JPH0474135A - Eye drop composition - Google Patents

Abstract

PURPOSE:To provide the title composition effectively having antiamnesic effects, containing as active ingredient a REM sleep inducer or neuropepetide. CONSTITUTION:The objective composition containing 1- 100 mg/l of (A) a REM sleep inducer (e.g. uridine, glutathione, sleep-promoting substance, prostaglandin D2, delta sleep-inducing peptide, piperidine, vasotocin, somatostatin, progesterone) or (B) a neuropeptide (e.g. vasopressin, oxytocin, neurotensin, vasoactive enteropeptide, neuropeptide Y, cholecystokinin, thyrotropic hormone-releasing hormone, enchephaline, nerve growth factor). The present composition will enable said components A and B to be acted directly on the center; such action has been impossible through oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an eye drop composition having an anti-amnestic effect, and more particularly to an eye drop composition containing a REM sleep inducer or a neuropeptide as an active ingredient.

[Prior Art] With the increase in the elderly population, dementia has come to occupy a large part of geriatric medical care, but no treatment method has been established yet. Cerebral metabolism activator, cerebral blood flow improving agent,
Although drug treatments such as tranquilizers and cholinergic agonists have been attempted, their effects have not been satisfactory, and the development of new drugs in this field has been desired.

On the other hand, it has been suggested that sleep, especially REM sleep (paradoxical sleep), which is one phase of sleep, plays a significant role in memory retention. For example, it has been shown that REM sleep increases after learning in animals, that memory is impaired when rats are experimentally deprived of REM sleep, and that in humans, REM sleep increases by 70 hours.
It is clear that REM sleep is a necessary factor for memory consolidation, as it rapidly decreases in older adults and in mentally retarded children and elderly people, REM sleep decreases when intellectual disability occurs. be. Therefore, drugs that increase REM sleep may have the effect of increasing learning ability and memory retention ability, but conventional sleeping pills conversely suppress REM sleep and induce amnesia that is thought to be caused by this. In some cases, it cannot be used for the above purpose. Therefore, it is expected that a biologically derived REM sleep inducing substance that has been reported in recent years may have an effect on improving memory disorders.

In addition to REM sleep-inducing substances, there are several neuropeptides in the brain that can improve memory disorders. For example, arginine vasopressin (AVP), a neuropeptide thought to be involved in memory retention, decreases with age in the suprachiasmatic angle, a region of the hypothalamus in the midbrain (Rosendaal et al.・Risachi (B
rain Research), 409:259(
) and that AVP is specifically decreased in the suprachiasmatic angle of patients with Alzheimer's type senile dementia (Sleeve et al., Brain Research
rch) 342:37 (1985)) has been reported,
Ru. In recent years, efforts have been made to improve amnesia associated with senile dementia by increasing the amount of AVP in the brain using inhibitors of prolyl endopeptidase, which is a ^vp degrading enzyme. However, methods using such enzyme inhibitors are likely to be accompanied by side effects and are highly dangerous. Therefore, if the amount of AVP in the suprachiasmatic angle can be increased directly by administration, it can be an effective treatment for dementia such as Alzheimer's disease. It has also been reported that other neuropeptides such as somatostatin, β-endorphin, and adrenocorticotropin-releasing hormone are reduced in the brains of Alzheimer's disease patients, and supplementation of these neuropeptides can be expected to have a therapeutic effect.

[Problems to be Solved by the Invention] However, the clinical application of conventional REM sleep inducing substances and neuropeptides has had problems with the route of administration.

The effectiveness of these substances is only apparent when administered directly into the brain. There are several other reports that large doses of intraperitoneal or subcutaneous administration are effective, but these substances are endogenous and are easily metabolized within the body, making it difficult for them to reach the area of action in the brain. These routes of administration are neither convenient nor practical as they have fatal drawbacks.

Furthermore, some of these substances have strong effects on peripheral organs such as the gastrointestinal tract, and so far it has been impossible to apply them to senile dementia, where long-term continuous administration of drugs is expected.

Therefore, the present invention solves the conventional problems as described above, and its purpose is to provide a drug containing a REM sleep-inducing substance or a neuropeptide that can improve amnesia in senile dementia patients and the like. Another object is to provide such a drug that is safe and easy to use by the patient's family.

[Means for Solving the Problems] As a result of extensive research to achieve the above object, the present inventors have discovered that REM sleep-inducing substances and neuropeptides are effective in treating amnesia, and that these are administered by eye drops. It was discovered that the anti-amnestic effect can be efficiently exerted, and the present invention was completed.

That is, the present invention relates to an eye drop composition containing a REM sleep inducer or a neuropeptide as an active ingredient.

