JPH10236972A - Tear secretagogue - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new lacrimal fluid-secretion promoter for promoting secretion of lacrimal fluid and effective to a disease caused by shortage of the secretion of the lacrimal fluid, such as dry eye by using a ligand of a corticotrophin hormone-releasing hormone receptor as an active ingredient. SOLUTION: This lacrimal fluid-secretion promoter contains a ligand of a corticotrophin hormone-releasing hormone receptor (a CRH receptor). The ligand of the CRH receptor is preferably a CRH analogue, more preferably the human CRH of the formula. The CRH analogue is readily obtained by a peptide synthetic method or a gene recombinant method. An administration form of the objective promoter is preferably an eye drop or an injection when the CRH receptor ligand is a peptide. When the CRH receptor is used as the injection, the active ingredient is usually included so as to be 0.001-1wt.% in physiological saline. When the CRH receptor is used as the eye drop, a buffer substance, an isotonizing agent, etc., are added to the solution obtained by dissolving 0.001-1wt.% active ingredient in water. Generally, the divided dose of the active ingredient is 1.5μg/kg body weight.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a lacrimation promoter composition comprising a ligand for a corticotropin-releasing hormone receptor as an active ingredient.

[0002]

2. Description of the Related Art At present, a large number of people around the world are suffering from diseases caused by a tear deficiency, which are diagnosed as dry eye, dry eye, dry keratitis and the like. One of the major causes of these diseases is considered to be an autoimmune abnormality called Sjogren's syndrome, and the possibility of treatment from this viewpoint is being examined (see new ophthalmology, 11
(8), 1187-1195, 1994). Also, it has been reported that anetholetrithione promotes lacrimal secretion for dry eyeballs in Sjogren's syndrome (Diagnosis and New Drugs, Vol. 26, No. 11, 105-127, 198).
9 years). Furthermore, it has been reported that vitamin A instillation is effective for dry eye (new ophthalmology, 10
(10), 1685-1686, 1993).

As described above, various drugs for diseases caused by tear deficiency such as dry eye have been examined, but no satisfactory drug has been found at present. on the other hand,
Corticotropin-releasing hormone (Corticot)
(Repeat Releasing Hormone; hereinafter sometimes abbreviated as “CRH”) is also called adrenocorticotropic hormone-releasing factor (CRF) and is a polypeptide consisting of 41 amino acids, which is secreted from the hypothalamus and anterior pituitary gland Is a hormone that promotes the synthesis and secretion of ACTH (adrenocorticotropic hormone). Its primary structure was first isolated and determined from sheep by Vale et al. (Vale W, et al., S.
science, 213 , 1394-1397 (198
1)) Furthermore, Shibahara et al. Revealed the structure of human CRH which differs from sheep by 7 amino acids (Shibahara S, et al., EM).
BOJ. , 2 , 775-779 (1883)). Since then, many researchers have been conducting basic and clinical studies.

[0004] Based on these studies, CRH has a direct and specific stimulating effect on human pituitary ACTH secretion, and distinguishes ACTH stimulants at the pituitary level, that is, hypothalamic lesions from pituitary lesions. (Endocrin) has been confirmed to be useful as a potential breakthrough diagnostic agent.
eJ. , 40 (5), 571-579 (1993),
581-589 (1993), 597-606 (1
993).

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a new drug for diseases caused by insufficient tear secretion such as dry eye.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies on the development of a more excellent tear secretion promoting agent, and as a result, have found that CRH acts on tear secretion in a promoting manner. The invention has been completed. That is, the present invention
It is a tear secretion promoting agent containing a CRH receptor ligand as an active ingredient.

According to a preferred embodiment of the present invention, CRH
The above-mentioned lacrimation promoter, wherein the receptor ligand is a CRH analog; the above-mentioned lacrimation promoter, wherein the CRH analog is represented by the amino acid sequence shown in SEQ ID NO: 1; The CRH analog is shown in SEQ ID NO: 2 The above-mentioned tear secretion promoting agent represented by an amino acid sequence; The above-mentioned tear secretion promoting agent which is a preventive and / or therapeutic agent for any of dry eye, dry keratitis and dry eye disease; Eye drops or injection or ointment The above agent for promoting lacrimal secretion is provided.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The tear secretion promoter of the present invention contains a CRH receptor ligand as an active ingredient. The ligand of the CRH receptor means a substance having a specific affinity or binding ability for the CRH receptor.

