JPH08277222A - Preventing and therapeutic agent for neuropathy - Google Patents

Abstract

PURPOSE: To obtain the subject medicine, containing prostaglandin E1 or its derivative as an active ingredient and useful for preventing and treating nonischemic or apotosis-intervening neuropathy such as Alzheimer disease or amyotrophic lateral sclerosis. CONSTITUTION: This preventing and therapeutic agent contains prostaglandin E1 (PGE1 ) or its derivative as active ingredient. A 9-acyloxy derivative of PGE1 such as 9-butyryloxy-11d,11S-dihydroxyprosta-8,13E-dien-1-oate is preferred as the active ingredient. The PGE1 s are preferably prepared into the form of a fat emulsion from the viewpoint of sustained releasability, persistence, local accumulating properties and preservation stability and preferably obtained by thermally dissolving a purified egg yolk phospholipid which is an emulsifying agent and PGE1 s in a high-purity refined soybean oil and dispersing the oily ingredient in purified water. The objective medicine is preferably intravenously administered according to a method for sustained infusion thereof, e.g. in 1-100μm daily dose expressed in terms of the PGE1 s once at 0.01-1000ng/kg body weight/min rate.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to prostaglandin E.
₁ (hereinafter referred to as “PGE ₁ ”) and a derivative thereof, and more particularly to a prophylactic / therapeutic agent containing these as active ingredients for preventing and / or treating a neurological disease having a special aspect. .

[0002]

[Prior Art and Problems to be Solved by the Invention] PGE ₁
Is present in a small amount in the living body and has various physiological actions such as vasodilating action, blood pressure lowering action, angiogenic action, platelet aggregation inhibiting action, epithelial regeneration promoting action, etc., and is a therapeutic agent for peripheral blood flow disorders. Is already on the market.

[0003]

The present inventors have found that PGE ₁
Or a derivative thereof (hereinafter collectively referred to as “PGE _{1 s} ”) is useful as a prophylactic / therapeutic agent for a neurological disease having a special mode, that is, a non-ischemic or apoptosis-mediated neurological disease. Heading
The present invention has been completed. Regarding the relationship between PGE ₁ and neurological diseases, application to anoxic diseases of cerebral nerve cells (JP-A-59-73522), application to diabetic peripheral neuropathy (JP-A-1-316323) and the like are applicable. It has been reported. However, nothing is mentioned regarding the relationship with the neurological diseases in the above-mentioned special mode, that is, the non-ischemic or apoptotic-mediated neurological diseases, and this finding is completely unexpected.

PG which is an active ingredient of the prophylactic / therapeutic agent of the present invention
E ₁ compound is a concept including PGE _1, derivatives having PGE ₁ activity, those expressing PGE ₁ activity is converted into PGE ₁ in vivo (PGE ₁ precursor) or the like. PGE
_As a derivative having _1- activity, a 7-thio compound (Japanese Patent Laid-Open No. 58-58)
No. 110562). Specifically 7
-Thio-PGE _{1 and the} like are exemplified.

The PGE ₁ precursor that can be used in the present invention is not particularly limited as long as it is a compound that can be converted into PGE ₁ and exhibit PGE ₁ activity in vivo.

[0006] The PGE ₁ include, for example, PGE ₁ alkyl ester (JP 59-216820 JP), alkoxycarbonylalkyl esters or acyloxyalkyl esters (JP 59-206
344, JP-A-60-13779), 9-
An acyloxy compound (JP-A-58-39660, JP-A-3-204853, JP-A-5-213862), a 7-thio compound (JP-A-58-110562), and the like are preferable, and preferably. It is a 9-acyloxy form.

The alkyl in the alkyl ester form, the alkoxycarbonylalkyl ester form and the acyloxyalkyl ester form is preferably an alkyl group having 1 to 30 carbon atoms, more preferably 1 to 10 carbon atoms. The alkoxy in the alkoxycarbonylalkyl ester form is preferably an alkoxy having 1 to 15 carbon atoms, more preferably 3 to 10 carbon atoms. The acyl in the acyloxyalkyl ester form preferably has 1 to 1 carbon atoms.
5, more preferably, acyl having 3 to 10 carbon atoms. 9-
The acyl in the acyloxy form preferably has 2 carbon atoms.
~ 6, more preferably acyl having 2 to 4 carbon atoms.

