JPH05320072A - Curing agent for ischemic encephalopathy - Google Patents

Abstract

PURPOSE:To obtain a curing agent for ischemic encephalopathy having strongly reducing action on ischemic cerebral edema and containing an interleukin I inhibitor as a main component. CONSTITUTION:This curing agent contains an interleukin I inhibitor such as zinc(II)-protoporphyrin IX complex, its salt, an antiinterleukin I antibody, etc., as an effective component. The agent is capable of being formulated in an oral drug, an injection, a suppository, etc., and an amount of the interleukin I inhibitor to be added will be 1-1000mg for the oral drug, 0.1-500mg for the injection and 5-1000mg for the suppository and 1mg-10 g administration/adult/day. A compound having interleukin I inhibiting activity suppresses cerebral edema, thus suppresses succeeded ischemic brain disorder and makes it easy to prevent and treat ischemic brain disorder which has been very difficult to cure.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel therapeutic agent for ischemic brain disease containing an interleukin 1 inhibitor as a main component.

[0002]

2. Description of the Related Art The brain is a central organ involved in various life activities such as thinking, learning, movement and emotion. The brain is the most vulnerable to oxygen deficiency and malnutrition compared to other organs, and causes cerebral edema when subjected to severe ischemic invasion due to cardiac arrest or cerebrovascular accident. Cerebral edema becomes an aggravating factor for nerve cell death, causes brain dysfunction, and is likely to lead to long-term functional paralysis or dementia. An important issue is how to reduce edema at the early stage of treatment, which leads to reduction of functional impairment later. Conventionally, osmotic therapy such as glycerol and mannitol and furosemide have been mainly used for the treatment of cerebral edema, but in many of these cases, due to hypertonic solution or diuretic action, water and electrolyte balance of the patient are often used. There was a defect associated with abnormalities in circulation and circulation [Cranial nerve No. 32, 293-296 (1980)].

On the other hand, it has been reported that interleukin 1 is released in the early stage of cerebral ischemic injury (Science 2
28 , 497-499 (1985)), inhibition of the action of interleukin 1 has not yet been known to reduce cerebral ischemic injury.

The protoporphyrin IX zinc (II) complex is a known compound and is commercially available (Aldric
h, code. No. 28282-0), it was announced that the heme oxygenase activity of neonatal rat was inhibited by injecting it subcutaneously or intraperitoneally (Biochem. J., 198).
5, 226 , 51-57, Biochem. J., 1984, 217 , 409-41
7). Although it has been reported as a liver injury inhibitor in JP-A-63-192718, it has not yet been known to exhibit a cerebral ischemic injury inhibitory action.

[0005]

An object of the present invention is to provide a drug having a strong ischemic cerebral edema reducing action.

[0006]

The present invention relates to a therapeutic agent for ischemic cerebral disease, which contains an interleukin 1 inhibitor as a main component.

Cerebral edema is a major problem in the acute stage of cerebral ischemic injury, and clinically, reduction of cerebral edema is the first step of treatment. Therefore, in order to prevent cerebral ischemic injury and search for therapeutic agents, it is usual to utilize these indices.

The present inventor has conducted diligent studies in view of the above circumstances, and as a result, interleukin 1 inhibitors, particularly anti-interleukin 1 antibody, protoporphyrin IX zinc (I
It was found that the complex I) and its pharmacologically acceptable salt have the effects of obviously suppressing cerebral edema that occurs after cerebral ischemic injury and reducing strong cerebral ischemic injury.

The interleukin-1 inhibitor used in the present invention may be any agent that inhibits the action of interleukin-1, and examples thereof include anti-interleukin-1 antibody, protoporphyrin IX zinc (II) complex and its pharmacologically. Acceptable salts, anti-interleukin 1 receptor antibodies, interleukin 1 receptor antagonists (proteins) (Nature vol.343 336-340, 1989), soluble interleukin 1 receptor (proteins) and the like can be mentioned.

The protoporphyrin IX zinc (II) complex and its pharmacologically acceptable salts can be easily synthesized from protoporphyrin IX by a known method. Examples of pharmaceutically acceptable salts include alkali metal salts such as sodium, potassium and lithium, alkaline earth metal salts such as calcium and magnesium, organic amine salts such as ammonia, cyclohexylamine, trimethylamine and diethanolamine, and arginine. , Basic amino acid salts such as lysine, and the like.

The therapeutic agent for ischemic brain disease according to the present invention can adopt various dosage unit forms depending on the purpose of prevention or treatment, and examples of such forms include oral preparations, injection preparations and suppositories. Any of these may be used, and each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.

