JPS6019290B2 - 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 (PGF2Q), or derivatives thereof.

These compounds exhibit various pharmacological effects such as labor induction, gastric acid secretion suppression, blood pressure lowering, and anti-asthmatic effects, and are expected to be used as medicines, and their 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, 10 to 0, most of them decompose within a few 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 obtain stable preparations for use as pharmaceuticals.

PGE PGA PGB As a result of extensive research from this perspective, the present inventors have surprisingly found that stability is significantly improved by forming a complex with protamine, which is a naturally occurring basic protein. They discovered this and completed the present invention.

That is, the present invention provides a prostaglan heat-stabilizing composition containing protamine.

Protamine is a basic protein containing a large amount of arginine residues obtained from wall spermatozoa, etc., and is generally commercially available as a sulfate salt, and is sometimes used in pharmaceutical preparations. For example, it is known that when insulin is complexed with protamine, the efficacy of insulin is sustained, but the present inventors were the first to discover that protamine has the effect of stabilizing prostaglandin. It is. The composition of the present invention is produced by adding prostaglandin to an aqueous solution (preferably pH 5-7) containing protamine (for example, sulfate) in a weight ratio of usually 1 to 50, preferably 10 to 200. This is preferably carried out by adding grandin in the form of crystals, powder, or a solution in water, a buffer solution, or a polar organic solvent such as alcohol or acetone, and mixing uniformly.

The thus obtained aqueous solution containing the prostaglandin-protamine complex can be prepared into a preparation such as an injection or a tablet by freeze-drying or drying under reduced pressure after performing aseptic operations. At this time, it is important to remove moisture as completely as possible. In addition, fillers and excipients such as starch, dextrin, hydroxyethyl starch, gum arabic, and tragacanth powder, tonicity agents, preservatives, soothing agents, and the like can also be used, if necessary. Furthermore, antioxidants such as vitamin C, glutathione, and vitamin E may be added in amounts that do not exhibit medicinal effects. Hereinafter, the thermostabilizing effect of protamine will be explained with reference to Examples.

At that time, the degree of prostaglandin decomposition is 100qo
After heat treatment for a certain period of time, the remaining prostaglandin was extracted with acid into the chloroform layer, and a certain amount of this was spotted on a thin layer plate of silica gel and mixed with ethyl acetate:isooctane:acetic acid:water (110:50:20: 100) was developed using the upper layer of the moat solution, and after uniformly spraying a 2% sulfuric acid aqueous solution containing 10% and ammonium sulfate, 18000, 1
Color was developed by heating for ~2 hours, and the color intensity was determined using a thin layer densitometer (Shimadzu, CS-900), and quantified from a standard prostaglandin calibration curve on the same plate. Example 1 Take 0.5 parts of protamine sulfate and dissolve by adding 30 parts of water.

IN- Caustic soda was added dropwise to adjust the pH to 6.3,
The total amount will be 50 shouts. Take the top of this solution 5 and add PGE2
Add 20 ml of methanol solution containing about 50 o/ml and incubate for 30 minutes at room temperature. Place each of the two into small test tubes, freeze-dry, and heat one at 100 qo for 7 hours.
Add 1 part of 2M sodium citrate aqueous solution with pH 2.5 to each, disperse well and dissolve, then add 1 part of chloroform.
Table 1 shows the results of quantification of the remaining PG by adding a certain amount of the extracted PG. PG without added protamine
When only E2 is heated at 100 qo, it completely decomposes and disappears in about 4 hours. Table 1 Example 2 1% protamine sulfate aqueous solution (pH 6.3) was taken at 1%, and prostaglandin E2 and F2Q were added at 200% each.
After adding the muta and mixing uniformly, 160 g of starch amylase decomposition product, so-called enzymatic dextrin, was added and dried under reduced pressure.

Claims (1)

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