PGE₁The alkyl ester form of
Specifically, PGE₁Methyl ester, PGE₁ethyl
Ester, PGE₁Propyl ester, PGE₁Butyl
Ester, PGE₁Pentyl ester, PGE₁Octi
And the like. PGE₁The alkoxycar
Specific examples of the bonylalkyl ester compound include PG
E₁Butoxycarbonyl methyl ester, PGE₁Heki
Syloxycarbonyl methyl ester, PGE₁Octi
Luoxycarbonyl methyl ester, PGE ₁Desirou
Examples include oxycarbonyl methyl ester and the like. PGE
₁Specific examples of the acyloxyalkyl ester of
In the PGE₁Acetoxymethyl ester, PGE₁Pi
Valoyloxymethyl ester, PGE ₁1-acetoki
Ciethyl ester, PGE₁1-hexanoyloxye
Chill ester, PGE₁1-decanoyloxyethyl ester
Stell etc. are mentioned.

The 9-acyloxy form of PGE ₁ is
For example, a compound represented by the following general formula [I] can be mentioned.

[0010]

Embedded image

[Wherein R ¹ is acyl, R ² is alkyl,
R ³ represents a hydrogen atom or a hydroxyl protecting group, R ⁴ represents a hydrogen atom or a hydroxyl protecting group, and R ⁵ represents an alkyl. ] R ¹
The acyl represented by is an acyl having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, pivaloyl, hexanoyl and the like. The alkyl represented by R ² is alkyl having 1 to 30 carbon atoms, preferably 1 to 4 carbon atoms, for example, methyl,
Ethyl, propyl, isopropyl, butyl, hexyl,
Examples include octyl, decyl, and icosyl. Examples of the hydroxyl-protecting group represented by R ³ or R ⁴ include acyl (eg acetyl, propionyl, benzoyl), aralkyl (eg benzyl, phenylethyl) and the like. The alkyl represented by R ⁵ is alkyl having 1 to 10 carbon atoms, preferably 5 to 7 carbon atoms, for example, methyl,
Ethyl, propyl, isopropyl, butyl, pentyl,
Hexyl, heptyl, 2-methylhexyl, octyl,
Decyl etc. are mentioned.

The 9-acyloxy form of PGE ₁ is
Specifically, methyl 9-acetoxy-11α, 15S
-Dihydroxyprosta-8,13E-diene-1-oate, methyl 9,11α, 15S-triacetoxy-prosta-8,13E-diene-1-oate, methyl 9,15R-diacetoxy-11α-hydroxyprosta-8, 13E-diene-1-oate, methyl
9,15 S-diacetoxy-11α-hydroxyprosta-8,13E-dien-1-oate, butyl 9-
Acetoxy-11α, 15S-dihydroxy-17S,
20-Dimethylprosta-8,13E-diene-1-oate, butyl 9-acetoxy-11α, 15S-dihydroxyprosta-8,13E-diene-1-oate, butyl 9-butyryloxy-11α, 15S-dihydroxyprosta-8 , 13E-diene-1-oate, butyl 9,11α-diacetoxy-15S-hydroxy-17S, 20-dimethylprosta-8,13E
—Diene-1-oate and the like.

The 7-thio form of PGE ₁ is the above-mentioned various PGs.
It means the one in which CH _{2 at} the 7-position of the E ₁ precursor is substituted with S. Specifically, 7-thio-PGE ₁ methyl ester,
7-thio-PGE ₁ ethyl ester, 7-thio-PGE
₁ -Butoxycarbonyl methyl ester, 7-thio-PG
E ₁ pivaloyloxymethyl ester, butyl 7-thio-9-butyryloxy-11α, 15S-dihydroxyprosta-8,13E-diene-1-oate and the like can be mentioned.

The PGE ₁ can be used by formulating it into a suitable form such as cyclodextrin (CD) inclusion, liposome formation, ethanol solution formation, fat emulsion formation and the like. It is preferably in the form of a fat emulsion, which is excellent in sustained release, sustainability, local accumulation and has good storage stability.

Next, a fat emulsion as a preferable form will be described. In the present invention, a PGE ₁ -containing fat emulsion (hereinafter referred to as “PGE ₁ -containing fat emulsion”).
Means a preparation containing PGE ₁ and having an oil component dispersed in a dispersion medium as droplets.

