JPH0710833A - Prostaglandin analog, its fat emulsion and its use - Google Patents

Abstract

(57) [Summary] [Structure] A prostaglandin analog represented by the following formula [1]. [Chemical 1] A fat emulsion of a prostaglandin analog represented by the following formula [2]. [Chemical 2] (In the formula, R represents an acetyl group or a butyryl group.) A platelet aggregation inhibitor, a blood flow increasing agent and an antihypertensive agent containing the fat emulsion. A fat emulsion comprising a fat emulsion of a prostaglandin analog represented by the following formula [3]. [Chemical 3] [Effect] Prostaglandin analogs and fat emulsions are excellent in stability (heat, storage, etc.) and are excellent platelet aggregation inhibitors, blood flow increasing agents, and hypotensive agents.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a prostaglandin analog having excellent stability and long-lasting activity, its fat emulsion, and uses of the fat emulsion.

[0002]

[Problems to be Solved by the Prior Art and Invention] Prostag
Landins (hereinafter referred to as PG) are derived from polyunsaturated acids.
Is a physiologically active substance. PGE in 1960₁, PGE
₂, PGE₃, PGF₁α, PGF ₂α and PGF₃
After the structure of 6 kinds of α was determined, the discovery of PG analogs
One after another, and its physiological effects have been clarified one after another.
It was

Examples of PGs include methyl 9-acetoxy-11α, 15S-dihydroxyprosta-8,1.
3E-diene-1-oate, methyl 9,11α, 15
S-triacetoxyprosta-8,13E-diene-1
-Oate, methyl 9,15R-diacetoxy-11α
-Hydroxyprosta-8,13E-dien-1-oate, methyl 9,15S-diacetoxy-11α-hydroxyprosta-8,13E-dien-1-oate and the like (Japanese Patent Publication No. 60-33827). .

Sim, AK, et al, Arzneim-Forsch / Drug
According to Res., 1206-1209, 1986, PGs are typical of local hormones, made locally when needed,
Since it is a local hormone that acts locally, it has been proposed that a drug delivery system that takes into account its autcoid properties and chemical properties is required. In other words, the conventional method of systemic administration has a weak local effect and a strong systemic side effect, and thus lipid microspheres (l
The use of ipid microspheres (hereinafter referred to as LM) as carriers in drug release systems for PGs has been investigated. However, although the preparation is called LM here, it is actually considered to be emulsified particles of a PG-containing lipid, and this LM dispersion is also called a fat emulsion.

Further, PGE ₁ is an L having a diameter of about 0.2 μm.
By using fat emulsion-PGE ₁ (which is a target therapeutic agent) encapsulated in M, the stability of PGE _{1 in} the body is increased, and a stronger vasodilatory action and platelet aggregation inhibitory action than when PGE ₁ is directly administered. Is known to show.

Furthermore, when the fat emulsion-PGE ₁ was administered in vivo, it became clear that a considerable amount of PGE ₁ was released from LM, and studies have been reported to suppress the released amount. (Riki Igarashi, Others, Inflammation, 8 ,
[3], 243-246 (1988)). In addition, PGE
_{When 1} is released from the fat emulsion, it is easily inactivated, so that the release has an important influence on the stability of PGE ₁ .

[0007] However, this document reports that the stability of each ester of PGE ₁ as an LM preparation was measured. That is, it is examined how much PGE ₁ ester is released from the LM preparation by incubating the fat emulsion in isotonic salt (BSA-saline). From the results of this study, we are trying to predict the stability of the LM preparation in blood.

On the other hand, when the production of LM preparations to enhance the sustained release PGE ₁ (persistence), it is necessary to lipids containing PGE ₁ finely dispersed in a dispersion medium such as water. In that case, heat treatment such as heat-dissolving PGE ₁ , lipids such as fats and oils, and other materials, and homogenizing it in water at a high temperature of about 80 to 90 ° C. is required. At high temperature in heat treatment, PGE ₁ decomposes rapidly. In addition, conventional PG
The E ₁ fat emulsion has poor storage stability, and therefore PGE ₁ is rapidly decomposed even in the commercial distribution route. As described above, there is a problem that PGE ₁ and its fat emulsion are very unstable.

