JP2503571B2 - Cerebral circulation metabolism improver - Google Patents

Description

TECHNICAL FIELD The present invention relates to a cerebral circulatory metabolism-improving agent comprising a combination of idebenone and vinpocetine.

(Prior Art) Idebenone has an immune stimulating action and an in vivo tissue metabolism activating action (JP-A-56-97223 and JP-B-62-3134),
It is marketed as a remedy for cerebral infarction sequelae, cerebral hemorrhage sequelae, motivation associated with cerebral arteriosclerosis, emotional disorders and speech disorders. In addition, vinpocetine has an effect of enhancing the deformation of red blood cells [Ge
riat.Med. 20, 151~156 (1982)], blood flow increasing action of the brain tissue Pharmacological and therapeutic 10, have 75 to 88 (1982)], cerebral infarction, in cerebral hemorrhage sequela, and cerebral arteriosclerosis Marketed as an ameliorating agent for various symptoms.

(Problems to be Solved by the Invention) The present invention intends to exert a particularly remarkable effect by using these two kinds of drugs in combination.

(Means for Solving the Problem) The present invention is a cerebral circulatory disorder therapeutic agent comprising a combination of idebenone and vinpocetine.

Idebenone is a common name and its chemical structure is And has a chemical name of 6- (10-hydroxydecyl-2,3-dimethoxy-5-methyl-1,4-benzoquinone.

Vinpocetine is a common name and its chemical structure is The chemical name is ethyl (13aS, 13bS) -13a-ethyl-2,3,5,6,13a.13b-hexahydro-1H-indolo [3,2,1-de] pyrido [3,2 , 1-ij] [1,5] naphthyridine-12-carboxylate.

The cerebral circulatory metabolism-improving agent according to the present invention can treat or ameliorate various symptoms due to cerebral circulatory disorders such as cerebral infarction sequelae, cerebral hemorrhage sequelae, cerebral arteriosclerosis in mammals including humans.

The cerebral circulatory metabolism-improving agent of the present invention contains idebenone and vinpocetine as active ingredients, and these active ingredients may be used alone or in combination with suitable pharmacologically acceptable additives (extending agent, diluent) and the like. They can be mixed to give a suitable pharmaceutical composition. When idebenone and vinpocetine are provided as separate compositions, they can be used in combination. In this case, both may be used at the same time, or may be used at intervals, and the daily dose may be within the specified range.

In the above pharmaceutical composition, the active ingredient is mixed with physiologically acceptable carriers, excipients, binders and diluents, for example, granules, powders, tablets, hard capsules, soft capsules, syrups, suppositories. It is administered orally or parenterally as a drug or injection.

For example, powders, granules, tablets, hard capsules, soft capsules and syrups that are orally administered can be prepared by known methods using carriers, excipients, binders, diluents, etc. which are conveniently used in the formulation. Can be adjusted by. Examples of preferable excipients, binders and lubricants include lactose, starch, sucrose and magnesium stearate. As the excipient for preparing the soft capsule, for example, pharmacologically acceptable animal oil, vegetable oil, mineral oil, etc. are used, and the active ingredient is dissolved in these fats and oils and filled in the soft capsule.

Dosage forms for parenteral administration include injections and suppositories. The injection may be a solution or a suspension. Since both idebenone and vinpocetine used as active ingredients in the present invention are poorly soluble in water, it is preferable to use a solubilizing agent to prepare an aqueous injection.
The suppository can be prepared by mixing the active ingredient with a suppository base such as triglyceride of medium-chain or higher fatty acid, polyethylene glycol or the like and molding.

The dose of the composition of the present invention varies depending on the type of disease, symptoms, administration method, etc.
Idebenone per day is 10 to 150 mg, preferably 30 to 90 mg,
Vinpocetine is administered in a range of 1 to 100 mg, preferably 5 to 60 mg. When used parenterally, the dose is about 1/10 of the above. The dose ratio is 0.01-10 parts by weight of vinpocetine, preferably 0.1 part by weight of idebenone.
05 to 2 parts by weight.

Both idebenone and vinpocetine have low toxicity, with LD _{50 s} in mice of ≥10,000 mg / kg and approximately 1,000 mg / kg, respectively.

[Experimental example]

1. Experimental Animal Male ICR mice (CLEA Japan, Inc.) aged 4 to 5 weeks were used for the experiment. All animals must have a 12-hour light-dark cycle (7 am to 7 pm light period) at room temperature of 24 ± 1 ° C after they are obtained.
In a breeding room with a relative humidity of 55 ± 5%, food (CLEA Japan, C
E-2 solid feed) and water were freely group-fed.

2. Drug Idebenone was suspended in 5% gum arabic saline, while vinpocetine was dissolved in saline containing 2% ascorbic acid. The administration volume was 0.1 ml per 10 g of mouse body weight.

3. Anoxia protection device The device was a bottomless odor bottle with a capacity of 1, filled with the mixed gas (N ₂ 98%, O ₂ 2%) from above, and constantly supplemented with the mixed gas at a constant flow rate. The mouse was swiftly put in from the bottom so that the outside air did not enter the device, and observed until breathing stopped. The survival time was measured by placing the mouse in the device and stopping breathing.

One group of 10 mice was divided into 4 groups, and each group was administered with 2 kinds of drug solutions (including solvent solution). That is, solvent liquid / solvent liquid, idebenone (10 mg / kg) / solvent liquid, solvent liquid / vinpocetine (1.5 mg / kg) and idebenone (10 mg / kg) /
Two drug solutions of vinpocetine (1.5 mg / kg) were simultaneously administered to each. All drugs are hypoxic 15
It was intraperitoneally administered at a minute before.

