JP2000169387A - Ophthalmic solution for promoting lacrimation or treating keratoconjunctive disorder containing natriuretic peptide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To find new actions of natriuretic peptide in ophthalmological field. SOLUTION: This ophthalmic solution for promoting lacrimation or treating keratoconjunctive disorder contains a natriuretic peptide as an active ingredient. The natriuretic peptide includes atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP) and C-type natriuretic peptide(CNP). As the keratoconjunctive disorder, are typically cited dry eye, abrasion of corneal epithelium and corneal ulcer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an ophthalmic solution containing natriuretic peptide as an active ingredient for promoting lacrimal secretion or treating keratoconjunctival disorders.

[0002]

2. Description of the Related Art Tear, which is one of the mechanisms for maintaining the wettability of a living body, covers the cornea and conjunctiva (corneal conjunctiva), maintains the wettability, and prevents them from drying. In addition, tears serve as a lubricant to protect the corneal conjunctiva from stimuli caused by blinks, and contribute to maintaining the smoothness of the corneal surface. Tear has a bacteriostatic action and protects against infection from bacteria, fungi, viruses, etc., and also supplies oxygen and various nutrients to the cornea and removes carbon dioxide and metabolites. When the keratoconjunctiva is impaired, the tears play a role in diluting and removing the impaired stimulus and, at the same time, dissociate humoral components such as epidermal growth factor and fibronectin which are involved in wound healing. It is involved in the regulation of wound healing as well as the retention of keratoconjunctival epithelial cells. It is known that such a small amount of tears regulates the physiological state of the corneal conjunctiva, thereby maintaining the transparency and homeostasis of the cornea (New Ophthalmology, 11 , 1179-1185, (199
Four)).

[0003] As a method of treating keratoconjunctival disorders such as dry eye (dry keratoconjunctivitis, etc.), a method of externally supplying a tear component with artificial tears, or a method of viscoelastically removing tears remaining on the surface of the keratoconjunctiva. There is known a method of holding by a substance and leading to treatment of the keratoconjunctiva. Since tears have the effect of healing keratoconjunctival disorders as described above, finding a compound that works directly on lacrimal gland function and promotes lacrimal secretion can be useful for finding dry eye and other keratoconjunctival epithelial disorders. It is expected to be useful for recognized corneal epithelial detachment and corneal ulcer.

[0004] Peptides belonging to the natriuretic peptide are widely distributed from mammals to birds, amphibians, and fish, and are classified into three groups in terms of structure: atrial natriuretic peptide (ANP), cerebral natriuretic peptide (BNP). ) And C-type natriuretic peptide (C
NP). Atrial natriuretic peptide (ANP) includes α-AN consisting of 28 amino acids.
Α-A from amino acids 4 to 28 of P, α-ANP
NP [4-28], amino acids 5 to 28 of α-ANP
Α-ANP [5-28], β-ANP having a structure in which α-ANP has become an antiparallel dimer, and a molecular weight of 13,000 in which a signal peptide is cleaved from an ANP precursor
Are known. Brain natriuretic peptide (BNP) includes BNP-26 consisting of 26 amino acids and BNP- consisting of 32 amino acids.
BNP-45, BNP consisting of 32, 45 amino acids
Approximately 13 molecular weight with signal peptide cleaved from precursor
000 high-molecular-weight γ-BNP and the like are known. As C-type natriuretic peptide (CNP), CNP-22 having 22 amino acids, CNP-53 having 53 amino acids extended to its N-terminus and the like are known. These natriuretic peptides act on the kidneys, adrenal glands, and vascular walls to play an important role in the regulation of systemic fluid electrolytes and blood pressure (circulation regulatory peptides and related diseases, 14-25, Yodosha, 1992 ).

[0005] α-ANP has a vasodilatory effect and a diuretic effect, and is used as a therapeutic agent for cardiovascular diseases such as heart failure (Pharmacology and Therapy, 23 , 949-952, (1995)).

In the field of ophthalmology, it has been reported that α-ANP exhibits an intraocular pressure lowering effect (Curr. Eye Res.,
6 , 1189-1196, (1987)), however, little studies have been made on other effects, and there is no report on the effects on the lacrimal glands or the effects on keratoconjunctival disorders by the ophthalmic administration of natriuretic peptides.

[0007]

There have been few studies on the application of natriuretic peptides in the field of ophthalmology except for intraocular pressure lowering, and research on new effects of natriuretic peptides in the field of ophthalmology is of great interest. It is.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to find a new effect of the natriuretic peptide in the field of ophthalmology. As a result, the natriuretic peptide has a lacrimal secretion promoting action, and It has been found to be useful as a therapeutic agent for disorders.