In the case of preparing an oral solid preparation, after adding an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. to the compound of the present invention, Tablets, coated tablets, granules, powders, capsules, pills and the like can be produced by a conventional method. Such additives may be those commonly used in this field, and examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. As the binder, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, methylcellulose, ethylcellulose, sierrac, calcium phosphate, polyvinylpyrrolidone, etc. are disintegrated. As the agent, dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, etc., and as lubricants, purified talc, stearic acid , Borax, polyethylene glycol, etc., as the corrigent,
Examples include sucrose, orange peel, citric acid, tartaric acid and the like.

In the case of preparing an oral liquid preparation, a suspending agent, a syrup preparation, an elixir preparation and the like are prepared by adding a flavoring agent, a buffering agent, a stabilizer, a flavoring agent and the like to the compound of the present invention by a conventional method. be able to. The flavoring agents in this case may be those mentioned above, examples of the buffering agent include sodium citrate, and examples of the stabilizing agent include tragacanth, gum arabic, gelatin and the like.

When preparing an injection, the compound of the present invention
Subcutaneous, intramuscular, and intravenous injections can be produced by a conventional method by adding a pH regulator, a buffer, a stabilizer, an isotonicity agent, a local anesthetic and the like. Examples of pH regulators and buffers in this case include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride. It is preferably dissolved in a replenisher and used as an intravenous infusion.

In the case of preparing suppositories, pharmaceutical compounds known in the art such as polyethylene glycol, lanolin, cacao butter, and fatty acid triglyceride are added to the compound of the present invention, and if necessary, as in Tween (registered trademark). It can be produced by a conventional method after adding a suitable surfactant and the like.

The amount of the compound of the present invention and the pharmacologically acceptable salt thereof to be blended in each of the above dosage unit forms is not constant depending on the symptoms of the patient to which it is applied or the dosage form thereof, etc. Generally, the dosage unit form is about 1 to 1000 mg for an oral preparation, about 0.1 to 500 mg for an injection, and about 5 for a suppository.
It is preferably 1000 mg. In addition, the daily dose of the drug having the above-mentioned administration form is the symptom, weight, age,
Although it varies depending on sex and cannot be generally determined, it is usually about 1 mg to 10 g, preferably 10 to 1000 mg per day for an adult, and if desired, it may be used in combination with other drugs. It is preferable to administer the drug once or in 2 to 4 divided doses.

[0017]

The present invention will be described in detail with reference to the following examples and reference examples, but the present invention is not limited thereto.

Example 1 Many ischemia models have been developed to experimentally investigate cerebral ischemic injury, and among them, a transient focal cerebral ischemic injury model using rat is often used. There is. This model is a reperfusion model that best reflects the clinical picture, and it is possible to create highly reproducible lesions in the cerebral artery dominated region.
The present invention also used this rat transient focal cerebral ischemic injury model. Details are as follows.

Using Wistar rats of 11-12 weeks of age,
Under halothane anesthesia, the rat neck was peeled off and the common carotid artery was separated. Insert a nylon plug from the external carotid artery into the internal carotid artery,
The origin of the middle cerebral artery was occluded. Remove the plug after 1 hour,
Blood flow was restarted from the common carotid artery (Stroke, 20 , 84-9).
1, 1989). Twenty-four hours after resumption of blood flow, the brain was taken out and divided into a dorsolateral part of the striatum (hereinafter referred to as DCP) and a ventromedial striatum (hereinafter referred to as VCP). 110 brain samples
After being dried at ℃ for 24 hours, the water content was determined by the dry-gravimetric method.

Anti-interleukin 1 antibody (manufactured by R & D,
(Hereinafter referred to as Anti-IL-1) was dissolved in phosphate buffered saline (hereinafter referred to as PBS), and was administered once in the lateral ventricle at a dose of 2 μl / ventricle during recanalization of blood flow. In the control group, PBS and goat IgG antibody (dissolved in PBS, hereinafter referred to as goatIgG) were administered at the same time. The normal group is untreated. The results are shown in Table 1.

[0021]

[Table 1]

According to these results, anti-interleukin-1
Cerebral edema associated with ischemic injury was dose-dependently suppressed by antibody administration. In addition, administration of 10 μg significantly reduced cerebral edema. Therefore, it has the effect of preventing cerebral ischemic injury.

Example 2 The same procedure as in Example 1 was carried out using a protoporphyrin IX zinc (II) complex (hereinafter referred to as Znpp). The results are shown in Table 2.

[0024]

[Table 2]

According to these results, the interleukin-1 inhibitor protoporphyrin IX zinc (II) complex suppressed cerebral edema associated with ischemic injury. Therefore, this has been shown to be effective in preventing cerebral ischemic injury.

Example 3 Acute Toxicity Test Protoporphyrin IX Zinc (II) complex 1000 mg dissolved in 10 ml of 0.5% methylcellulose aqueous solution was used as male ddY.
Mice were orally administered at a rate of 10 ml / kg. Using 3 mice per group, the number of deaths was observed for 7 days after administration. In addition, a 0.5% aqueous solution of methylcellulose was added to the control group at 10 ml / k.
It was orally administered at a rate of g.