Although PGs have a very excellent pharmacological action, they are excellent in the stability of the drug itself and also in the preparation, and can exert excellent activity (especially excellent in local concentration). It is the actual situation that the development of new medicinal uses containing PGs as active ingredients is highly anticipated.

The object of the present invention is to provide a stable PGE ₁ analog,
An object of the present invention is to provide a PGE ₁ analog having good stability even at high temperatures. Another object of the present invention is stable P
It is an object of the present invention to provide a GE ₁ analog fat emulsion, particularly a PGE ₁ analog fat emulsion having good stability even at high temperature. Still another object of the present invention is to provide a fat emulsion having improved storage stability. Yet another object of the present invention is to provide a fat emulsion of PGE ₁ analogs having sustained PG activity.

Still another object of the present invention is to provide a platelet aggregation inhibitor containing a PGE ₁ analog, which is stable and durable and has excellent pharmacological activity. Still another object of the present invention is to provide a blood flow-increasing agent containing a PGE ₁ analog, which has stability and durability and is excellent in pharmacological activity. Still another object of the present invention is PG
The purpose of the present invention is to provide a blood pressure-lowering agent containing an E ₁ analogue, which is stable and durable and has excellent pharmacological activity.

[0012]

The first aspect of the present invention relates to a prostaglandin analog represented by the following formula [1].

[0013]

[Chemical 4]

The second invention of the present invention relates to a fat emulsion of a prostaglandin analog represented by the formula [2].

[0015]

[Chemical 5]

(In the formula, R represents an acetyl group or a butyryl group)

The PG analogs represented by the formulas [1] and [2] have various stereoisomers because they have asymmetric carbon atoms at the 9-, 11-, 12- and 15-positions. However, the present invention may be any PG analog thereof or a mixture thereof.

The third invention of the present invention relates to a platelet aggregation inhibitor comprising the fat emulsion according to the second invention.

A fourth invention of the present invention relates to a blood flow increasing agent comprising the fat emulsion according to the second invention.

The fifth invention of the present invention relates to an antihypertensive agent containing the fat emulsion according to the second invention.

The sixth invention of the present invention relates to an antihypertensive agent containing a fat emulsion of a prostaglandin analog represented by the formula [3].

[0022]

[Chemical 6]

The PG analogs represented by the formulas [1], [2] and [3] can be produced by a known method. For example, a substituted 1-iodoalkane is reacted with an alkyllithium to give a substituted 1-lithioalkene, which is then reacted with a trialkylphosphine-copper (I) iodide complex to give an organolithiocuprate. Next, this organolithiocuprate is subjected to 1,4-conjugated addition to a substituted 2-cyclopenten-1-one, and then the reaction mixture is quenched with a carboxylic acid anhydride, a carboxylic acid mixed anhydride or a carboxylic acid halide. It is manufactured by Details of this method are described in, for example, Japanese Patent Publication No. 60-33827 and Sih, et a.
l. J. Am. Chem. Soc. , 97 , 857,
865 (1975), J. Am. Am. Chem. Soc. ，
110 , 3588 (1988) and the like.

The fat emulsion described in the present specification means P
A lipid emulsifier such as a lipid containing a G analog (oil-in-water emulsion).

In the present invention, the glyceride or its and phospholipid are preferable as the lipid for producing the fat emulsion. Soybean oil is particularly preferable as the glyceride. The amount of glyceride in the fat emulsion is suitably 5 to 50% (W / V), and when phospholipid is used in combination, glyceride is 10
1 to 50 parts by weight, especially 5 to 30 parts by weight, of phospholipid
The use of parts by weight is preferred. In addition, if necessary, an emulsification aid (for example, a fatty acid having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms or a physiologically acceptable salt thereof in an amount up to 0.3% (w / v)). , Stabilizers (eg,
Cholesterol at 0.5% (w / v), preferably 0.1% (w / v) or less, or phosphatidic acid in an amount of 5% (w / v), preferably 1% (w / v) or less. Etc.), polymeric substances (for example, 0.1 to 5 parts by weight, preferably 0.5 to 1 parts by weight of albumin, dextran, vinyl polymer, nonionic surface active agent relative to 1 part by weight of PGE ₁ analog). Agents, gelatin, hydroxyethyl starch, etc.), tonicity agents (eg, glycerin, glucose, etc.)
Etc. can also be added. With respect to the present invention, the content of the PG analog in the fat emulsion of the PG analog can be appropriately changed depending on the form of the emulsion, the use, etc., but in general, an extremely small amount, for example, 100 to 0.2 μg / It is sufficient to contain the solution in an amount of ml, preferably 10 to 1 μg / ml.

