JPS6019741B2 - 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 prostanoic acid having 20 carbon atoms, which have been proven to exist in living organisms, such as prostaglandin A, (PGA,), Prostaglandin ~ (PGA2), Prostaglandin E, (PGE,
), prostaglandin E2 (PGE2), prostaglandin F, Q (PGF,Q), and prostaglandin F2Q (POF2Q), or derivatives thereof.

These compounds have the effect of inducing labor, suppressing gastric acid secretion,
It exhibits various pharmacological effects such as blood pressure lowering effect and anti-asthmatic effect, and is expected to be applied as a medicine, and its development is progressing. 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 qo, 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 it is essential to suppress such decomposition and stabilize them in order to use them as pharmaceuticals.

As a result of extensive research from this perspective, the present inventors have surprisingly discovered that stability is significantly improved when brostaglandin is mixed and adsorbed onto pentonite in an aqueous medium and then freeze-dried. The present invention was completed.

That is, the present invention provides a prostaglandin heat-stabilizing composition containing pentonite.

Pentonite used in the present invention is a naturally occurring colloidal hydrated aluminum silicate whose main component is montmorillonite described in the Japanese Pharmacopoeia, and is frequently used as an excipient and binder in pharmaceuticals and cosmetics. This property was discovered for the first time by the present inventors to have the effect of stabilizing gin, and as mentioned above, its practical value is extremely large.

Furthermore, acidic Shirashi, kaolin, etc. have no stabilizing effect, which is considered to be a characteristic unique to pentonite. The composition of the present invention is produced by suspending pentonite in water in a weight ratio of usually 10 to 100 parts per 1 part of prostaglandin, and gently stirring the prostaglandin or its salt into crystals, powder, or water. Alternatively, it is preferably carried out by adding in the form of a solution of a polar organic solvent such as alcohol or acetone, and then freeze-drying. In freeze-drying, it is desirable to reduce moisture as much as possible. When suspended in water, pentonite has a pH of approximately 10, and PGEs are known to be particularly unstable at high alkaline pH, so the final pH of a pentonite suspension adsorbed with prostaglandin is approximately 6. It is preferable to fall within the range of 8 to 8.

Normally, just by adding free prostaglandin, the pH will be 7~
It drops to 8. If the pH is too low, the adsorption power of pentonite tends to decrease, so care must be taken. Further, if necessary, fillers or excipients such as starch, dextrin, hydroxyethyl starch, hydroxypropyl starch, gum arabic, tragacanth powder, etc. may be used.

In addition, vitamin C, glucthione, and
Antioxidants such as vitamin E may be added. The thermal stabilizing effect of pentonite will be explained below using examples.
At this time, the degree of decomposition of prostaglandin is determined by heating the remaining prostaglandin in an open system for a certain period of time at 100:00, and then cleaning the remaining prostaglandin with acid. This was extracted into the roform layer, and a certain amount of this was spotted on a thin layer plate of silica gel, and ethyl acetate: iso-octane: acetic acid: water (110:50:20) was extracted.
180 qo
The color was developed by heating for 1 to 2 hours, and the color intensity was measured using a thin-layer densitometer (Shimadzu, CS-900), and quantified using a standard prostaglandin calibration curve on the same plate. Example 1 Pentonite is 9 of 10, 9 of 20, and 9 of 50, respectively.
, and suspend in 1 part of water per 100 women.

While gently stirring this suspension, add 20 grams of a methanol solution containing 9 of prostaglandin E21, mix uniformly, and freeze-dry. 100% of the obtained powder
Table 1 shows the results of measuring the remaining PGE2 after heating at ℃ for 7 hours. 1 only PGE2 without using pentonite
When heated at 00qo, it completely decomposes and disappears in about 4 hours.
Table 1 Example 2 Disperse 50 parts of pentonite in 1 part of water and gently stir under ice cooling.

Next, PGE20.5 female and PGF2QO. Add 10 ml of methanol solution containing 9 of 5, mix, and lyophilize thoroughly. After heating the obtained powder at 100 qo for 7 hours, the amount of PG present is measured. Exactly the same test was further conducted under conditions in which ribonucleic acid 50:9, vitamin CIO0:0, or reduced glutathione: 100:3 coexisted. The results are summarized in Table 2. Table 2 Example 3 The ratio of pentonite and PGE2 was set to 50/1, the final pH of the suspension was adjusted to 5.5 and 7.0 by adding diluted hydrochloric acid, and tested in the same manner as in Example 1. Result, residual P
GE2 is 30% at pH5.5 and 65% at pH7.0
Met.

Claims (1)

[Claims] 1. A prostaglandin heat-stabilizing composition comprising a mixture of bioactive prostaglandin and bentonite.