Examples of the oil component include vegetable oil, medium chain fatty acid triglyceride (so-called MCT), fish oil and the like.
These may be used alone or in combination of two or more,
A combination of vegetable oil and MCT or fish oil is preferred. Examples of the vegetable oil include soybean oil, sesame oil, castor oil, cottonseed oil, olive oil and the like. High-purity refined soybean oil is preferable, and more preferable is high-purity refined soybean oil obtained by further refining refined soybean oil by, for example, steam distillation (purity: 99.9% or more as triglyceride, diglyceride and monoglyceride). Contained).

In order to disperse the oil component in the dispersion medium, phospholipid or the like is used as an emulsifier. Examples of the phospholipid include egg yolk phospholipid, soybean phospholipid, and the like, and the purified phospholipids thereof are particularly preferably used. This purified phospholipid can be prepared by a fractionation method using an organic solvent according to a conventional method. The purified phospholipid mainly consists of phosphatidylcholine and phosphatidylethanolamine, and also contains phosphatidylinositol, phosphatidylserine, sphingomyelin and the like as other phospholipids. Alternatively, purified phospholipids from which phosphatidylethanolamine has been removed may be used. This is a method in which phospholipids such as egg yolk and soybeans are used, and after organic solvent fractionation by a conventional method, silica gel, alumina, etc. It is obtained by purification with an inorganic adsorbent. The phospholipid thus obtained mainly consists of phosphatidylcholine (JP-A-60-149524). Furthermore, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol itself can be used. Examples of the dispersion medium include water, preferably purified water.

The PGE ₁ -containing fat emulsion is mainly composed of 5 to 50% (w / v) vegetable oil, and 1 to 50 parts by weight, preferably 5 to 30 parts by weight of phospholipid based on 100 parts by weight of vegetable oil.
It is composed of parts by weight and an appropriate amount of water.

In addition to the above components, the PGE ₁ -containing fat emulsion according to the present invention may further contain an emulsification auxiliary agent, a preservative, a stabilizer, a polymeric substance, an isotonicity agent, etc., if necessary. You can also

Examples of the emulsification aid include fatty acids having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms or pharmacologically acceptable salts thereof, and aliphatic amines having 2 to 22 carbon atoms. The fatty acid is not particularly limited as long as it can be added to a pharmaceutical product, and may be linear or branched,
Specifically, linear stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid and the like are preferably used. Examples of pharmacologically acceptable salts of these fatty acids include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.) and the like. Furthermore, the aliphatic amine is not particularly limited as long as it can be added to a pharmaceutical product, and examples thereof include linear or branched C2-C22 primary amines and secondary amines.
Specific examples include ethanolamine, propylamine, octylamine, stearylamine and oleylamine. The blending amount of the emulsification aid is 0.3% (w / v) or less for fatty acid or a salt thereof, and 0.
The amount is preferably 1% (w / v) or less.

The stabilizer is not particularly limited as long as it can be used for medicine, and examples thereof include cholesterols and phosphatidic acid. Cholesterol content is preferably 0.5% (w / v) or less, more preferably 0.1% (w / v) or less, and phosphatidic acid is preferably 5% (w / v). Or less, more preferably 1% (w / v) or less.

The polymer substance is not particularly limited as long as it can be used as a medicine, and examples thereof include albumin, dextran, vinyl polymers, nonionic surfactants, gelatin, hydroxyethyl starch and the like. Human-derived albumin is used because of its antigenicity. Examples of the vinyl polymer include polyvinylpyrrolidone. As the nonionic surfactant, a polyalkylene glycol (for example, an average molecular weight of 1,000 to 10,000) is used.
0, preferably 4,000 to 6,000 polyethylene glycol), polyoxyalkylene copolymer (for example, polyoxyethylene-polyoxypropylene copolymer having an average molecular weight of 1,000 to 20,000, preferably 6,000 to 10,000), hydrogenated castor oil polyoxy Alkylene derivative [eg hydrogenated castor oil polyoxyethylene- (20) -ether, hydrogenated castor oil polyoxyethylene- (40) -ether,
Hydrogenated castor oil polyoxyethylene- (100) -ether etc.], castor oil polyoxyalkylene derivative [eg castor oil polyoxyethylene- (20) -ether, castor oil polyoxyethylene- (40) -ether, castor oil Polyoxyethylene- (100) -ether and the like] and the like can be used. The blending amount is PGE
_The polymer substance is preferably 1 per 100 parts by weight of the _first class.
The amount is 0 to 500 parts by weight, and more preferably 50 to 100 parts by weight.