The soybean oil preferably used as the glyceride herein is a highly purified soybean oil, and preferably a highly purified soybean oil (purity: Triglyceride,
99.9% or more as diglyceride and monoglyceride).

Phospholipids are purified phospholipids such as egg yolk lecithin and soybean lecithin and can be prepared by a conventional fractionation method using an organic solvent. That is, for example, crude egg yolk phospholipid is dissolved in cold n-hexane-acetone, acetone is gradually added under stirring, insoluble matter is collected by filtration, and this operation is repeated once more, and then the solvent is distilled off. By doing so, a purified phospholipid can be obtained. It mainly consists of phosphatidylcholine and phosphatidylethanolamine, and also contains phosphatidylinositol, phosphatidylserine, sphingomyelin and the like as other phospholipids.

The fatty acid having 6 to 22 carbon atoms as an emulsification aid can be used as long as it can be added to a pharmaceutical product. This fatty acid may be linear or branched, but linear stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid or the like is preferably used. These salts may be physiologically acceptable salts, and examples thereof include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metals (calcium salt, etc.), and the like.

Cholesterol or phosphatidic acid as a stabilizer may be any one that can be used for medicine. The following are preferable as albumin, vinyl polymer and nonionic surfactant used as the polymer substance. That is, as the albumin, human-derived one is used because of the problem of antigenicity. Examples of vinyl polymers include polyvinylpyrrolidone.

As the nonionic surfactant, a polyalkylene glycol (for example, an average molecular weight of 1000 to 1000) is used.
10000, preferably 4000-6000 polyethylene glycol), polyoxyalkylene copolymer (for example, average molecular weight 1000-2000, preferably 60)
00-10,000 polyoxyethylene-polyoxypropylene copolymer), hydrogenated castor oil polyoxyalkylene derivative (eg hydrogenated castor oil polyoxyethylene-
(40) -ether, same- (20) -ether, same-
(100) -ether and the like, castor oil polyoxyalkylene derivative (for example, castor oil polyoxyethylene-
(20) -ether, same- (40) -ether, same-
(100) -ether and the like can be used.

The fat emulsion of the present invention is produced, for example, by the following method. That is, a predetermined amount of soybean oil, phospholipids, PG analogs and other additives described above are mixed,
Heat to form a solution and use a standard homogenizer (for example,
A pressure-injection type homogenizer, an ultrasonic homogenizer, etc.) is used to make a water-in-oil dispersion by homogenizing at a temperature of about 80 to 90 ° C., and then a necessary amount of water is added to The fat emulsion of the present invention can be produced by homogenizing with the homogenizer and converting into an oil-in-water emulsion. Depending on production convenience, additives such as stabilizers and isotonic agents may be added after the formation of the fat emulsion.

The PG analog of the present invention, and by extension, its fat emulsion, especially the prostaglandin analog of the formula [2], and its fat emulsion have a platelet aggregation inhibitory action and a blood flow increasing action (especially for peripheral and brain). ), Has a blood pressure lowering action, etc., and is useful as a platelet aggregation inhibitor, a blood flow increasing agent, a blood pressure lowering agent and the like. More specifically, in addition to treatment of chronic arterial occlusion (Buerger's disease, arteriosclerosis obliterans), extremities, skin ulcers, peripheral blood circulation disorders, vibration diseases, arterial tube-dependent congenital heart disease, etc., antiplatelet It is also useful as a coagulant, especially as a therapeutic agent for thrombosis, therapeutic agent for cerebral infarction, myocardial infarction and the like. Further, due to the above-mentioned effects, it is also useful as a vasodilator as a therapeutic agent for hypertension, ischemic heart disease (angina, etc.), and cerebral and peripheral circulatory disorders (transient cerebral ischemic attack, etc.). . Further, the prostaglandin analog represented by the formula [3] has a hypotensive action and is useful as a hypotensive agent.