The active ingredient of the tear secretion-promoting agent of the present invention is a ligand of the above-mentioned CRH receptor, which functions to promote tear secretion and is physiologically and pharmaceutically acceptable. Any substance can be used. Among these CRH receptor ligands, as the active ingredient of the lacrimation promoter composition of the present invention, a CRH analog is preferable, and in particular, human CRH represented by SEQ ID NO: 1 in the Sequence Listing (JP-A-59-1984) Sheep CRH (US Pat. No. 4,415,558) is more preferred, and human CRH is most preferred.

[0010] Here, the CRH analog refers to the amino acid sequence of human CRH of SEQ ID NO: 1, the sheep CRH of SEQ ID NO: 2 or CRH derived from other substances, and one or several amino acid residues relative to those amino acid sequences. A modified amino acid sequence in which a group is substituted, deleted, inserted or modified, and a conjugated amino acid sequence in which CRH and the modified amino acid sequence are bound to cytotoxin, etc., which have specific affinity or binding ability for CRH receptor; Means a substance having Specifically, JP-A-59-199662 and JP-A-59-2996
No. 06342, Tokuyo Sho 61-502396, Tokuyo Sho 6
1-502396, Tokuhoku Hei 5-501616, Tokuhyo Hei 3-501858, Tokuhyo Hei 5-505821, Tokuhyo Hei 5-508871, Tokuhyo Hei 5-502336,
U.S. Pat. No. 4,415,558 and U.S. Pat.
39,885, etc., the amino acid sequences of CRH and its variants, and US Pat. No. 5,132,1
Gelonin and ricin A described in No. 11
(RicinA) and the like.

The CRH analog used in the present invention can be easily produced by a known peptide synthesis method or a method analogous thereto, or a gene recombination method described in the above publications and the like. Can be. The above publication describes that the CRH analog has an ACTH secretion promoting action, a blood pressure lowering action, etc. No mention or suggestion is made.

The lacrimation promoter composition of the present invention promotes lacrimation without eye irritation, and therefore promotes lacrimation and protects the cornea, such as dry eye, dry keratitis, and dry eye. Is effective for the prevention and treatment of various diseases and symptoms that require it. The lacrimation promoter composition according to the present invention is administered as an injection, an eye drop, an ointment or an oral preparation. Among these administration forms, when the CRH receptor ligand is a peptide, eye drops or injections are preferred.

In the case of oral preparations, any conventional forms such as tablets, capsules, powders, solutions, elixirs and the like can be used. For example, in the case of a capsule, an ordinary gelatin type capsule is used. In the case of tablets and powders, various adjuvants commonly used in pharmaceutical preparations can be blended. These capsules, tablets and powders usually contain 5 to 95% by weight, preferably 25 to 90% by weight.
Contains active ingredients.

In the case of liquids, various natural or synthetic liquids such as water, mineral oil, soybean oil, peanut oil, sesame oil, propylene glycol and polyethylene glycol are used. In particular, when a liquid is prepared by using water, it is preferable to use a basic amino acid such as arginine, lysine and histidine as an auxiliary agent (Japanese Patent Laid-Open Publication No.
No. 108737).

In the case of an injection, the physiologically active saline may contain the active ingredient in an amount of 0.001 to 1% by weight. In the case of eye drops, the active ingredient is 0.001 to water.
To the solution dissolved to 1% by weight, various commonly used auxiliaries such as a buffering agent, an isotonic agent, a preservative, and a thickener may be appropriately added.

Examples of the buffer include a phosphate buffer,
Borate buffers, citrate buffers, tartrate buffers, acetate buffers, amino acids and the like are used. Examples of the tonicity agent include sugars such as sorbitol, glucose, and mannitol; polyhydric alcohols such as glycerin and propylene glycol; and salts such as sodium chloride.

Examples of preservatives include quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride, paraoxybenzoic acid esters such as methyl paraoxybenzoate and ethyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid and the like. Their salts, thimerosal, chlorobutanol and the like are used.

As the thickener, for example, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof are used. In the case of an ointment, the active ingredient is mixed with a suitable base such as petrolatum so as to be 0.001 to 1% by weight and uniformly mixed. Further, if necessary, a preservative, a stabilizer and other suitable It is prepared by adding various additives.