Idebenone (10 mg / kg) / solvent liquid administration group and solvent liquid /
In the vinpocetine (1.5 mg / kg) administration group, no significant prolongation of survival time was observed as compared with the solvent / solvent control group. However, the combination of idebenone (10 mg / kg) and vinpocetine (1.5 mg / kg) significantly prolonged survival time (t = 2.98, P <0.01).

4. Effects on amnesia induced by carbon dioxide exposure A step-through type passive avoidance device consisting of two light and dark chambers was used. In the acquisition trial, the mouse was placed in a bright room (9 × 9 × 25
cm) and the mouse moved to a dark room (25 × 25 × 30 cm), the partition door was closed, and a 0.4 mA electric shock was applied from the floor grid for 3 seconds. Immediately after the shock was given, the mouse was taken out of the dark room and placed in a desiccator having a volume of 4 l filled with carbon dioxide. After confirming respiratory arrest (25
~ 35 seconds), the mouse was removed and resuscitated by artificial respiration.
The retention test was performed 24 hours later. In the retention test, the mouse was placed in the light room again, and the latency until moving to the dark room was measured up to 300 seconds.

The mice were divided into 4 groups of 20 to 22 mice each, and two kinds of drug solutions were simultaneously administered to each group. That is, solvent liquid / solvent liquid,
Two drug solutions, idebenone (5 mg / kg) / solvent solution, solvent solution / vinpocetine (10 mg / kg) and idebenone (5 mg / kg) / vinpocetine (10 mg / kg), were administered to each. In addition, idebenone (5 mg / kg) / vinpocetine (10 mg) was administered to 8 mice that were not given electric shock in the acquisition trial.
/ kg) was administered and the effect of the drug on the motor system and drive was examined. All drugs were administered intraperitoneally 30 minutes before the retention test.

Idebenone (5mg / kg) / solvent liquid administration group and solvent liquid /
The vinpocetine (10 mg.kg) -administered group showed no significant prolongation of the avoidance time at any of these doses as compared with the solvent / solvent-administered control group. However, the group coadministered with these doses of idebenone and vinpocetine showed a significant (t = 3.98, P <0.001) avoidance time extension relative to the control group. Furthermore, the avoidance time of the combined administration group was significantly extended (t = 3.15, P <0.01) compared with that of the idebenone (5 mg / kg) / solvent solution administration group. In addition, in order to investigate the effect of the combined administration of idebenone (5 mg / kg) and vinpocetine (10 mg / kg) on the motor system and motility of mice, a group was set in which no electric shock was given in the acquisition trial, and re-evaluation was performed 24 hours later. The time required to enter the room and move to the dark room was measured. The average response latency for this combination group was 11.2
Seconds, no difference was observed between the non-shock-loaded solvent-administered group and 10.4 seconds. From this, it was clarified that the prolongation of the avoidance time by the combined use of both drugs is not secondary to the suppression of the movement or drive of the mouse.

Example 1 (Tablet) Idebenone 30 mg Vinpocetine 5 mg Lactose 74 mg Starch 10.6 mg Starch (for paste production) 5 mg Magnesium stearate 0.4 mg Carboxymethylcellulose calcium salt 25 mg Total 150 mg The above ingredients were mixed and tableted according to a conventional method.

Example 2 (sugar-coated tablet) Tablet (Example 1) 150 mg Talc 30 mg Gum arabic 6 mg Sucrose 74 mg Total 260 mg The tablet prepared in Example 1 was coated with the above-mentioned components in a conventional manner to give a sugar-coated tablet.

Example 3 (Fine granule) Idebenone 20 mg Vinpocetine 3 mg Lactose 677 mg Den powder 300 mg Total 1,000 mg The above ingredients were mixed to obtain a fine granule according to a conventional method.

Example 4 (Capsule) Idebenone 10 mg Vinpocetine 20 mg Microcrystalline cellulose 30 mg Lactose 47 mg Magnesium stearate 3 mg Total 110 mg The above components were mixed according to a conventional method and filled into a gelatin capsule to give a capsule.

Example 5 (Soft Capsule) Idebenone 15 mg Vinpocetine 15 mg Corn oil 120 mg Total 150 mg The above ingredients were mixed and encapsulated in a film consisting of gelatin, glycerin and sorbitol preservative according to a conventional method to give a soft capsule.

Example 6 (Suppository) Idebenone 30 mg Vinpocetine 20 mg Triglyceride of saturated fatty acid having 11 to 17 carbon atoms (hydroxyl value 12) 1450 mg Total 1500 mg The above ingredients were mixed to prepare a suppository according to a conventional method.

(Effects of the Invention) The cerebral circulatory metabolism-improving agent of the present invention, which is a combination of idebenone and vinpocetine, exhibits a strong cerebral circulatory metabolism-improving action which cannot be obtained by using each alone.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Junko Nakaoka 5-18 Tsuzudaidai, Suita City, Osaka Prefecture D73-105 (56) References JP-A-56-97223 (JP, A) Edited by Osaka Hospital Pharmacists Association " "Fully-Edited Pharmaceutical Manual" (Sho 61-9-10) Pharmaceutical Industry Bulletin P1502-1503

Claims (1)

(57) [Claims] 1. A cerebral circulation metabolism improving agent comprising a combination of idebenone and vinpocetine.