[Example] In the present invention, a REM sleep-inducing substance refers to an endogenous (biologically derived) substance that induces REM sleep, and specific examples thereof include uridine, glutathione, and sleeve-bromoting substances (SPS). ), prostaglandin D2 (PGD2), delta sleep-inducing peptide (D
SIP), piperidine, vasotocin, somatostatin,
Examples include progesterone, 2-octyl-gamma-bromoacetoacetate (gamma brome), and melatonin. Among the above compounds, SPS is a sleep-inducing substance purified from the brains of sleep-deprived rats, and uridine and oxidized glutathione have been identified as part of it, but other components are still unknown and the structure is currently unknown. Currently being analyzed.

In addition, neuropeptides here refer to peptidic information transmitters distributed in the hypothalamus, and specific examples include vasopressin, oxytocin, neurotensin,
Neuropeptide Y, substance P, vasoactive intestinal peptide (
VIP), cholecystokinin (CCK), thyrotropin-releasing hormone (TRH), dynorphin,
These include endorphins, enkephalins, somatostatin, nerve growth factors, bombesin, luteinizing hormone-releasing hormone, corticotropin-releasing hormone, growth hormone-releasing hormone, melanocyte-stimulating hormone, and adrenal stimulating hormone.

The concentration of these substances in the eye drops varies depending on the type of the substance, and is usually contained in the eye drops at a ratio of 1 to 1 g/L.

The ophthalmic composition of the present invention may contain additives commonly used in ophthalmic preparations, such as tonicity agents, buffers, and preservatives, as well as additives for enhancing the action of the substance. Letsuru. The tonicity agent is sodium chloride, the buffering agent is boric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, and the preservative is hensalkonium chloride, pencetoniram chloride, chlorobutanol. can be given. Examples of additives for enhancing the action include degradative enzyme inhibitors and thickeners. The amount of each additive is determined depending on the drug used and the type of each additive.

An eye drop containing a REM sleep-inducing substance or a neuropeptide can be obtained by dissolving the eye drop composition in sterile purified water or by dissolving it in water and then sterilizing it.

As for the method of administering the eye drops of the present invention, for example, eye drops containing a REM sleep inducer may be administered once before use, and eye drops containing a neuropeptide may be administered approximately 3 times a day, with 1 to several drops in each eye. Dripping is preferred.

When the eye drops obtained according to the present invention are administered, the REM sleep-inducing substance or neuropeptide contained in the eye drops is taken up by the ganglion cells of the retina, and the substance is transported in the nerve cells of the nerve conduction pathway (retinohypothalamic projection). system (axonal flow) and is thought to be transported to the suprachiasmatic angle in the brain. The suprachiasmatic angle is part of the hypothalamus, which regulates sleep and appetite, and is the site of the biological clock, especially in mammals. REM sleep-inducing substances administered eye drops act on this region and directly or indirectly induce REM sleep,
It is thought to improve amnesia. Furthermore, although the mechanism of the anti-amnestic effect of neuropeptides is currently unknown, as will be discussed later, when TRH is administered subcutaneously, 500
Since it is effective at a concentration one-fold lower, it is thought that it is a central effect due to the above-mentioned transport mechanism, rather than a peripheral effect.

Regarding the retinohypothalamic projection that exists between the retina of the eyeball and the hypothalamus, Moore et al., Journal of Comparative Neurology (J, Coff1p, Neur.
), 146:1 (1972). Nishino also injected horseradish peroxidase, an enzyme with a molecular weight of about 40,000 (often used as a tracer because it can be histochemically stained), into the eyeball, which was taken up by ganglion cells in the retina, and then transferred to the thalamus by axonal flow. It has been reported that the biorhythm and its mechanism are transported to the lower part of the body (“Continued: Biorhythm and its mechanism” (Kodansha Scientific) 203-214
(1978)).

When eye drops containing the composition of the present invention are administered, in addition to the above-mentioned mechanism of action, the substance is transported to the hypothalamus or other brain regions via other nerve conduction pathways, and It is also possible that this is expressed by directly acting on nerves such as the retina.

For example, CCK, TR)! Many neuropeptides such as , VIP, somatostatin, and enkephalin are known to exist in the retina, and may act on nerves distributed in the retina and eyeball.

Next, the ophthalmic composition of the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

(Test Method) The experiment was conducted using a passive avoidance test experimental device for mice (Ohara Medical Sangyo Co., Ltd.) consisting of a box partitioned into two light and dark rooms. i.e. a dark room (height 8 cm.

The inverted trapezoidal box with 5 marks on the base, 9.5σ on the hypotenuse, and length 14 (7) is shielded from light by a black plastic outer box, and the floor is equipped with a stainless steel grid to provide electrical stimulation. If the photo beam installed in the room is interrupted, the power will be turned on after a certain period of time. On the other hand, from 25 cm above, 8
A circular doorway with a diameter of 3 (to) that could be opened and closed with a guillotine door was installed between the light room (a box of the same shape as the dark room and 18 cm in length) made of transparent plastic that was illuminated by a 0W light bulb and the dark room.

Experiments were conducted in the following order using such a light/dark box.

