JPS6152146B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a stabilized composition of prostaglandin (hereinafter abbreviated as PG) or a PG-like compound. More specifically, PGE or PGF or similar compounds thereof,
and PGE characterized by consisting of oligosaccharides or
The present invention relates to stabilizing compositions of PGF or similar compounds thereof. Prostaglandin (hereinafter abbreviated as PG) is a prostanoic acid derivative represented by the following formula (). Different types of prostaglandins are known, the type depending, among other things, on the structure of the five-membered ring and on the substituents. For example, the five-membered rings of prostaglandin E (PGE), F (PGF), and A (PGA) each have the following structure.

【formula】 【formula】

[Formula] Such compounds are subclassified according to the position of the side chain double bonds at positions 8 and 12 of the five-membered ring. PG-1 compounds have a trans double bond between C ₁₃ and C ₁₄ , and PG-2 compounds have a cis double bond between C ₅ and _{C 6} and a trans double bond between C ₁₃ and C ₁₄ . Has a double bond. For example, prostaglandin F ₁
(PGF ₁ 〓) and prostaglandin E ₁ (PGE ₁ ) are represented by the following structural formulas () and (). The structures of PGF ₂ 〓 and PGE ₂ as compounds of the PG-2 group correspond to formulas () and () in which a cis double bond is inserted between the carbon atoms at the 5th and 6th positions.
A compound in which the double bond between the 13th and 14th carbon atoms of the PG-1 group is replaced with an ethylene group (-CH ₂ CH ₂ -) is dihydroprostaglandin, that is, dihydroprostaglandin. They are known as F ₁ 〓 (dihydro-PGF ₁ 〓) and dihydroprostaglandin-E ₁ (dihydro-PGE ₁ ). Prostaglandins are generally known to have pharmacological properties. For example, they stimulate smooth muscle, have hypotensive and antilipolytic effects, and inhibit platelet aggregation. It is therefore effective in the treatment of hypertension, thrombosis, asthma, ulcers of the stomach and intestines, induction of labor and abortion in pregnant mammals, and prevention of arteriosclerosis. They are fat-soluble substances;
It is obtained in small amounts from each organ of animals that secrete prostaglandins in vivo. For example, PGE and PGA have the effect of suppressing gastric juice secretion and are used to treat gastric ulcers. They also inhibit epinephrine-induced fatty acid release and, as a result, reduce the concentration of free fatty acids in the blood, so they are effective in preventing arteriosclerosis and hyperlipidemia. PGE ₁ inhibits platelet aggregation, thereby removing blood clots and preventing thrombosis. PGE and
PGF stimulates smooth muscle and increases intestinal peristalsis. These effects are effective in treating postoperative intestinal obstruction and can be used as a laxative. Furthermore, with PGE
PGF is used as a labor stimulant, an abortifacient in the first or second trimester, and even for expulsion of the placenta after delivery.
It is also used as an oral contraceptive because it has the effect of regulating the sexual cycle of female mammals. PGE and PGA have vasodilatory and diuretic effects. PGE increases cerebral blood flow and is therefore effective for diseases of the cerebrovascular system. It is also effective in treating asthma because of its bronchodilatory effect. Because of the above-mentioned properties, prostaglandins are expected to be applied to medicines, but the following three drawbacks can be cited as obstacles to this application. (i) Since prostaglandins have many of the actions mentioned above, when one action is used for treatment, the other actions become side effects. (ii) It easily loses its activity in vivo due to the action of prostaglandin-degrading enzymes, and its action is temporary. (iii) Prostaglandins are unstable with respect to temperature and are difficult to formulate into formulations. Therefore, we synthesized various prostaglandin analogs with the aim of unifying and sustaining the activity, and succeeded in synthesizing a compound that is far superior to prostaglandins in terms of (i) and (ii). . However, many of these compounds, like prostaglandins, are thermally unstable when formulated.
Particularly unstable are PGE analogue compounds, and the reason for this is that the hydroxyl group of the 5-membered ring is easily detached under the influence of the carbonyl group at the 9-position as shown below, creating a double bond and prostaglandin. This is because it becomes Jin A. Other similar compounds also contain double bonds, hydroxyl groups, etc. in their structures, making them more unstable than general medicines. Regarding stabilization of PG or PG-like compounds,
A method of converting PG or a PG-like compound into a cyclodextrin clathrate (Japanese Patent Publication No. 50-3362 or 1977-31404), adding vitamin C or citric acid to an aqueous solution of a cyclodextrin clathrate of PGE or a PGE-like compound. (Japanese Patent Publication No. 54-43570) and a method of freeze-drying by adding oligosaccharides or polysaccharides with a molecular weight of 5000 or less to an aqueous solution of cyclodextrin and citric acid of PG or PG-like compounds (Japanese Patent Publication No. 54-1989) -103844), and inclusion with cyclodextrin, addition of citric acid, and addition of oligosaccharides or polysaccharides with a molecular weight of 5000 or less are PG or PG.
It is thought to be involved in the stabilization of similar compounds. However, as a result of various studies aimed at finding an even better stabilization method for PG or PG-like compounds, the present inventors found that a system consisting of PGE or PGF or their similar compounds, cyclodextrin, and oligosaccharides was developed. We have completed the present invention by discovering that the stability of PGs is significantly improved. As shown in the table below, the composition obtained by the present invention is based on the method described in JP-A-54-103844, which is considered to be the most excellent method for stabilizing PGs that requires PGs and cyclodextrin. method, i.e.
It has a stabilizing effect comparable to that of systems consisting of PG or PG-like compounds, cyclodextrin, citric acid, and oligosaccharides or polysaccharides with a molecular weight of 5000 or less. This is not something that can be easily thought of at present, as citric acid is thought to be involved in stabilizing PGs, and furthermore, since PGs are used in medicine, it is difficult to simplify their composition. This is valuable, and the degree of use of the present invention is high. Examples of PGEs used in the present invention include:
PGE ₁ , PGE ₂ , 17(S)·20-dimethyl-trans-Δ ² -PGE ₁ , 16·16-dimethyl-trans-Δ ² -PGE ₁ , 17(S)·20-dimethyl-6-keto- Examples of PGE ₁ and their alkyl esters include 16-(3-trifluoromethylphenoxy)-ω-tetranol-
trans-Δ ² -PGE ₂ 〓, 16-(3-chlorophenoxy)-ω-tetranor-trans-Δ ² -
Examples include PGE ₂ 〓 and their alkyl esters. The cyclodextrin used in the present invention is α-,
β- or γ-cyclodextrin or two thereof
It is a mixture of the above. Examples of oligosaccharides used in the present invention include disaccharides such as maltose, lactose, and sucrose, and trisaccharides such as raffinose. The proportion of each component in the composition of the present invention is PGE or
The amount of cyclodextrin is 2 to 50 mol, preferably 3 to 15 mol, per 1 mol of PGF or a similar compound thereof. The amount of oligosaccharide is 0.1 to 100 times the weight of cyclodextrin, preferably 0.5 to 50 times the weight of cyclodextrin. The composition of the present invention can be produced by dissolving PGE or PGF or a similar compound thereof in an aqueous solution of cyclodextrin, adding an oligosaccharide or an aqueous solution thereof to dissolve it uniformly, and freeze-drying the resulting aqueous solution. be exposed. The sample used in the experiment of the stabilizing effect of the present invention was prepared as follows. 10 ml of an aqueous solution of 1.6 g of α-cyclodextrin (hereinafter abbreviated as α-CD) or 1.6 g of β-cyclodextrin (hereinafter abbreviated as β-CD) in 50 mg of PGE or PGF or similar compounds thereof
Add 80 ml and dissolve, then add 50 g of lactose and water and dissolve, then add water to bring the total volume to 1. After sterile filtration according to the usual method, 1
Fill ml each into ampoules, freeze-dry and melt.
Alpur containing citric acid was prepared in exactly the same manner except that 10 mg of citric acid was added as a control. Store each ampoule at 50°C for 30 days to ensure residual
PG or PG-like compounds and decomposition products were quantified by reverse layer chromatography. That is, 1 ml of water is added to 1 ml of lyophilized product to dissolve it, extracted 3 times with ethyl acetate, dried, and concentrated under reduced pressure. The residue was subjected to high performance liquid column chromatography using a reverse phase column (Shimadzu LC).
-3A) and a UV detector (Shimadzu SPD-
2A) and a data processor (C-RIA manufactured by Shimadzu Corporation) by a conventional method, PG or PG-like compounds and decomposition products were quantitatively analyzed. The results are shown in the table.

