JPS5976017A - Preparation of stable prostaglandin e pharmaceutical - Google Patents

Abstract

PURPOSE:To obtain the titled pharmaceutical having high stability for a long term, by adding a thiol compound, a high polymer and/or a water-soluble salt of deoxycholic acid to a prostaglandin E, and freeze-drying the resultant mixture. CONSTITUTION:A thiol compound, e.g. glutathione, a high polymer, e.g. dextran, and/or a water-soluble salt of deoxycholic acid are added to a prostaglandin E1 of formula I , prostaglandin E2 of formula II, prostaglandin E3 of formula IIIor a prostaglandin E containing a derivative at the side chain thereof, and the resultant mixture is then freeze-dried to give the aimed stable prostaglandin E pharmaceutical. The amounts of the compounds per one ampule are as follows; 1-20mg thiol compound, 5-250mg high polymer and 5-100mg water-soluble salt of the deoxycholic acid. The addition of the compound provides the preservation of the pharmaceutical at room temperature for a long term.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is characterized by adding an amount of a water-soluble salt of a thiol compound, a polymer compound, and/or a water-soluble salt of deoxycholic acid that does not exhibit medicinal efficacy to prostaglandin E class, and subjecting the prostaglandin E class to freeze-drying. The present invention relates to a method for producing a stable prostaglandin E preparation.

In the present invention, prostaglandin E is 1- 6th item Prostaglandin E1 shown as formula Prostaglandin E2 represented by formula Prostaglandin E, shown as

or derivatives in the side chains of these compounds (
・Ru.

Prostaglandin E has a small role in regulating uterine contractility, lowering blood pressure, and treating and preventing gastrointestinal ulcers.

Although it is a drug that has a wide range of pharmacological effects such as regulation of lipid metabolism and bronchodilatory effects, it is extremely unstable and easily decomposed, not only in the solution state but also in the crystalline state.
It is stored as crystals or an ethanol solution in a freezer at 0C.

Conventionally, methods for stabilizing prostaglandin E, which are unstable and easily decomposed, have been proposed.

A method of dissolving it in an organic solvent such as N,N-dimethylacetamide with a water content of 01% or less is known (Belgium Patent No. 790,840).

However, when administering medicine directly to the human body, especially as an injection, if it is not possible to make it into an aqueous solution due to stability, solubility, etc., it may be administered as an organic solvent solution or diluted with water. C.Dispenses
ing of Medication, 976°7t
hEd, Mackpublishing Compa
ny 1971].

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 added a thiol compound, a polymer compound, and/or a water-soluble salt of deoxycholic acid in an amount that does not exhibit medicinal efficacy to prostaglandin E, and freeze-dried the mixture. The present inventors have discovered that the preparation of prostaglandin E obtained by the method is stable and difficult to decompose even when stored at room temperature 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 the thiol compound include glutathiono, cysteine, acetyl cysteino, etc., and examples of the polymer compound include dextran.

Examples of the water-soluble salts of deoxycholic acid include alkali metal salts, arginine 7 salts, and lysine salts.

The method of the present invention is carried out by adding water to prostaglandin E and a thiol compound in an ineffective amount.

Add a polymeric compound or a water-soluble salt of deoxycholic acid to make an aqueous solution, adjust the liquid properties, and perform a sterile procedure using a standard method. Dispense into ampoules and then freeze according to a standard method. This is done by drying. When using a water-soluble salt of deoxycholic acid, a base that forms a water-soluble salt and deoxycholic acid may be added to form the salt in an aqueous solution.

Although prostaglandin E is water-soluble, it takes a long time to dissolve the crystals in water, so when using the crystals, add ethanol in advance.

It is dissolved in an organic solvent such as ethyl acetate, and then the organic solvent is distilled off at ℃ to form an amorphous solid, thereby increasing the contact area with water (preferably at ℃ 0 in the present invention). The amount of the thiol compound, polymer compound, or water-soluble tI salt of deoxycholic acid added is an amount that does not exhibit any medicinal effect, but 1
The preferred amount added per ampoule is 1 to 20 mg in the case of a thiol compound, 5 to 250 mg in the case of a polymer compound, and 5 to 100 mg in the case of a water-soluble salt of deoxycholic acid. mg.

To the stable prostaglandin E thus obtained, tonicity agents, preservatives, excipients, soothing agents, etc. may be added as necessary.゛・Next, the following experimental example shows 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 ampule of the freeze-dried product obtained in Examples 1 to 5 and 1 ampule of water.
ml to dissolve it, add citric acid to adjust the pH to 3, extract with ethyl acetate, dry, and concentrate. Add 1 ml of water to dissolve, add citric acid and adjust pH≦
When adjusted to 3, deoxycholic acid precipitates, so this is removed, extracted with ethyl acetate, dried, and concentrated. )
Next, the entire amount was subjected to silica gel thin layer chromatography and developed with a chloroform-methanol-acetic acid-water mixture (volume ratio 90:8:1:08) [obtained in Examples 4 and 5, Mugata! Thread + 'i':'/: When using a roasted product, use a mixture of ethyl acetate-acetic acid-iso71-cutane-water (volume ratio 90: 20: 50: 1)
00)], sprayed with 5% phosphomolybdic acid-ethanol solution and heated at 105 to 110C for 10 minutes.
After color development, glostaglandin E2 and its decomposition products (prostaglandin A2 and brostaginodin B)
2) Measure the absorbance of each column and column using a recording type densitometer CC08M0 Pushtometer Chromato Ace D-1.
09 type] and find the peak area of each Smooth Z7.
Its area ratio, J Nili test bite.

