) | 2004-08-30 | 2008-06-24 | Seo Hong Yoo | neuroprotective effect of solubilized udca in the focal ischemic model |
ATE506955T1 (en) | 2004-10-15 | 2011-05-15 | Seo Hong Yoo | COMPOSITIONS FOR REDUCING THE TOXICITY OF CISPLATIN, CARBOPLATIN AND OXALIPLATIN |
BRPI0419213A (en) * | 2004-11-24 | 2007-12-18 | Seo Hong Yoo | Dry forms of aqueous solubilized bile acid dosage formulation: preparation and uses of these |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5976017A (en) * | 1983-01-20 | 1984-04-28 | Yamanouchi Pharmaceut Co Ltd | Preparation of stable prostaglandin e pharmaceutical |
-
1985
- 1985-08-23 JP JP18523085A patent/JPS61171421A/en active Granted
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5976017A (en) * | 1983-01-20 | 1984-04-28 | Yamanouchi Pharmaceut Co Ltd | Preparation of stable prostaglandin e pharmaceutical |
Also Published As
Publication number | Publication date |
---|---|
JPS61171421A (en) | 1986-08-02 |
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