JPS6019740B2 - Prostaglandin heat-stabilized composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to prostaglandin heat stabilizing compositions.

In the present invention, bioactive prostaglandins are a group of physiologically active substances whose basic skeleton is brostanic acid with 20 carbon atoms, which has been proven to exist in living organisms, such as prostaglandin A, (PGA,), Prostaglandin (PGA2), Prostaglandin E, (PGE
, ), prostaglandin E2 (POE2), prostaglandin F, Q (PGF2Q), and prostaglandin F2Q (PGF2Q), or their humble conductors.

These compounds exhibit various pharmacological effects such as labor induction, gastric acid secretion suppressing, blood pressure lowering, and anti-asthmatic effects, and are expected to have a medicinal effect and are being developed.

However, prostaglandins are generally unstable compounds and are highly susceptible to decomposition by acids, alkalis, and heat.

When stored at room temperature, decomposition products are observed after several weeks, and when heated to a high temperature, for example, 100:00, most of them decompose within several hours.

It is also known that it gradually decomposes even when stored at low temperatures, for example in a refrigerator. In particular, PGEs are prone to dehydration reactions at the 5-membered ring moiety as shown below, and in order to be used as medicines, it is essential to suppress such decomposition and obtain stable preparations.

The present inventors have studied in detail the stabilizing effects of various water bathing polymer compounds from this perspective, and have found that the stabilizing effects vary significantly depending on the type of polymer compound.

For example, polyacrylic acid, polyglutamic acid, alginic acid, pectin, polyethyleneimine, etc. have no stabilizing effect on PGEs, and guaya bean gum, locust bean gum, gum arabic, powdered tragacanth, agar, inulin, etc. have no stabilizing effect. It is recognized, but its effectiveness is weak. However, completely unexpectedly, amylose, a linear polymer consisting of Q-1,4 bonds of glucose, has a weak stabilizing effect on PGEs, but it is not possible to use enzyme-degraded amylose, hydroxyethylated or carboxymethylated amylose. It was found that chemically modified amylose and those treated with the hydrolytic enzyme amylase exhibited a remarkable thermostabilizing effect.
On the other hand, it was discovered that amylobectin, a branched polymer compound consisting of Q-1,4 and Q-1,6 bonds of glucose, exhibits a clear stabilizing effect when used as is or after being treated with amylase. As a result, we have completed the present invention. That is, the present invention provides a mixture of bioactive prostaglandin and at least one member selected from the group consisting of hydroxyethyl amylose, poxymethyl amylose, amylovectin, hydrolytic enzyme-treated products thereof, and enzymatically decomposed amylose. The present invention relates to prostaglandin heat stabilizing compositions. These materials are easily available as commercial products and can be easily prepared by methods known per se.

Preferably, the composition of the present invention is manufactured by first adding the above-mentioned materials to 1 part of brostaglandin in a normal weight ratio of 10 to 10 parts.
00 and dissolve or suspend it in water.

At this time, if it is difficult to dissolve, add salt to the suspension, or add 0.0% salt to the suspension.
Once dissolved in a 05-0.1N caustic soda aqueous solution, a suitable acid such as acetic acid or hydrochloric acid may be added to adjust the pH to 4-7. Next, prostaglandin or a salt thereof is added as a crystal, powder, or a solution in water, alcohol, or a liquid organic solvent such as acetone, and mixed thoroughly and uniformly. By subjecting this to a treatment such as vacuum drying or freeze drying to remove water, a dry powder, which is a heat-stable prostaglandin composition, is obtained, which can be made into a preparation such as an injection or a tablet. At this time, it is desirable to remove moisture as completely as possible.

Further, if necessary, commonly used fillers, turquoise agents, disintegrants, tonicity agents, preservatives, habit-stimulating agents, etc. can be used. It is also possible to use antioxidants such as vitamin C, glutathione, and vitamin E in amounts that do not exhibit medicinal effects.

A detailed explanation will be given below using examples.

At that time, the degree of prostaglandin decomposition is 1000
After heating in an open system for a certain period of time at 0, the remaining prostaglandins were extracted with acidic chloroform, a certain amount of which was spotted on a silica gel plate and extracted with ethyl acetate:isooctane:acetic acid:water (110:50:20:100). ), and after uniformly spraying a 2% aqueous sulfuric acid solution containing 10% ammonium sulfate, the color was developed by heating at 180 qo for 1 to 2 hours, and the intensity was measured using a Shimadzu densitometer CP-900. Quantification was determined from a standard prostaglandin calibration curve on the plate.

Example 1 Enzymatically decomposed amylose, hydroxyethyl amylose or carboxymethyl amylose were separately taken as 9 out of 40,
Add one drop of water and dissolve.

Add 200 grams of PGE2 to this and freeze dry at 100°C.
Table 2 shows the results of heating for 7 hours and determining the amount remaining. Table 1 Example 2 Amylobectin was dispersed in water to make a 2% suspension, and 100%
Heat to ℃.

Take one coolant, mix with PCE2200, freeze-dry, and heat at 100 oo for 7 hours. The residual E2 was measured and found to be 41%.

Add 0.5% 4% aqueous solution of hydroxyethyl starch, 1.
Prostaglandin E2200 Butsu and F2Q200 Sanyu were added to No. 0 and No. 2, respectively, and after mixing, freeze-drying was carried out, and the residual rate after 7 hours treatment with 10000 was shown in Table 3. Table 3 Example 3 Amylobectin and prostaglandin E2 in weight ratio of 2
Mix with aqueous solution so that the ratio is 00/1 and freeze-dry it to 1000
The residual rate after heating for 0 and 7 hours was investigated.

Pu as a control. Using 8-cyclodextrin, which is known to form an inclusion compound with staglandin and exhibit a stabilizing effect, the remaining PGE2 was measured in the same manner, and it was 79% for amylobectin and 79% for 3-cyclodextrin. It was 56%. Comparative Example 1 9 of 50 of each material was dissolved in 1 cup of water, brostaglandin E21 was added thereto, lyophilized, and the remaining amount of PGE2 was measured when heated at 10500 for 1 hour and 7 hours. The results are shown in Table 2.

Table 2

Claims (1)

[Claims] 1. A prostaglandin heat-stabilizing composition formed by mixing a biologically active prostaglandin with at least one member selected from the group consisting of hydroxyethyl amylose, carboxymethyl amylose, amylopectin, hydrolytic enzyme-treated products thereof, and enzymatically decomposed amylose. thing.