Containment of Glotaglandin E2 in - Calculated by Kuma 1111~
is.

The residual rate is the freeze-dried chestnut A obtained in Examples 1 to 5. +1
3 for the content of Glotaglandin E2 in the ampoule
The ratio of the content of prostaglan/gin E2 in the 1 ampoule of the freeze-dried product after storage at 5υ for 30 days was calculated as the residual rate. The results are shown in Table 1 below.

Table 1 Furthermore, when prostaglandin E2 with no stabilizer added was similarly stored at 35C for 30 days, the residual rate was 10% and 9
It was 0% for 0 days.

7- Example 1 A solution prepared by dissolving 100 ml of prostaglandin E2 crystals in 1 ml of ethanol is placed in a 21° container, the walls of the container are moistened with the solution, and the ethanol is distilled off by reducing pressure or passing nitrogen gas through the container. Then 30g of glutathione and 19g of distilled water
00 ml was added to dissolve glutathione, an aqueous sodium hydroxide solution was added to adjust the pH to 6.5, stirred in a nitrogen gas stream to dissolve prostaglandin E2, and then distilled water was added to bring the total volume to 2000 ml. After sterile filtration, each 1 ml of the mixture is filled into ampoules, freeze-dried, and then melted in a conventional manner.

Example 2 A solution prepared by dissolving 100 μm of prostaglandin E2 crystals in 1 ml of ethanol is placed in a 21° container, the walls of the container are moistened with the solution, and the ethanol is distilled off by reducing pressure or passing nitrogen gas through the container. Next, dextran 20 (average molecular weight 2
When dextran is dissolved by adding 400 g of 0,000 g and 1200 g of distilled water, the pH becomes approximately 6.5.

Stir further and add Prostagrange/E to 8- After dissolving, add distilled water to make a total volume of 2000ml.

After sterile filtration, each 1 ml of the mixture is filled into ampules, freeze-dried, and then melted in a conventional manner.

Example 3 A solution of 100 μm of prostaglandin E crystals dissolved in 1 ml of ethanol is placed in the container of 21°, the walls of the container are moistened with the solution, and the ethanol is distilled off by reducing pressure or passing nitrogen gas through the container. . Then 50g of gelatin and 18g of distilled water
Add 00ml to dissolve the gelatin and add ice water to bring the total volume to 2.
000mt. After sterile filtration according to the usual method, 1
Fill each ml into ampoules, freeze-dry, and then melt.

Example 4 A solution prepared by dissolving 100 μl of grosstaglandin E2 crystals in 1 ml of ethanol is placed in a container 2e, the walls of the container are moistened with the solution, and the ethanol is distilled off by reducing pressure or passing nitrogen gas through the container. Next, add 60 g of deoxycholic acid, 293 g of arginine, and 18 ml of water to dissolve the deoxycholic acid arginine salt, and add naric acid to adjust the pH.
After adjusting to 7.0 and stirring to dissolve prostaglandin E, distilled water was added to make a total of 17t:2000mZ. After sterile filtration, each 1 ml of the mixture is filled into ampoules, freeze-dried, and then melted in a conventional manner.

A solution prepared by dissolving 1 mL of ethanol in 1 ml of ethanol is input, the walls of the vessel are moistened with the solution, and the ethanol is distilled off by reducing pressure or passing nitrogen gas through the vessel. Next, add 60 g of deoxycholic acid, 29.3 g of arginine, and 1800 ml of water to dissolve deoxycholic acid arginine salt.Add an aqueous solution of arginine to adjust the pH to 8.5, stir, and dissolve prostaglandin E2, then add distilled water. In addition, the total amount is 2000mt
shall be. After sterile filtration, each 1 ml of the mixture is filled into ampoules, freeze-dried, and then melted in a conventional manner.

Example 6 A solution of 100 mg of 16-methyl-prostaglasin E2 crystals dissolved in 1 ml of ethanol is placed in the container of 21, the walls of the container are moistened with the solution, and the ethanol is distilled off by reducing pressure or passing nitrogen gas through the container. . Then dextran 20
(Average molecular weight 20,000) 400g and distilled water 15
Add 00ml and dissolve, then add distilled water to make a total volume of 200ml.
0m1. 1 m after sterile filtration according to the usual method.
1 of each vial, freeze-dried, and then sealed.