A ddY male mouse (5 weeks old, weight 25-35 g), which had been previously acclimated to a light/dark box, was placed in a light room and the guillotine door was opened. Three seconds after the mouse moves into the dark room and crosses the photobeam, the extremities are exposed to 0.3+l from the floor grid.
An electric shock of 1A was delivered for 3 seconds (acquisition trial). Immediately after the mouse jumped out into the light room, the door was closed, and the mouse was taken out of the light room and returned to its home cage. After 24 hours, the mouse was placed in the light room again, and the time from opening the guillotine door to completely entering the dark room was measured as reaction latency up to a maximum of 300 seconds (retention trial).

Amnesia is cycloheximide 120 dissolved in saline
mg/kg was administered subcutaneously 10 minutes before the acquisition trial for induction. All test drugs were 0.1% bovine serum albumin (
It was dissolved in physiological saline containing BSA), and immediately after the electric shock, a total of 10 μg was administered to each eye, approximately 5 μg per eye. Furthermore, the same amount of physiological saline containing 0.1% BS^ was administered to the eyes of the control group.

For convenience, the ratio of mice showing a response latency longer than 100 seconds in the retention trial to the number of animals used was expressed as a percentage as a memory rate.

Example 1 (Effect of eye drop administration of REM sleep inducer on experimental memory impairment in mice) Table 1 shows the results of eye drop administration of REM sleep inducer at 10 μg per mouse (5 μfI per eye).

Most of the mice in the cycloheximide-untreated control group did not forget the previous day's electric shock, and learning was successful.
Memory impairment was significant in the cycloheximide-treated control group.

However, immediately after learning, prostaglandin D2 (PGD2)
), uridine, oxidized and reduced glutathione, piperidine, delta sleep-inducing peptide (DSIP), arginine vasotocin (AVT) and progesterone.
When administered as eye drops at a concentration of 0 μM, a clear improvement effect on response latency and memory rate was observed. There was also a tendency for improvement in memory rates in the group administered with somatostatin, melatonin, and pipecolic acid, a derivative of piperidine. However, serotonin and its precursor tryptophan were not found to have any memory-improving effects.

[See the margins below] Example 2 (Effects of ophthalmic administration of neuropeptides on experimental tt disorders in mice) Table 2 shows the results of ophthalmic administration of neuropeptides distributed in the hypothalamus in the same manner as in Example 1. Among these neuropeptides, there are several molecular types of vasopressin, dynorphin, endorphin, enkephalin, and cholecystokinin, and we selected the most representative ones for the experiments.

Similar to [Example], significant memory impairment occurred due to cycloheximide administration, but immediately after learning, arginine vasopressin (AVP), oxytocin, neurotensin, neuropeptide Y1 vasoactive intestinal peptide mP)
Cholenstokinin octapeptide (CCK-8),
Eye drops of thyrotropin-releasing hormone (TRH), kyotorphin, dynorphin A1β-neoendorphin, methionine enkephalin (Met-enkephalin), and nerve growth factor (NGF) have a clear improvement effect on response latency and memory rate. was recognized.

The dose of TRI in this experiment was the minimum effective concentration of 10 mg/kg when administered subcutaneously (see Yamazaki et al., "Drugs, Psychiatry, and Behavior", pp. 3, 127-136 (191t3)).
It was about 1/500th of that.

[Margin below] The effects of all the test compounds used in Examples 1 and 2 on the eyelids and eyeballs were investigated. Immediately after administration and twice 24 hours later, the subjects were visually observed for abnormal behavior, screams, blink reactions, eyelid edema, corneal opacity, exudates, bleeding, etc., but no abnormalities were observed in either case. , no changes were found relative to the control group.

Furthermore, when 100μ of uridine was administered eye drops to 7926 ICR animals for 2 weeks continuously, there was no change in body weight gain compared to the control group, and no macroscopic changes were observed in the eyeballs or various organs. Therefore, eye drop compositions containing these compounds as active ingredients are considered to be highly safe.

[Effects of the Invention] By using eye drops containing the eye drop composition of the present invention containing a REM sleep-inducing substance or a neuropeptide as an active ingredient, the substance can be delivered directly to the central nervous system, which was previously impossible with oral administration. It becomes possible to make it work. Therefore, it becomes possible to administer safe REM sleep-inducing substances or neuropeptides by a simple method and at low cost.

Claims (1)

[Scope of Claims] 1. An eye drop composition containing a REM sleep inducer or a neuropeptide as an active ingredient. 2 The REM sleep inducing substance is uridine, glutathione,
The composition according to claim 1, which is at least one selected from the group consisting of sleep promoting substances (SPS), prostaglandin D_2, delta sleep-inducing peptide, piperidine, vasotocin, somatostatin, progesterone, and derivatives thereof. 3. The neuropeptides consist of vasopressin, oxytocin, neurotensin, vasoactive intestinal peptide, neuropeptide Y, cholecystokinin, thyrotropin-releasing hormone, kyotorphin, dynorphin, endorphin, enkephalin, nerve growth factor, and derivatives thereof. The composition according to claim 1, wherein the composition is at least one selected from the group consisting of: