JPS6019743B2 - Prostaglandin E heat-stabilized composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a prostaglandin E heat-stabilized composition.

Prostaglandin E has a wide range of pharmacological effects, including bronchodilation, regulation of uterine contractility, suppression of gastric acid secretion, treatment and prevention of peptic syndrome, lowering of blood pressure, inhibition of platelet aggregation, and regulation of lipid metabolism. However, the problem when prescribing and using these substances as medicines lies in their stability.

These compounds are sensitive to acids or bases.
Alternatively, it has the property of being extremely easily decomposed by heating. 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, such as in a refrigerator. Therefore, the present inventors conducted intensive studies on the stabilization of prostaglandin E, and as a result, they discovered that citrate ester exhibits a heat stabilizing effect, and thus arrived at the present invention.

That is, the present invention provides a heat-stabilized prostaglandin E composition which is dissolved in or mixed with citric acid ester.

Examples of prostaglandin E stabilized by the present invention include prostaglandin E2 (hereinafter abbreviated as TPGE2), prostaglandin E, (hereinafter abbreviated as PGE), and 13,14-dihydroprostaglandin E. , (hereinafter abbreviated as PGEo), 13,14-dihydroPOE2,
15-methyl-PGE2,15-methyl-PGE,15
-Methyl-PGE〇,16-Methyl-PGE2,16-
Methyl-PGE, ,16-methyl-PGE.

,16,16-dimethyl-PGE2,16,16-dimethyl-PGE,,1616-dimethyl-PGE〇,16
, 16-propano PGE 2,16,16-propano PGE, , 1016-o/zeno PGE. , 16-cyclohexyl-tetranol-PGE2,16-phenyl-tetra/ru-PGE2,17-phenyl-trinor PGE2,16-phenoxy-tetranor PGE2,16-m-chlorophenoxy-tetranor PGE2, etc. These esters such as methyl ester, ethyl ester, or dezyle ester may be used, or may be esters of the general formula (1) [wherein R, , R4 and R5 may be the same or different and are a hydrogen atom and a lower alkyl group, respectively] Or indicates a fluorine atom.

R2 and R3 may be the same or different and each represents a hydrogen atom, a lower alkyl group, or a hydroxyl group-protecting group. R6 is C, ~C, o alkyl group, C, ~C
, 5-substituted alkyl group, C, ~C,. cycloalkyl group,
It represents a substituted cycloalkyl group, an aryl group such as a phenyl group, or a substituted aryl group such as a substituted phenyl group, and Z represents a single bond, a sulfur atom or an oxygen atom. A is one C
H2-CH2- or cis-CH=CH- and B is -
CQC day 2-, trans-CH=CH- or 1C2-C
It is one.

× is a C, -C5 alkylene group or C, -C,. Indicates a substituted alkylene group. Y represents a carboxyl group, an alkoxycarbonyl group, a hydroxymethyl group, an alkoxymethyl group, or a substituted alkoxymethyl group. ] may be used. These compounds can be easily produced by, for example, the following known documents or published techniques.

As a known document, for example, E. J. Corey et al. [J. A
mChem. Soc. Volume 91, pages 5675-5677 (196); Volume 92, pages 397-398 (197
The published techniques include, for example, Tokuko Sho 48-10236, 46-24599, and Tokko Sho 51-1.
28492,51-115991,51-43749,
51-43744, 51-35413 51-1415
0,48-52745 47-3 total 20,47-343
55 47-30641 and 47-6264.

The instability of prostaglandin B is due to the fact that its five-membered ring has a hydroxyl group, acyloxy group, or alkoxy group that is easily eliminated. In normal decomposition, conversion of prostaglandin E to prostaglandin A is observed due to elimination of these easily-eliminated groups. Furthermore, brostaglasozin A is found to be decomposed into prostaglandin B and prostaglandin C, and in some cases even more complex decomposition occurs. Citrate esters, as discussed below, control this type of degradation to a surprising degree.

Therefore, stabilization by citric acid ester can be achieved by the general formula (1
), but is applied to all prostaglandin E having the five-membered ring partial structure of the general formula (1).
Some examples are known as methods for stabilizing prostaglandin E.

It is known that stability is increased by dissolving acid esters such as ethyl acetate, alcohols such as ethyl alcohol, or prostaglandin E such as chloroform. C. As reported by Srivastava et al. [For details, see K. C. Srivasta
vanandJ. Clausen, Lirp Ship Volume 8 5
See pages 92-594 (King 1973).