Examples of the tonicity agent include glycerin, glucose and the like.

The amount of PGE ₁ to be contained in the above fat emulsion can be appropriately increased or decreased depending on the form and use of the emulsion, but in general, an extremely small amount, for example, 0.1 to 10 is contained in the emulsion.
It is sufficient to contain 0 μg / ml.

The following are examples of particularly preferable compositions of the PGE ₁ -containing fat emulsion used in the present invention. PGE 1s ₁ to 100 μg Purified soybean oil 50 to 500 mg Highly purified lecithin 5 to 50 mg Oleic acid 0.1 to 5 mg Concentrated glycerin 5 to 50 mg Distilled water Total amount 1 ml

The method for producing the PGE ₁ -containing fat emulsion is not particularly limited, and can be prepared by various methods. Basically,
It is prepared by adding water, particularly purified water, as a dispersion medium to an oil liquid containing PGE ₁ and other oil components and emulsifying the mixture by a suitable method to homogenize the whole quality. Specifically, the following method may be used. That is, a predetermined amount of PGE
Type ₁ , oil component (preferably soybean oil), phospholipids, and optionally other additives described above are mixed and heated to form a solution, and a conventional homogenizer (for example, high-pressure jet homogenizer, ultrasonic wave) Produced by making a water-in-oil dispersion by homogenizing with a homogenizer, etc., then adding the required amount of water to this, homogenizing again with the homogenizer and converting to an oil-in-water emulsion. can do. Depending on the production convenience, additives such as a stabilizer and a tonicity agent may be added after the preparation of the fat emulsion (JP-A-58-222014).

A sterilization process may be performed subsequent to the above process. As the sterilization treatment, a usual method is used, and examples thereof include a sterilization filter method, a γ-ray irradiation method, and a high-pressure heat treatment method.

The thus-prepared PGE ₁ -containing fat emulsion can be used as the preventive or therapeutic agent of the present invention as it is, or by optionally adding other additives. Examples of other additives include eicosapentaenoic acid (so-called EPA) and docosahexaenoic acid (so-called DHA).

The average particle size of the fat emulsion is preferably 1 μm or less, more preferably 0.2 to 0.4 μm.
Is.

The case of using the PGE ₁ to formulate into a form other than a fat emulsion will be described below.

The inclusion of cyclodextrin (CD) is carried out, for example, by adding a solution of cyclodextrin dissolved in water or the like to a solution of PGE ₁ dissolved in a solvent (ethanol or the like), followed by cooling and precipitation. The precipitation can be carried out by filtering and drying under reduced pressure. Cyclodextrins include α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. CD
As an example of the inclusion, the method described in JP-B-52-31404 can be mentioned.

To form liposomes, for example, a solution prepared by dissolving PGE ₁ in a solvent (such as ethanol) is added to a solution prepared by dissolving phospholipids in a solvent (such as chloroform), and then the solvent is distilled off. It can be carried out by adding a phosphate buffer, shaking, sonicating and centrifuging, and then filtering the supernatant with a membrane filter or the like. As an example of liposome formation, Chemical Abstracts Vol.
36f (80 years) and 95: 91231w (81 years).

The ethanol solution can be prepared by dissolving PGE ₁ in ethanol. The PGE ₁ content in the ethanol solution is usually _{1 to} 1000 μg /
It is about ml. The ethanol solution is diluted with physiological saline or glucose solution before use.

The prophylactic / therapeutic agent of the present invention can be parenterally administered in the form of an injection or the like, and intravenous administration is particularly preferable. The administration is, for example, ₁ to 10 as PGE ₁ class.
00 μg is administered by continuous intravenous infusion once a day at a rate of 0.01 to 1000 ng / kg body weight / minute.

[0035]

EXAMPLES / TEST EXAMPLES In order to explain the present invention in more detail, examples and experimental examples are given, but the present invention is not limited to these. Example 1 (CD inclusion) A solution prepared by dissolving 257 mg of β-cyclodextrin in 6 ml of water with heating was added to a solution of 17 mg of PGE ₁ dissolved in 0.2 ml of ethanol, and dissolved by heating at 45 ° C. After that, the mixture was cooled to room temperature and a precipitate was deposited. This was left overnight at 0 ° C., filtered, washed with 50% aqueous ethanol solution, and dried under reduced pressure to prepare a CD inclusion preparation.