A solution of 100,111 g of crystals of 16-methyl-prostaglandin E dissolved in 1 ml of ethanol was placed in the container of Example 7.21, the walls of the container were moistened with the solution, and the ethanol was removed by reducing the pressure or passing nitrogen gas through the container. To leave.

Then dextran 70 (average molecular weight 70,000) 1
Add 20 g and 1500 ml of distilled water to dissolve, and then add distilled water to make a total volume of 2000 ml. After sterile filtration, fill 1 ml portions into vials according to a conventional method, freeze-dry, and seal.

Example 8 A solution prepared by dissolving 1100 n1 of 3-methyl-prostaglandin E2 crystals in 1 m of ethanol was placed in a container No. 21, the walls of the container were moistened with the solution, and the ethanol was distilled off by reducing pressure or passing nitrogen gas through the container. leave Next, 120 g of Dextran 20 (average molecular weight 20,000) and 1 portion of distilled water were added.
After adding and dissolving 500 ml, add 1100 TIl1 of crystals of 3,16(R)-dimethyl-prostaglandin E2 to the container of Example 9゜21 and add 1 ml of ethanol.
Pour the solution dissolved in l and moisten the vessel wall with the solution,
Ethanol is distilled off under reduced pressure or by blowing nitrogen gas.

Then dextran 20 (average molecular weight 20,000) 1
20g and 1500ml of distilled water were added and dissolved, then steamed 1
3- Add distilled water to make a total volume of 2000ml. After sterile filtration, fill 1 ml portions into vials according to a conventional method, freeze-dry, and seal.

Example 10 A solution of 110011t of crystals of 17-oxo-15-epi-prostagladin E dissolved in 1 mZ of ethanol was placed in the container of Example 10.21, and the walls of the container were moistened with the solution, and the pressure was reduced or nitrogen gas was aerated. to distill off the ethanol. Next, 10 Qg of dextrin and 1500 ml of distilled water were added to dissolve the dextrin, and after dissolving hydroxide E2, distilled water was added to make the total volume 2000 ml. After sterile filtration, 1 ml of the solution is filled into vials according to a conventional method, freeze-dried, and sealed.

Example 11 A solution prepared by dissolving 1100 rl1 of crystals of 16(R)-hydroxy-prostaglasin E2 in 1 rntK of ethanol is placed in the container of No. 21, and the wall of the container is covered with the solution. ! i+! it
Ethanol is distilled off under reduced pressure or by blowing nitrogen gas. Then add 740 g of glutathione and distilled water + 5 (1 Oml) to dissolve glutathione] 7
．． Adjust the pH to 6.5 by adding an aqueous solution of hydroxide-1,,! 16 (R1-Hydroxy-Prostagraft 12) After dissolving, add distilled water to make a total volume of 2000 ml 1, J: J, "l' Fill in 1 ml portions into vials after sterile filtration according to the usual method. Freeze-dry and seal.

11. Pour a solution of 100,111 g of 16(R)-hydroxy-p[1-stagladine E2 crystals dissolved in 1 ml of ethanol into a container in step 21, and moisten the wall of the container with the solution.
Ethanol is distilled off under reduced pressure or by blowing nitrogen gas.

Next, 40 g of oxidized glutathione and 1500 m of distilled water
1 to dissolve the oxidized glutathione.

Add an aqueous sodium hydroxide solution to adjust the pH to 6.5, stir to dissolve 16+R1-hydroxy-glostaglandin E, and then add distilled water to make a total volume of 2000 mt. After sterile filtration, fill 1 ml portions into vials according to a conventional method, freeze-dry, and seal.

Example 13 A solution prepared by dissolving 100 ml of crystals of 3.16 (R)-dimethyl-prostaglandin E2 in 1 mtK of ethanol was placed in the container of 21, and the walls of the container were moistened with the solution. to remove. Then 10 g of polyvinylpyrrolidone and 150 Oml of distilled water
Add to dissolve the polyvinylpyrrolidone, add an aqueous sodium hydroxide solution to adjust the pH to 6.5, and mix.3.
1.6 After dissolving (R)-dimethyl-prostaglasin E2, add distilled water to make a total volume of 2000 mt. After sterile filtration, fill 1 ml portions into vials according to a conventional method, freeze-dry, and seal.

Next, the stabilizing effect of each prostaglasin E2 derivative was investigated according to the experimental example described above, and the results are shown in Table 2.

15- Table ■ 16- The substances marked with * in the table above are new products, *1 is based on Japanese Patent Application No. 49-23972, and *2 is based on Japanese Patent Application No. 49-530.
No. 98, and *3 are synthesized according to Japanese Patent Application No. 78464/1983, respectively.

patent applicant Yamanouchi Pharmaceutical Co., Ltd.

Claims (1)

[Claims] A stable prostaglandin E type preparation, which is characterized by adding a non-medicinal amount of a thiol compound, a polymer compound, and/or a water-soluble salt of deoxycholic acid to prostaglandin E type, and freeze-drying the mixture. Manufacturing method.