The fat emulsion of the present invention, of course, has the pharmacological activity of PG and can be administered orally or parenterally. When the administration is, for example, intravenous administration, the administration is performed as an adult PG analog by 1 to 1 per day.
It is carried out by continuous intravenous infusion once a day at a rate of 1000 μg, 0.02-2000 ng / kg / min.

[0034]

EXAMPLES The present invention will be specifically described below with reference to examples of fat emulsifiers of the present invention and examples of PG analog synthesis, but the present invention is not limited to these examples.

Example 1 Butyl 9-butyroxy-11α, 15S-dihydroxy
Synthesis of cyprosta-8,13E-diene-1-oate

[0036]

[Chemical 7]

(1E, 3S) -1-iodo-3- (t-
Butyldimethylsiloxy) -1-octene (4.95
g, 13.44 mmol) in ether (100 ml)-
After cooling to 78 ° C., t-butyllithium (f = 1.5 hexane solution 18.1 ml, 27.1 mmol) was added dropwise. After stirring at the same temperature for 2 hours, a solution of tributylphosphine-copper (I) iodide complex (4.63 g, 12.31 mmol) and tributylphosphine (2.92 ml, 12.16 mmol) in ether (40 ml) was added dropwise. After stirring at −78 ° C. for 50 minutes, 4R-t-butyldimethylsiloxy-2- (6-carbobutoxyhexyl) -2-cyclopenten-1-one (4.75 ml, 11.3 mmol) in ether (160 m).
l) The solution was added dropwise. 20 minutes at −78 ° C., then −23
After stirring for 35 minutes at ~ -18 ° C, butyric anhydride (3.0 m
(1, 30 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. to room temperature for 15 hours. A saturated aqueous ammonium sulfate solution (200 ml) was added to separate the organic layer, and then the aqueous layer was ether (100 m).
l) extracted twice, and the combined organic layers were saturated brine (120 m
l) washed. After dried over anhydrous magnesium, filtered,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography at 0 ° C. (hexane: ethyl acetate = 20: 1 to 1: 1).
4: 1) and the adduct was obtained. The produced adduct (5.50 mg, 8.25 mmol) was added to acetonitrile (10
0 ml) and 40% hydrofluoric acid aqueous solution (1
0 ml) was added and the mixture was stirred at the same temperature for 30 minutes. 2 reaction solutions
It was poured into a mixture of 0% potassium carbonate aqueous solution (150 ml) and methylene chloride (150 ml). After drying over magnesium sulfate, the mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel at 0 ° C. (methylene chloride: acetone = 2:
Purification in 1) gave the labeled compound in a yield of 73.6%.

¹ H-NMR (CDCl ₃ ): δ 0.86 (9
H, m), 1.2-2.42 (29H, m), 2.8-2.95 (1H, m), 3.0-3.1
(1H, m), 4.0-4.2 (4H, m), 5.4-5.7 (2H, m).

The title PG analog 500 produced as described above
Purified soybean oil 10 g and purified egg yolk lecithin 1.2 μg
g was added, and the mixture was heated and dissolved at 90 ° C using a homogenizer at 90 ° C. To this, 2.5 g of Japanese Pharmacopoeia glycerin and 90 ml of distilled water for injection were added, and the mixture was coarsely emulsified at 90μ using a homogenizer. This was emulsified using a Manton-Gaurin homogenizer to prepare a fat emulsion having a final concentration of 5 μg / ml.