As a result of the above test, it was confirmed that the protoporphyrin IX zinc (II) complex and the pharmacologically acceptable salt thereof of the present invention have low toxicity without any death. Indicated.

Reference Example 1 C3H / HeJ mouse thoracic cord cells were isolated, and cells not aggregated by lecithin were treated with RPM1 containing 10% fetal bovine serum.
The cells were cultured in 1640 culture medium (2 × 10 ⁶ cells / well). 10 U
/ Ml recombinant mouse IL-1α (Genzyme, U.
S.A. ) And each concentration of Znpp. Then 72
After culturing in a CO ₂ incubator at 37 ° C for 18 hours, 0.5 µCi ³ H-thymidine (NEN) was added after 18 hours, and the cells were collected on a glass filter. The uptake was measured with a liquid scintillation counter. The results are shown in Table 3.

[0029]

[Table 3]

These results suggest that the protoporphyrin IX zinc (II) complex has interleukin-1 inhibitory activity.

Formulation Example 1 Tablets Tablets having the following compounding ratios and 300 mg per tablet were prepared according to a conventional method. Protoporphyrin IX Zinc (II) complex 100 mg Lactose 47 mg Corn starch 50 mg Crystalline cellulose 50 mg Hydroxypropyl cellulose 15 mg Talc 2 mg Magnesium stearate 2 mg Ethyl cellulose 30 mg Unsaturated fatty acid glyceride 2 mg Titanium dioxide 2 mg Total 300 mg

Formulation Example 2 Granules Granules were prepared in the following mixing ratio according to a conventional method. Protoporphyrin IX Sodium salt of zinc (II) complex 200 mg Mannitol 540 mg Corn starch 100 mg Crystalline cellulose 100 mg Hydroxypropyl cellulose 50 mg Talc 10 mg Total 1000 mg

Formulation Example 3 Capsules 250 mg per capsule according to a conventional method in the following blending ratio
Capsules were prepared. Protoporphyrin IX Zinc (II) complex 100 mg Lactose 50 mg Corn starch 47 mg Crystalline cellulose 50 mg Talc 2 mg Magnesium stearate 1 mg Total 250 mg

FORMULATION EXAMPLE 4 Injection Preparation An injection preparation was prepared in the following blending ratio according to a conventional method. Protoporphyrin IX Calcium salt of zinc (II) complex 100mg Distilled water for injection Appropriate amount 2ml in 1 tube

Formulation Example 5 Suppository A suppository was prepared according to a conventional method in the following mixing ratio. Protoporphyrin IX Zinc (II) complex 100mg Witepuzole W-35 1400mg (registered trademark, Dynamite Nobel) 1500mg per piece

[0036]

INDUSTRIAL APPLICABILITY According to the present invention, it has been suggested that a group of compounds having interleukin-1 inhibitory activity suppresses cerebral edema and subsequent cerebral ischemic injury, which has been difficult in the past. The prevention and treatment of blood disorders can be facilitated.

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[Procedure amendment]

[Submission date] July 19, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0020

[Correction method] Change

[Correction content]

[0020]GoatAnti-interleukin 1 antibody (R & D
(Hereinafter referred to as Anti-IL-1) is a phosphate buffered physiological
Dissolve in saline (hereinafter referred to as PBS) to restart blood flow
At that time, it was administered once into the lateral ventricle at a dose of 2 μl / ventricle.
The control group had PBS and goat Ig at the same time.G 
(Dissolved in PBS, hereinafter referred to as goat IgG)
It was The normal group is untreated. The results are shown in Table 1.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0028

[Correction method] Change

[Correction content]

Reference Example 1 C3H / HeJ mouse thoracic cord cells were isolated, and cells not aggregated by lecithin were treated with RPM1 containing 10% fetal bovine serum.
1640 were cultivated in culture ^{(2 × 10 6 cell s /} well). Ten
U / ml recombinant mouse IL-1α (Genzyme, U.
S.A. ) And each concentration of Znpp. Then 72
Incubate in CO ₂ incubator at 37 ℃ for 0.5 hours
i ³ H-thymidine (NEN) was added, and 18 hours later, it was recovered on a glass filter. The uptake was measured with a liquid scintillation counter. The results are shown in Table 3.

[Procedure 3]

[Document name to be amended] Statement

[Name of item to be corrected] 0029

[Correction method] Change

[Correction content]

[0029]

[Table 3]

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Claims (3)

[Claims] 1. A therapeutic agent for ischemic brain disease, which comprises an interleukin 1 inhibitor as a main component. 2. The therapeutic agent for ischemic brain disease according to claim 1, wherein the interleukin-1 inhibitor is a protoporphyrin IX zinc (II) complex and a pharmacologically acceptable salt thereof. 3. The therapeutic agent for ischemic brain disease according to claim 1, wherein the interleukin 1 inhibitor is an anti-interleukin 1 antibody.