Therefore, it is a known fact that prostaglandin E is generally stabilized by mixing with or dissolving in compounds such as esters, alcohols, or chloroform. However, the present inventors found that dissolving prostaglandin E in citrate ester or mixing it with citrate ester significantly thermally stabilizes prostaglandin E to an extent that could not be predicted from the above-mentioned facts. This discovery led to the completion of the present invention.

The citric acid esters of the present invention include triethyl citrate, trimethyl citrate, tripropyl citrate, tributyl citrate, tribentyl citrate, tricyclohexyl citrate, tribenzyl citrate, trihexyl citrate, triheptyl citrate, and citric acid. Examples include trioctyl, tridecyl citrate, etc.;
may be the same or different and represent an alkyl group, a substituted alkyl group, an aromatic group or a substituted aromatic group.

] Preferred are compounds defined as: In carrying out the present invention, prostaglandin B may simply be dissolved in or mixed with the citrate ester. To prepare a solution or mixture of prostaglandin E and citrate, prostaglandin E can be directly dissolved in citric acid, or if it is difficult to dissolve both in ethyl acetate,
It is also possible to explore a method of dissolving both the prostagrange E such as acetone and the citric acid ester in an organic solvent, thoroughly mixing the two, and then removing the organic solvent under reduced pressure.

Although it is desirable that the citric acid ester used in the present invention be pure, the stabilizing effect will not be significantly affected even if one containing a certain amount of water or organic acid is used.

Preferably, citric acid ester is used in a content of 1% or less of both water and organic acid. The ratio of citrate to prostaglandin E in the solution or mixture can be arbitrarily selected within a wide range.

Generally, the object of the present invention can be achieved by using 1 to 1 times (weight ratio) citric acid ester to prostaglandin E, but more preferably 10 to 1 times
Use 1,000 times more citric acid ester. In general, if the above magnification is small, the thermal stability tends to decrease, and conversely, if the magnification is very large, the amount of the entire preparation increases, causing problems in use as a medicine, so it is preferably selected within the above range. The prostaglandin E composition thus obtained can be further mixed with other substances if necessary.

Here, other substances may be anything as long as they do not significantly impair the stability of the above-mentioned mixture, and such substances include generally known pharmaceutical additives such as starch, cellulose, hydroxyethyl cellulose, Cellulose derivatives such as carboxymethylcellulose and methylcellulose, or dextrin, dextran,
Polysaccharides or polysaccharide derivatives such as cyclodextrin, disaccharides or monosaccharides such as white rice bran, lactose, maltose, glucose, fructose, mannitol, sorbitol, proteins,
Biological substances such as nucleic acids and bile acids, vitamins and vitamin derivatives such as ascorbic acid, tocopherol, hesveridine, and methylhesveridine, or inorganic substances such as pentonite and turk, or antioxidants, stabilizers, emulsifiers, and acidulants. Randomly selected from among the representative food additives. The composition of the present invention can be formulated as an injection, an aerosol, a suppository, an oral preparation, etc. by generally known pharmaceutical means.

The thus obtained heat-stabilized preparation of prostaglandin E can be used for the purposes for which prostaglandin E is generally used, such as bronchodilation, regulation of uterine contractility, suppression of gastric acid secretion, and prevention of digestive deconcentration. It is used for a wide variety of purposes including treatment and prevention, lowering blood pressure, inhibiting platelet aggregation, and regulating lipid metabolism.

In particular, the compositions according to the invention have advantageous characteristics since they are often in liquid form. That is, it is particularly useful when prostaglandin E is used as a propellant for the purpose of treating edge breath.

For such purposes, the composition of the present invention may be mixed with other liquid substances before or after use. Other liquid substances include water, organic solvents, and halogenated carbons having 2 or less carbon atoms, which become liquid under pressure and are generally used as main components of aerosol agents. EXAMPLES Next, the present invention will be explained in more detail with reference to examples, but the scope of the present invention is of course not limited by these examples.

In the examples, the amount of residual prostaglandin E was determined as follows.

That is, a solution or mixture that has been exposed to harsh conditions for a predetermined period of time is extracted with a certain amount of organic solvent (ethyl acetate, chloroform, etc.), and then a certain amount of the extracted solution is subjected to thin layer chromatography (ethyl acetate, : lso-octane : acetic acid : water). =11
0:40:20:100 (developed in the upper layer) and a dilute aqueous solution of ammonium sulfate-sulfuric acid was atomized, and then 1800
The concentration of the colored spot after heating at 0 for 1 hour was quantified using a recording densitometer (Shimadzu CS-90 model), and the remaining prostaglandin E was determined from the calibration curve of standard prostaglandin E obtained separately. The absolute amount was calculated and the percentage relative to the initial value was calculated. Example 1 An ethyl acetate solution containing PGE20.5-9 is placed in a glass ampoule, and the ethyl acetate is removed under reduced pressure or by bubbling inert gas.

Triethyl citrate 100 Sanyu is added to this, shaken well to mix, and the space is replaced with argon, followed by melt sealing. After heating the obtained preparation in a 10- and 0-temperature bath for a certain period of time, the amount of residual PGE2 was determined by the method described above, and the residual rate was calculated with respect to the initial value. Table 1 shows the results.

Table 1 also shows the results obtained using the same method for the formulations prepared in Examples 2 to 13 and Reference Examples 1 to 4 below. Example 2 Example 1 was prepared without replacing the space inside the ampoule with argon.

Example 3 An ampoule of a PCE2-containing formulation is prepared by replacing triethyl citrate with tri-n-butyl citrate in Example 1.

Example 4 The water content of triethyl citrate used in Example 1 was determined to be 0.27% by Karl Fischer method.

An ampoule was prepared in exactly the same manner as in Example 1 using triethyl citrate dried with Molecular Sieve-4A and triethyl citrate containing 1.0% water.
Example 5 The water content of tri-n-butyl citrate used in Example 3 was determined to be 0.
It was 0.6%.

Citric acid tri-n-dried with molecular sieve 4A
PGE2-containing formulation as shown in Example 1 using butyl, tri-n-butyl citrate containing 0.26% water, and tri-n-butyl citrate containing 1.06% water. Prepare ampoules.

Example 6 An ampoule is prepared by changing the amount of triethyl citrate used in Example 1 to 20 meta and 500 triethyl citrate.

Example 7 An ampoule is prepared in the same manner as in Example 1, using triethyl citrate containing 5% acetic acid.

Example 8 20.5 parts of PGE and 50 parts of triethyl citrate were dissolved in 3 parts of ethyl acetate, 2 parts of 200 parts of dextrin powder was added thereto, and the ethyl acetate was distilled off under reduced pressure.

The resulting wet powder is placed in a glass ampoule, replaced with argon, and then sealed. Example 9 An ampoule is prepared in which PGE2 is replaced with PGE in Example 1.

Example 10 In Example 1, PGE2 was replaced with 13,14 dihydro PG
Prepare an ampoule labeled E.

Example 11 In Example 1, PGE2 was replaced with 16,16 dimethyl-PG
Prepare an ampoule named E2.

Example 12 In Example 1, PGE2 was replaced with 16,16-dimethyl-P
Prepare an ampoule with CB.

Example 13 An ampoule is prepared in which PGE2 in Example 1 is changed to 161m-chlorophenoxy17,18,19,20-tetra/l PGE2.

Reference Example 1 PGE20.5 9 is placed in a glass ampoule, replaced with argon, and then melt-sealed.

Reference Example 2 A preparation is prepared by adding 8-cyclodextrin to an 8-cyclodextrin inclusion compound containing 9 of PGE20.5 and mixing the total amount to 9 of 200.

Reference Example 3 The preparation of Reference Example 2 is placed in a glass ampoule, replaced with argon, and then sealed.

Reference Example 4 The formulation prepared in Example 8 without using triethyl citrate is prepared.

Reference Example 5 An ampoule is prepared in which triethyl citrate is replaced with butyl acetate in Example 1.

Reference Example 6 An ampoule is prepared in which triethyl citrate is replaced with triacetin in Example 1.

Reference Example 7 An ampoule is prepared in which triethyl citrate is replaced with jetyl adipate in Example 1.

Reference Example 8 An ampoule is prepared in which triethyl citrate is replaced with diethyl carbonate in Example 1.

Reference Example 9 An ampoule is prepared in which triethyl citrate is replaced with ethyl lactate in Example 1.

Reference Example 10 An ampoule is prepared in which triethyl citrate in Example 1 is replaced with IJ jetyl nate.

Claims (1)

[Claims] 1. A heat-stabilized prostaglandin E composition prepared by dissolving or mixing prostaglandin E in a citric acid ester.