Example 2 Butyl 9-acetoxy-11α, 15S-dihydroxy
Synthesis of cyprosta-8,13E-diene-1-oate

[0041]

[Chemical 8]

(1E, 3S) -1-iodo-3- (t-
Butyldimethylsiloxy) -1-octene (4.95
g, 13.44 mmol) in ether (100 ml)-
After cooling to 78 ° C., t-butyllithium (f = 1.5 hexane solution 18.1 ml, 27.1 mmol) was added dropwise. After stirring at the same temperature for 2 hours, a solution of tributylphosphine-copper (I) iodide complex (4.63 g, 12.31 mmol) and tributylphosphine (2.92 ml, 12.16 mmol) in ether (40 ml) was added dropwise. After stirring at −78 ° C. for 50 minutes, 4R-t-butyldimethylsiloxy-2- (6-carbobutoxyhexyl) -2-cyclopenten-1-one (4.75 ml, 11.3 mmol) in ether (160 m).
l) The solution was added dropwise. 20 minutes at −78 ° C., then −23
After stirring for 35 minutes at ~ -18 ° C, butyric anhydride (3.0 m
(1, 30 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. to room temperature for 15 hours. A saturated aqueous ammonium sulfate solution (200 ml) was added to separate the organic layer, and then the aqueous layer was ether (100 m).
l) extracted twice, and the combined organic layers were saturated brine (120 m
l) washed. After dried over anhydrous magnesium, filtered,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography at 0 ° C. (hexane: ethyl acetate = 20: 1 to 1: 1).
4: 1) and the adduct was obtained. The produced adduct (5.50 mg, 8.25 mmol) was added to acetonitrile (10
0 ml) and 40% hydrofluoric acid aqueous solution (1
0 ml) was added and the mixture was stirred at the same temperature for 30 minutes. 2 reaction solutions
It was poured into a mixture of 0% potassium carbonate aqueous solution (150 ml) and methylene chloride (150 ml). After drying over magnesium sulfate, the mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel at 0 ° C. (methylene chloride: acetone = 2:
1) to obtain the title compound (340 mg, yield 53)
%).

¹ H-NMR (CDCl ₃ ): δ0.85 (3H,
t, J = 7Hz), 0.95 (3H, t, J = 7Hz), 1.2-2.9 (29H, m + s
(δ 2.15, 3H, s)), 3.0-3.05 (1H, m), 4.1 (2H, t,
J = 7Hz), 4.0-4.2 (2H, m), 5.45 (1H, dd, J = 7Hz), 5.6
(1H, dd, J = 7.1Hz).

The title PG analog 500 produced as described above
Purified soybean oil 10 g and purified egg yolk lecithin 1.2 μg
g was added, and the mixture was heated and dissolved at 90 ° C using a homogenizer at 90 ° C. To this, 2.5 g of Japanese Pharmacopoeia glycerin and 90 ml of distilled water for injection were added, and the mixture was coarsely emulsified at 90μ using a homogenizer. This was emulsified using a Manton-Gaurin homogenizer to prepare a fat emulsion having a final concentration of 5 μg / ml.

Example 3 Butyl 9-acetoxy-11α, 15S-dihydroxy
Sea-17S, 20-dimethylprostar-8,13E-di
Synthesis of ene-1-oate (formula [3]) (1E, 3S, 5S) -1-iodo-3- (t-butyldimethylsiloxy) -5-methyl-1-nonene (5.3
A solution of 8 g, 13.56 mmol) in ether (100 ml) was cooled to -78 ° C and t-butyllithium (f = 1.5 hexane solution 18.1 ml, 27.1 mmol) was added dropwise. After stirring at the same temperature for 2 hours, a solution of tributylphosphine-copper (I) iodide complex (4.63 g, 12.31 mmol) and tributylphosphine (2.92 ml, 12.16 mmol) in ether (40 ml) was added dropwise. After stirring at −78 ° C. for 50 minutes, 4R-t-butyldithymersiloxy-2- (6-carbobutoxyhexyl) -2-cyclopenten-1-one (4.75 ml, 11.3 mmol) in ether (160 ml).
The solution was added dropwise. 20 minutes at −78 ° C., then −23 to −
After stirring at 18 ° C for 35 minutes, acetic anhydride (3.0 ml, 3 ml
(0 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. to room temperature for 15 hours. Add saturated ammonium sulfate aqueous solution (200 ml),
After separating the organic layer, the aqueous layer was washed with ether (100 ml).
It was extracted twice, and the combined organic layer was washed with saturated brine (120 ml). After drying over anhydrous magnesium, it was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 20: 1 to 4: 1) at 0 ° C to obtain an adduct. The adduct prepared (5.50 mg, 8.
25 mmol) is dissolved in acetonitrile (100 ml) and 0
40% Hydrofluoric acid aqueous solution (10 ml) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into a mixed solution of 20% potassium carbonate aqueous solution (150 ml) and methylene chloride (150 ml). After drying over magnesium sulfate, the mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride: acetone = 2: 1) at 0 ° C. to give the title compound (3.27 g, yield 83%).

[0046] _{^{1 H-NMR (CDC1 3)}} : δ0.8 -1.0
(9H, m), 1.2-2.9 (30H, m + s (δ2.15, 3H)), 3.1 (1H,
m), 4.05 (2H, t, J = 7Hz), 4.1-4.2 (2H, m), 5.48 (1H, d
d, J = 7.1Hz), 5.6 (1H, dd, J = 7Hz). The PG analog 50 represented by the formula [3] produced by the above
Purified soybean oil to 0 μg 10 g to purified egg yolk lecithin 1.2 g
Was added, and the mixture was heated and dissolved at 90 ° C using a homogenizer at 90 ° C. To this, 2.5 g of Japanese Pharmacopoeia glycerin and 90 ml of distilled water for injection were added, and the mixture was coarsely emulsified at 90μ using a homogenizer. This was emulsified using a Manton-Gaurin homogenizer to prepare a fat emulsion having a final concentration of 5 μg / ml.

[0047]

[Operation and effect of the invention]

Test Example 1 The stability of each PG analog fat emulsion produced in each of the above Examples and the PGE ₁ fat emulsion produced in the same manner as above was compared, and the results are shown in Table 1. The test method is as follows. In addition, the measurement of the residual rate in the stability test,
Using a separation and quantification method by high performance liquid chromatography,
The residual amount was the measured amount relative to the amount at the start of the test.

(Stability Test Method) The fat emulsion produced in each example was stored at a temperature of 80 ° C. for 16 hours, and the residual rate (%) after 16 hours was measured. For comparison, PG
A similar process was performed on E ₁ to prepare a fat emulsion, which was tested in the same manner. The results are as shown in Table 1.

[0049]

[Table 1]

As is clear from the above results, the fat emulsion of the PG analog of the present invention and thus the PG analog is
It has a superior stabilizing effect as compared with the E ₁ fat emulsion.

Test Example 2 The platelet aggregation inhibitory effect was measured as follows, and the results are also shown in Table 2. The test method is as follows.

Human peripheral blood collected using sodium citrate (3.8%) (9 parts by volume of blood, 1 part by volume of sodium citrate) was centrifuged at 1000 rpm for 10 minutes to obtain a platelet rich plasma. Fractions were collected, and the remainder was centrifuged at 3000 rpm for 20 minutes to collect plate poor plasma. 50 μl of each sample prepared in the example was put into 225 μl of platelet rich plasma, and 1 minute later, 20 μM ADP solution 2
Platelet aggregation was induced with 5 μl, and the aggregation rate when physiological saline was added instead of the sample was set to 100%, and the aggregation inhibition rate (%) was calculated. The results are shown in Table 2.

[0053]

[Table 2]

The fat emulsions of the PG analogs of the present invention and thus the PG analogs all showed excellent inhibition of platelet aggregation.

Test Example 3 (Blood flow increasing action, blood pressure lowering action) Test method 1) Preparation of diabetic rats For diabetic rats, streptozotocin (hereinafter STZ, citrate buffer (dissolved in pH 4.5) 60 mg / 3 ml).
/ Kg was administered once intravenously.

2) Method for measuring carotid blood pressure and foot skin blood flow Animals were anesthetized with urethane 1.2 g / kg ip and fixed in the dorsal position. The neck was incised, a polyethylene catheter was inserted into the common carotid artery, and blood pressure was monitored via a pressure transducer. In addition, a skin probe is attached to the skin of the toes of the right hind leg, and ADVANCE LASER FLOWMETER (MOD
Skin blood flow was measured using EL: ALF2100). The test drug was administered through the tail vein while the blood flow was stable, and changes in blood flow and blood pressure were observed. Regarding blood flow, strength (maximum increase rate relative to pre-administration value) and duration (10
The time when the increase is more than%) was calculated. As for blood pressure, the maximum blood pressure reduction rate of the average blood pressure was obtained.