Example 2 (liposome formation) 60 mg of egg yolk phosphatidylcholine and 11 mg of oleylamine were dissolved in 5 ml of chloroform and then PGE ₁₃
A solution prepared by dissolving 0 μg in 100 μl of ethanol was added thereto, placed in an eggplant-shaped flask, and the solvent was distilled off with a rotary evaporator. 0.1 M isotonic phosphate buffer (p
H5) Add 1 ml, shake, sonicate (sonicate)
And, after centrifugation, the supernatant was filtered through a 0.2 μm membrane filter to collect and prepare the liposome preparation.

Example 3 (Solution in ethanol) An ethanol solution was prepared by dissolving 500 μg of PGE _{1 in 1} ml of ethanol. Before use, dilute with physiological saline or glucose solution before use.

Example 4 (fat emulsification) 30 g of purified soybean oil, 5.4 g of purified egg yolk phospholipid and PGE
₁ 1.5 mg and oleic acid 0.72 g were added, 40
Dissolved by heating at ~ 75 ° C. To this, 200 ml of distilled water was added, and then 7.5 g of glycerin in the Japanese Pharmacopoeia was added.
The total amount was adjusted to 300 ml with distilled water for injection at -40 ° C, and the mixture was roughly emulsified with a homogenizer. Using a Menton-Gaurin type homogenizer, this was 120 kg / cm ^{2 for} the first time, 5 in total.
It was emulsified by passing 10 times under a pressure of 00 kg / cm ² . This gave a homogenized fat emulsion containing very fine PGE ₁ . The average grain size of this emulsion is 0.2 to 0.
4 μm, and did not contain particles of 1 μm or more.

Examples 5 to 8 Instead of PGE ₁ in Example 4, PGE ₁ ethyl ester (Example 5), PGE ₁ pivaloyloxymethyl ester (Example 6), PGE ₁ octyloxycarbonyl methyl ester ( Example 7), Butyl 9-butyryloxy-11α, 15S-dihydroxyprosta-8,1
A homogenized extremely fine fat emulsion was obtained according to the method of Example 4 except that 3E-diene-1-oate (Example 8) was used. The average grain size of the emulsion was 0.2 to 0.
It was 4 μm.

Experimental Example 1 As a model of apoptosis, which is non-ischemic cell death, an incremental compression method of the sciatic nerve was used for evaluation of PGE ₁ on neurodegeneration. Preparation of nerve-promoting compression model Wistar male rats (body weight: around 350 g) were anesthetized by intraperitoneal administration of pentobarbital and fixed in the abdominal position, and an incision was made in the right thigh to expose the sciatic nerve, and then observed under a microscope. The connective tissue was carefully peeled off with, and the sciatic nerve was incompletely ligated to the upper part of the bifurcation with an intestinal suture at 4 places at 1 mm intervals. That is, at the time of ligation, a 26-gauge injection needle was added to ligate, and this was removed after the fact.

Administration of test drug Two weeks from the day after model preparation, fat emulsion (vehicle) and PGE ₁ fat emulsion (1,3,10 μg / kg body weight)
Was intravenously administered every day. Carbacyclin (1,3,1), which is a stable derivative of prostaglandin I ₂ (hereinafter referred to as PGI ₂ ) that can be intravenously administered as a control drug, is also used.
0 μg / kg body weight) was used.

Spinal Blood Flow Measurement After a test drug administration period of 2 weeks, the test animal was anesthetized with pentobarbital, fixed in the abdominal position, and the fourth and fifth lumbar spinal cords were exposed protectively under a microscope. The tissue blood flow in the dorsal horn of the spinal cord was measured from the epidural region using a laser Doppler flowmeter.

