JPH04342530A - 7-fluoroprostacyclin fatty emulsion - Google Patents

Abstract

PURPOSE:To provide the subject stable fatty emulsion containing a 7- fluoroprostacycline useful as a drug for circulatory organs, e.g. an antithrombotic drug as the active component. CONSTITUTION:A fatty emulsion containing a chemically stable compound of the formula (R<1> is H or alkyl; R<2> is F; R<3> is 1-10C alkyl which may be substituted or cycloalkyl which may be substituted), e.g. 7-fluoro-1,6,17,18,19,20- pentanol-15-cyclopentylprostacycline as the active component. The above- mentioned fatty emulsion is mainly composed of a 7-fluoroprostacycline, 5-50W/V% soybean oil, preferably high-purity refined soybean oil, a phospholipid (e.g. yolk lecithin or soybean lecithin) in an amount of 1-50 pts.wt., preferably 5-30 pts.wt. based on 100 pts.wt. soybean oil and a proper amount of water and an auxiliary emulsifier, a stabilizer, an isotonicity forming agent, such as a polymer substance are added thereto as necessary.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to fat emulsions containing 7-fluoroprostacyclines.

More specifically, the present invention relates to a new fat emulsion containing 7-fluoroprostacyclin as an active ingredient, which is useful as a cardiovascular agent including an antithrombotic agent.

0003

[Prior Art] Prostaglandins (PGs) exhibit a wide variety of physiological activities, and are used as pharmaceuticals due to their various useful physiological effects such as improving peripheral circulation, dilating blood vessels, anti-ulcer, lowering blood pressure, regulating pregnancy, anti-thrombotic, and anti-asthma. It is being used as a. Recently, applications in new fields such as anti-cancer, bone metabolism improvement, anti-virus, liver protection, and diuresis are being considered.

However, when using these useful PGs as medicines, there are many problems such as side effects due to the in vivo instability and wide range of physiological effects of PGs, and difficulty in formulation due to chemical instability. There is a problem.

Among these, natural prostacyclin is a local hormone produced primarily in the inner walls of arteries in the living body, and its powerful physiological activities, such as platelet aggregation inhibitory activity and vasodilatory activity, regulate the cellular functions of the living body. Efforts are being made to directly provide this substance as a pharmaceutical product [P.J. Lewis, J.O.
．． O. Grady et al., “Clinical Pharmacology of Prostacyclin.
Pharmacology of Prostacy
clin)”, Raven Pre
ss), New York (N.Y.) (1981)]
.

However, since natural prostacyclin has an enol ether bond in its molecule that is highly susceptible to hydrolysis, it is easily deactivated under neutral or acidic conditions, and due to its chemical instability, it is not a preferred compound as a pharmaceutical. I can't say that. For this reason, chemically stable synthetic prostacyclin derivatives that have physiological activities similar to natural prostacyclin have been intensively investigated at home and abroad.

On the other hand, efforts have been made to stabilize chemically unstable prostacyclin as a preparation and to improve its medicinal efficacy. For example, a method of stabilizing it as an inclusion compound using cyclodextrin (see Joseph Suseshitri et al., Japanese Patent Application Publication No. 54-56685), a method of stabilizing it with a surfactant (Mu Yan Chou et al., Japanese Patent Application Publication No. 54-56685), (Refer to Publication No. 55-15470), a novel ester derivative of prostacyclin with increased fat solubility was obtained, and this ester derivative was used as a fat emulsion to form a preparation that maintained the same activity as the original prostacyclin (Fukaya et al. , JP-A-60-13779), etc. have been proposed.

On the other hand, in recent years, PGE1 and PGA have been developed as stabilized prostaglandins as fat preparations.
1 has been proposed for the purpose of vasodilatory effect, platelet aggregation inhibition, and hypotensive effect [Mizushima et al., JP-A-58-222014, JP-A-59-1415].
No. 18 and Mizushima et al., Ann. Rheum.
Seasons), 41, 263 (1982); Journal of Pharmacy and Pharmacol., 3
5,398 (1983)]. This method has also been applied to anticancer drugs, and proposals have been made to improve the selective reach of anticancer drugs to target organs (Okamoto et al.
(See Publication No. 122423).