【table】

[Table] Next, the present invention will be explained by examples, but the present invention is not limited thereto. Example 1 Add 10 ml of an aqueous solution of 1.6 g of α-CD to 50 mg of PGE ₁ , stir until homogeneous, then add 50 g of lactose.
Add 800ml of distilled water to dissolve, and bring the total volume to 1 with distilled water. 1 ml after sterile filtration following standard method
Each sample was filled into ampoules, freeze-dried, and sealed. Example 2 17(S)・20-dimethyl-6-keto-PGE ₁ Add 1 of an aqueous solution of 160 g of α-CD to 5 g of methyl ester, stir until homogeneous, and add 5 g of lactose.
Kg and distilled water were added to uniformly dissolve the mixture, followed by freeze-drying according to a conventional method to obtain a freeze-dried powder. The composition obtained by the method of Example 1 can be used as an injection to be dissolved before use. Further, the composition obtained by the method of Example 2 can be formulated into a dosage form such as an oral preparation such as a tablet or capsule, or a suppository such as a pettuary by a conventional method.

Claims (1)

[Claims] 1 Stabilization of prostaglandin E or prostaglandin F or similar compounds thereof, characterized by freeze-drying prostaglandin E or prostaglandin F or similar compounds thereof, cyclodextrin, and oligosaccharides composition.