Biochemical / Histological Study on Neuronal Degeneration After the blood flow measurement was completed, the fourth and fifth examinations under a microscope were performed.
The lumbar spinal cord was excised and tissue-fixed by cryopreservation and lily buffer, respectively, and DNA analysis was performed by the following biochemical and histological techniques. As a control, the thirteenth thoracic spinal cord, which had no nerve fiber input from the sciatic nerve, was collected and subjected to the same operation as above. GNOM from 4th lumbar spinal cord cryopreserved
The extracted genomic DNA was subjected to agarose electrophoresis using E DNA ISOLATION KIT to examine the presence or absence of fragmentation. Paraffin sections were prepared from the tissue-fixed 5th lumbar spinal cord, dark cells were stained with toluidine blue, and image analysis was performed to show the appearance frequency of dark neurons in a certain visual field. Was quantified. On the other hand, dUTP to specifically detect DNA damage
(Deoxyuridine 5'-triphosphate) was used to stain nerve cells in the area of interest. The obtained sample was subjected to image analysis processing to quantify the degree of DNA damage in a certain area.

Experimental Results i) Tissue blood flow in the dorsal horn of the spinal cord in the lumbar region did not decrease even with increasing pressure on the sciatic nerve. From this, it is concluded that there was no fact that the region of interest suffered from ischemia as compared to normal animals.

Ii) Due to the progressive compression of the sciatic nerve, the frequency of appearance of dark cells in the lumbar spinal cord on the ipsilateral side significantly increased.
The GE ₁ fat emulsion significantly improved to near normal levels. On the other hand, although some reduction was observed in the carbacycline administration group, it was not significant. The frequency of appearance of dark cells in the ipsilateral lumbar spinal cord is shown in Table 1. On the contralateral side, no particular change was observed.

[0046]

[Table 1]

Iii) Apoptosis-like cell death was observed by spinal cord nerve cell staining using dUTP, and the PGE ₁ fat emulsion clearly suppressed the frequency of cell death in the highest dose group (10 μg / kg body weight). .

Iv) As a result of taking out DNA from the spinal cord tissue and analyzing it, DNA fragmentation of nucleosome units was observed in the lumbar spinal cord tissue of the animal in which the sciatic nerve was progressively pressed, and this was observed in the thirteenth spinal cord used as a control. No such phenomenon was observed. In contrast, no DNA fragmentation was observed with PGE ₁ fat emulsion at any dose. On the other hand, in the carbacyclin administration group, the lowest dose (1 μg / k
A clear phenomenon of DNA fragmentation was observed in (g body weight).

Conclusion In the frequency of appearance of dark cells, PG which is a PGE-based drug
The E ₁ fat emulsion significantly suppressed it, while the effect of the carbocyclin, which is a PGI ₂ type drug, was not significant, and regarding the fragmentation of DNA, the PGE ₁ fat emulsion suppressed fragmentation from the lowest dose. On the other hand, considering the effect of carbacyclin, which was ineffective at the same dose, EP is effective in suppressing the apoptosis observed in spinal dorsal horn neurons.
It was suggested that the receptor (receptor for E-type prostaglandin) may be predominantly involved.

Experimental Example 2 Toxicity Test The prophylactic / therapeutic agent of the present invention prepared in Example 4 was used in mice and rats.
To dogs and dogs ₁Up to 250 μg / kg body weight
There were no deaths and no serious toxicity was observed when administered intravenously.
There wasn't.

[0051]

INDUSTRIAL APPLICABILITY The prophylactic / therapeutic agent of the present invention is particularly useful as a prophylactic / therapeutic agent for neurological diseases in mammals (eg, mouse, rat, rabbit, dog, cat, human, etc.) It is useful for prevention and / or treatment of neurological diseases associated with apoptosis, associated with apoptosis, or involved in apoptosis. Therefore, it is useful for the prevention or treatment of diseases considered to be applicable to these, such as Alzheimer's disease and Parkinson's disease in the central nervous system, and amyotrophic lateral sclerosis in the peripheral nervous system. Further, it is useful for prevention and / or treatment of nonischemic or apoptosis-mediated diseases among sudden hearing loss and other diseases.

When the preventive / therapeutic agent of the present invention is in the form of a fat emulsion, the stability of PGE ₁ as an active ingredient of the preventive / therapeutic agent for the above-mentioned neurological diseases is improved and the action is prolonged. As a result, the above-mentioned usefulness is improved, and a formulation suitable for large-scale formulation can be obtained. Furthermore, it is excellent in sustained release, sustainability and local accumulation, and also has good storage stability.

Claims (2)

[Claims] 1. A preventive / therapeutic agent for a non-ischemic or apoptosis-mediated neurological disease, which comprises prostaglandin E ₁ or a derivative thereof as an active ingredient. 2. The preventive and therapeutic agent according to claim 1, which is in the form of a fat emulsion.