[0009]

Purpose of the Invention The present inventors focused on this fact, and as a result of intensive research in order to maintain the action and enhance the clinical effect of a specific stable prostaglandin I2 class, we found that the stable prostaglandin I2 When a preparation was prepared by encapsulating grandin I2 in LM, it was discovered that such a preparation could achieve these objectives, and the present invention was achieved. An object of the present invention is to provide a novel fat emulsion containing the conventionally known chemically stable prostaglandin I2 class. This fat emulsion has a sustained action and is a useful preparation for intravenous administration.

0010

[Structure and effects of the invention] The present invention is based on the following formula [I]

001
1]

[In the formula, R1 is a hydrogen atom or an alkyl group, and R1 is a hydrogen atom or an alkyl group,
2 is a fluorine atom, and R3 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group having 1 to 10 carbon atoms. ] This is a fat emulsion containing 7-fluoroprostacyclin.

The 7-fluoroprostacyclines of the above formula [I] are compounds known as stabilized prostaglandins I2 (Japanese Unexamined Patent Publications No. 150583/1983 and No. 32981/1983).

As related to the present invention, the following formula [I
a]

[0014]

embedded image [In the formula, R1 and R3 are the same as defined above. R2' represents a hydrogen atom. ] Examples include isocarbacyclines represented by the following.

In the above formula [I], R1 represents a hydrogen atom or an alkyl group. Examples of such alkyl groups include alkyl groups having 1 to 10 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, and decyl. R1 is preferably a hydrogen atom or a methyl group.

In the above formula [I], R3 has 1 carbon number
~10 substituted or unsubstituted alkyl groups, or substituted or unsubstituted cycloalkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, butyl,
Examples include pentyl, hexyl, octyl, and decyl groups. Examples of the cycloalkyl group include cyclopentyl and cyclohexyl groups. Examples of substituents for these alkyl groups and cycloalkyl groups include those having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, and hexyl groups.
alkyl groups; halogen atoms such as fluorine and chlorine; lower alkoxy groups such as methoxy, ethoxy, propoxy and butoxy groups; and halogenated alkyl groups such as trifluoromethyl groups.

The 7-fluoroprostacyclines of formula [I] can be produced, for example, by the methods described in JP-A-58-150583 and JP-A-57-32981.

Specific examples of stable 7-fluoroprostacyclines represented by the above formula [I] are as follows. Note that (1) to (4) are examples related to formula [Ia]. (1) Isocarbacycline (2) 16,17,18,19,20-pentanol-15-cyclopentyl isocarbacycline (3)
16,17,18,19,20-pentanol-15-
Cyclohexylisocarbacycline (4) 17,
20-dimethylisocarbacycline (5) 7-fluoroprostacycline (6) 7-fluoro-1
6,17,18,19,20-pentanol-15-cyclopentylprostacyclin (7) 7-fluoro-16,17,18,19,2
0-Pentanol-15-cyclohexylprostacyclin (8) 7-fluoro-17,20-dimethylprostacyclin (9) 7-fluoro-16,16-dimethylprostacyclin (10) 7,16-difluoroprostacycline (1
1) Methyl esters of (1) to (10).

The fat emulsion of the present invention contains 7-fluoroprostacyclin of formula [I], 5 to 50 w/v% soybean oil, 1 to 50 parts, preferably 5 to 50 parts per 100 parts of soybean oil.
It consists primarily of 30 parts of phospholipids and a suitable amount of water.

The soybean oil is a high-purity refined soybean oil, preferably a high-purity refined soybean oil obtained by further refining the refined soybean oil by, for example, steam distillation (purity: 99.9% as triglyceride, diglyceride, and monoglyceride). 9%
or more).