3) Preparation Method and Administration Method of Test Drug The test drug was diluted with Vehicle before use. The liquid dose of the drug was 0.5 ml / 1 kg, and pourous was administered through the tail vein. The number of cases was 5 in all.

[0058]

[Table 3]

It has been found that the fat emulsion of the present invention has a blood flow increasing action, and the action continues.

[0060]

[Table 4]

Both the fat emulsions of the present invention were found to have a blood pressure lowering action.

Test Example 4 (Cerebral blood flow increasing action) Adult dogs (body weight: 9 to 16 kg, 4 animals per group) were intravenously administered with various test agents at a dose of 0.3 μg / kg body weight, and then cerebral blood was sequentially changed. The flow rate was measured and the rate of blood flow increase was calculated. Cerebral blood flow is measured by attaching an electromagnetic flow meter probe to the left vertebral artery,
Continuous recording on a polygraph. The number of cases was 4 in each group. The results are shown in Table 5.

[0063]

[Table 5]

Both of the fat emulsions of the present invention were found to have a cerebral blood flow increasing action.

Test Example 5 (Hypotensive action) As a test animal, a dog having a body weight of 7 to 12 kg was used. 1 group 3
I made it The animals were anesthetized by intravenous administration of sodium pentobarbital and fixed in the dorsal position. The systolic and diastolic arterial pressure was measured by a pressure transducer (Statham P-5) using a polyethylene catheter inserted in the right femoral artery.
0; Gould, Inc.) was measured by intervening and continuously recorded on a polygraph. The fat emulsion prepared in Example 3 was continuously administered into the right cutaneous vein using a drip pump. The administration rate is 0.
1 ml / kg body weight / minute and the drip time was 30 minutes. And
The degree of blood pressure drop was examined. The results are shown in Table 6.

[0066]

[Table 6]

The fat emulsion of Example 3 was found to have a blood pressure lowering action.

Test Example 6 (toxicity) When the fat emulsion of the present invention was administered through the tail vein of mice (body weight 20 to 25 g), the dose of each of the fat emulsions of Examples 1, 2 and 3 was 10 mg (as a PG analog). No case of death per kg body weight was observed.

In addition to the above-mentioned effects, the PG analog fat emulsion of the present invention is expected to have effects such as sustained release, lesion selectivity, fast-acting effect, and reduction of side effects.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (71) Applicant 000137764 Midori Cross Co., Ltd. 1-3-3 Imabashi, Chuo-ku, Osaka-shi, Osaka (72) Inventor Yu Mizushima 1-1-11 Umeoka, Setagaya-ku, Tokyo (72) ) Inventor Riki Igarashi 3-3-12 Minami Ikuta, Tama-ku, Kawasaki City, Kanagawa Prefecture (72) Inventor Toshihide Inoma 2-5-1-5 Nihonbashihonmachi, Chuo-ku, Tokyo Seikagaku Corporation (72) Inventor Yasuda Shin-Kanagawa, Kanagawa-ku, Kanagawa-ku, 3-18-18 Kandaiji (72) Inventor Kureyo Araki 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor, Imakawa Hirakata, Osaka Invited 2-25-1 Otani Co., Ltd. Midori Cross Central Research Institute (72) Inventor Takeshi Uchida Invited 2-25-1 Otani Otani, Hirakata, Osaka Central within the Institute

Claims (6)

[Claims] 1. A prostaglandin analog represented by the following formula [1]. [Chemical 1] 2. A fat emulsion of a prostaglandin analog represented by the following formula [2]. [Chemical 2] (In the formula, R represents an acetyl group or a butyryl group) 3. A platelet aggregation inhibitor comprising the fat emulsion according to claim 2. 4. A blood flow increasing agent comprising the fat emulsion according to claim 2. 5. A blood pressure lowering agent comprising the fat emulsion according to claim 2. 6. A prostaglandin chloroplast represented by the following formula [3] (butyl-9-acetoxy-11α, 15S).
-Dihydroxy-17S, 20-dimethylprostar
8.13 E-dien-1-oate), a hypotensive agent comprising a fat emulsion. [Chemical 3]