The dose of the lacrimation promoter composition according to the present invention varies depending on the age, weight, symptoms, severity of the disease and the like of the patient.
Although ultimately to be determined by the clinician, generally about 1.5 μg / kg body weight /
Administered once.

[0020]

Example 1 The effect of CRH solution on tear secretion was examined using male Japanese rabbits weighing about 2 kg. CRH (Mitsubishi Chemical's recombinant human CRH) solution is 0.01% by weight in physiological saline.
Was used (pH 7.5).

[0030] Eight rabbits were instilled with 0.4% oxybuprocaine hydrochloride (Santen Pharmaceutical Co., Ltd.) twice at 3 minute intervals for 30 μl each. After 3 minutes, water in the conjunctival sac was absorbed with water-absorbing paper. ,
One eye was instilled with 50% of a 0.01% CRH solution and the other eye with a physiological saline solution. Three minutes after the instillation, the water in the conjunctival sac was again absorbed with water absorbing paper,
After a minute, a strip of filter paper having a size of 5 × 30 mm was inserted between the lower eyelid and bulbar conjunctiva to collect tears, and the weight was measured. As a result, the amount of tears 10 minutes after the instillation was 0.01% CRH for 4.6 ± 0.6 mg in the physiological saline group.
The solution group was 7.3 ± 0.4 mg, and the tear volume 20 minutes after instillation was 6.7 ± 0.5 mg in the physiological saline group and 8.5 in the 0.01% CRH solution group. ± 0.9 mg, indicating a significant increase in tear volume in the CRH solution instillation group compared to the control group in which physiological saline was instilled. Note that, after instillation, no remarkable behavior indicating eye irritation of the administered drug such as eye closure or blinking was observed.

[0022]

(Sequence list)

 SEQ ID NO: 1 Sequence length: 41 Sequence type: amino acid Number of chains: 1 chain Topology: linear Sequence type: peptide Origin: Biological name: human Sequence Ser Glu Glu Pro Ile Ser Leu Asp Leu Thr Phe His Leu Leu Arg 1 5 10 15 Glu Val Leu Glu Met Ala Arg Ala Glu Gln Leu Ala Gln Gln Ala His 20 25 30 Ser Asn Arg Lys Leu Met Glu Ile Ile 35 40 [Sequence listing] SEQ ID NO: 2 Sequence length Length: 41 Sequence type: amino acid Number of chains: 1 chain Topology: linear Sequence type: peptide Origin: Sheep sequence Ser Glu Glu Pro Pro Ile Ser Leu Asp Leu Thr Phe His Leu Leu Arg 15 10 15 Glu Val Leu Glu Met Thr Lys Ala Asp Gln Leu Ala Gln Gln Ala His 20 25 30 Ser Asn Arg Lys Leu Leu Asp Ile Ala 35 40

[Brief description of the drawings]

FIG. 1 is a graph showing the effect of human CRH on promoting lacrimal secretion, in which the vertical axis indicates the amount of lacrimal secretion, and * indicates a control group (Con).
trol: physiological saline instillation group) (p <0.0
1) is shown.

Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07K 14/47 ZNA A61K 37/24 (72) Inventor Shinji Yano 2-5-2-2 Marunouchi, Chiyoda-ku, Tokyo Mitsubishi Pharmaceutical Co., Ltd. In company

Claims (6)

[Claims] 1. An agent for promoting lacrimal secretion, comprising a ligand for a corticotropin-releasing hormone receptor as an active ingredient. 2. The lacrimation promoter composition according to claim 1, wherein the ligand of the adrenocorticotropic hormone releasing hormone receptor is a CRH analog. 3. The lacrimation promoter composition according to claim 2, wherein the adrenocorticotropic hormone-releasing hormone analog is represented by the amino acid sequence shown in SEQ ID NO: 1. 4. The agent for promoting lacrimal secretion according to claim 2, wherein the adrenocorticotropic hormone-releasing hormone analog is represented by the amino acid sequence represented by SEQ ID NO: 2. 5. The agent for promoting lacrimal secretion according to claim 1, which is a preventive and / or therapeutic agent for any of dry eye, dry keratitis and dry eye disease. 6. The agent for promoting lacrimal secretion according to claim 1, which is an eye drop, an injection or an ointment.