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 phospholipids are dissolved in cold n-hexane-acetone, acetone is gradually added under stirring, insoluble materials are collected by filtration, this operation is repeated one more time, and then the solvent is distilled off. Purified phospholipids can be obtained by It mainly consists of phosphatidylcholine and phosphatidylethanolamine. Other phospholipids include phosphatidylinositol, phosphatidylserine, sphingomyelin, and the like.

[0022] In the fat emulsion of the present invention, emulsifying aids, stabilizers, tonicity agents such as polymeric substances, etc. can be further added as required.

[0023] As the emulsification auxiliary agent, for example, 0.3 w/v
% of fatty acids having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms, or physiologically acceptable salts thereof. Any fatty acid having 6 to 22 carbon atoms can be used as long as it can be added to medicines. Such fatty acids are linear,
It may be branched, and linear stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, etc. are preferred. As these salts, physiologically acceptable salts such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, etc. can be used.

[0024] As the stabilizer, for example, 0.5 w/v%
The following examples include cholesterol in an amount of preferably 0.1 w/v % or less or phosphatidic acid in an amount of 5 w/v % or less, preferably 1 w/v % or less.

[0025] Cholesterol and phosphatidic acid can be used as long as they can be used medicinally.

[0026] Examples of the polymeric substance include albumin, Textran, vinyl polymer, and non-albumin in an amount of 0.1 to 5 parts by weight, preferably 0.5 to 1 part by weight, per 1 part by weight of 7-fluoroprostacyclin. Examples include ionic surfactants, gelatin, and hydroxyethyl starch.

As the albumin, vinyl polymer and nonionic surfactant, the following are preferred. That is, as albumin, human-derived albumin is used due to antigenicity issues. Examples of vinyl polymers include polyvinylpyrrolidone. Nonionic surfactants include polyalkylene glycols (for example, those with an average molecular weight of 1
000 to 10,000, preferably 4,000 to 6,000), polyoxyalkylene copolymers (e.g., polyoxyethylene-polyoxypropylene copolymers with an average molecular weight of 1,000 to 20,000, preferably 6,000 to 10,000), hydrogenated castor oil Polyoxyalkylene derivatives (for example, hydrogenated castor oil polyoxyethylene-(40)-ether, hydrogenated castor oil polyoxyethylene-(20)-ether, hydrogenated castor oil polyoxyethylene-(100)-ether, etc.), castor oil polyoxyalkylene derivatives (for example, castor oil polyoxyethylene Oxyethylene-(20)-ether, oxyethylene-(40)-ether, oxyethylene-(100)-ether, etc. can be used.

The content of 7-fluoroprostacyclines in a fat emulsion can be increased or decreased as appropriate depending on the form of the emulsion and its intended use, but generally a very small amount of 7-fluoroprostacyclin, for example 1.
It is sufficient to contain 0 mg to 0.2 μg/ml.

The fat emulsion of the present invention is produced, for example, by the following method. That is, predetermined amounts of soybean oil, phospholipids, 7-fluoroprostacyclines, and other additives are mixed and heated to form a solution, and then processed using a common homogenizer.
For example, the fat emulsion of the present invention can be produced by homogenizing using a pressure injection type homogenizer, ultrasonic homogenizer, etc., then adding the required amount of water, and homogenizing again using the former homogenizer. . Depending on manufacturing convenience, additives such as stabilizers and tonicity agents may be added after the production of the fat emulsion.

The fat emulsion of the present invention can be administered parenterally, such as by injection, and intravenous administration is particularly preferred. For example, the administration may include 1 to 7-fluoroprostacyclines.
1000μg/kg, 0.02-2000ng/kg/
It is administered by continuous intravenous infusion once a day. The fat emulsion of the present invention has strong action and sustained release properties,
Due to its focus-selectivity, effective treatment is possible with small doses.

[0031] Since it can be administered intravenously, rapid efficacy can be expected, and the drug's efficacy is stable. Furthermore, since the dosage may be small, side effects are less likely to occur.

Furthermore, the particles are extremely fine, with an average particle size of 1.0 μm or less, and the storage stability is extremely good.

[0033]

[Example] The present invention will be specifically explained below by giving an example of preparation of the preparation of the present invention and an example of the duration of action on human platelets, but the present invention is not limited to these. .

[0034]

[Reference Example 1] Isocarbacycline (Compound I) Encapsulation 1
Preparation of 0% soybean oil-containing fat emulsion (LM) Dissolve in soybean oil and encapsulate the compound by the method described above (LM) (fat emulsion I)
to prepare LM containing 10% soybean oil with a final concentration of 10 μg/ml.

[0035]

[Example 1 and Reference Examples 2 and 3] 16, 17, 18, 19
, 20-pentanol-15-cyclopentylisocarbacycline (Compound II), 7-fluoro-16,17
, 18,19,20-pentanol-15-cyclopentyl prostacyclin methyl ester (compound III), and isocarbacycline methyl
Preparation of 10% soybean oil-containing fat emulsion (LM) encapsulating ester (compound IV) Compound (III) as Example 1, Reference Example 2,
Compounds (II) and (IV) as 3 were prepared in the same manner as in Reference Example 1, and the final concentrations of 10 μg/ml, 5 μg/ml, and 10 μg/ml, respectively, were prepared.
% soybean oil containing LM was prepared.

[0036]

[Examples 2-4, Comparative Examples 1-3, Reference Examples 4-18] Evaluation of drug activity using human platelets Cyclic AMP (Cyclic AMP) of the fat emulsion of the present invention
The time course of icAMP) production was measured using human platelets and compared to that of the non-fat emulsified compound. 50 ml of human blood was collected at a ratio of 9 volumes of blood to 1 volume of 3.8% sodium citrate, and the mixture was heated at 1300 rpm 10
Centrifuged for minutes. Separate the upper layer as PRP (platelet rich plasma) 300
The precipitate (platelets) obtained by centrifugation at 0 rpm for 20 minutes was mixed with Tris buffer-saline-glucose-EDTA (pH 7.
4) Float in 2 ml.

[0037] In advance, attach a T to the plastic tube.
After adding 350 μl of SG-EDTA and 50 μl of platelet suspension and warming to 37°C, fat emulsion was added, and at a predetermined time (between 0 and 120 minutes) 5 m
50 μl of M isobutylmethylxanthine was added, and the reaction was stopped after 2 minutes with 0.5 ml of 10% trichloroacetic acid. Cells are disrupted by freezing and thawing, and intracellular cyclic
After liberating AMP and removing TCA with water-saturated ether, the amount of cAMP was quantified by radioimmunoassay.

The results are shown in Table 1. As is clear from this, it was found that the C-AMP producing ability of the fat emulsion was well maintained over time.

[0039]

[Table 1]

Compound (I): Isocarbacycline compound (II): 16,17,18,19,20-pentanol-15-cyclopentylisocarbacycline compound (III): 7-fluoro-16,17,18,19
,20-pentanol-15-cyclopentyl prostacyclin methyl ester

Claims (3)

[Claims] [Claim 1] The following formula [I] [In the formula, R1 is a hydrogen atom or an alkyl group, and R
2 is a fluorine atom, and R3 represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted cycloalkyl group. ] 7-
Fat emulsion containing fluoroprostacyclins. 2. The fat emulsion containing 7-fluoroprostacyclines according to claim 1, wherein R1 is a hydrogen atom or a methyl group. 3. The fat emulsion containing 7-fluoroprostacyclines according to claim 1 or 2, wherein R3 is a pentyl group, a 2-methylhexyl group, or a cyclopentyl group.