[0009]

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an ophthalmic solution containing natriuretic peptide as an active ingredient for promoting lacrimal secretion or treating keratoconjunctival disorders.

In the present invention, the natriuretic peptide refers to atrial natriuretic peptide (ANP), cerebral natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). ANP, BNP and CNP having various structures are known, and the natriuretic peptide of the present invention includes all of them.

[0011] Natriuretic peptides are useful drugs as therapeutic agents for cardiovascular diseases, but few reports have been made in the ophthalmology field other than the action of lowering intraocular pressure.

The present inventors have studied the application of the natriuretic peptide to the field of ophthalmology, and as a result, the details will be described in the section of pharmacological test. It has been found that it has a lacrimal secretion promoting action. As described in detail in the section of the prior art, tears have an effect of curing disorders of the keratoconjunctiva, and it is expected that this drug is useful as a therapeutic agent for keratoconjunctival disorders. As a typical example of keratoconjunctival disorders,
These include dry eye, corneal epithelial detachment and corneal ulcers.

The eye drops of the present invention can be prepared by dissolving a natriuretic peptide in a commonly used eye drop base at the time of use. Isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surfactants such as polyoxyethylene sorbitan monooleate, polyoxy 40 stearate, and polyoxyethylene hydrogenated castor oil; Stabilizers such as sodium citrate, sodium edetate, benzalkonium chloride,
A preservative such as paraben or the like can be formulated by using an appropriate amount as needed. The pH may be within the range acceptable for ophthalmic preparations, but is preferably in the range of 4 to 8.

[0014] The concentration of the active ingredient in the eye drops is 0.1.
001 to 1% (W / V), preferably 0.005 to 0.5
% (W / V), more preferably 0.05 to 0.5% (W / V)
Is selected. Administration is carried out by instilling the eye drops once or several times a day.

Hereinafter, formulation examples and pharmacological tests are shown as examples.

[0016]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Formulation Examples Representative formulation examples are shown below.

Formulation 1 (Preparation of 0.1% eye drops) Natriuretic peptide (100 mg) was dissolved in physiological saline (100 ml) to prepare 0.1% eye drops.

Further, by changing the amount of the added natriuretic peptide, the concentration can be reduced to 0.001, 0.005,
0.01, 0.05, 0.5 and 1.0% (W / V) natriuretic peptide eye drops were also prepared.

2. Pharmacological test One method of capturing changes in tear volume during instillation of drugs in normal animals is the Schirmer test strip method used to measure human tear volume. Therefore, in the present invention, the tear volume when the natriuretic peptide was instilled was measured using the Schirmer test paper method, and the effect of the natriuretic peptide on the amount of lacrimal secretion was examined.

(Experimental method) [Experimental animals] Male Japanese white rabbits weighing 1.8 to 2.2 kg were used in the experiments.

[Preparation of Test Drug Solution] Natriuretic peptide (0.56 mg) was dissolved in sterile purified water.
A 1% solution was prepared fresh before use. This is used as a test drug solution.

[Drug Administration Method] The test drug solution (50 μm)
1) was instilled once into the left eye. In order to examine the effect of the base (purified water) on tear secretion, only the base (50 μl) was used.
1) was instilled once into the right eye.

[Measurement Method] The measurement of tear volume was carried out on the eye to which the drug was administered and the eye to which the drug was not administered using Schirmer test paper before the start of the administration of the drug and at a predetermined time after the instillation. A Schirmer test paper whose end was bent was inserted into one third of the rabbit lower eyelid ear side, and one minute later, the length (Schirmer value, mm) of the wet portion of the test paper was measured from the fold.

Three minutes before the measurement of the amount of tears, a local anesthetic 0.4% oxybuprocaine hydrochloride ophthalmic solution (10 μl) was used.
Was instilled once in both eyes.

(Results) The effect of the test drug solution on the amount of tear secretion at time t after the instillation is indicated by the amount of increase in tear (mm) obtained by the following equation.

Tear increase (mm) = [SM (Dt) −SM (D−
0)]-[SM (Vt) -SM (V-0)] SM (Dt): Schirmer value in the drug-administered eye (right eye) at t hours after drug administration SM (D-0): before starting drug administration Schirmer value in drug-administered eye (right eye) SM (Vt): Schirmer value in base-administered eye (left eye) t hours after vehicle administration SM (V-0): Base-administered eye before start of vehicle administration Schirmer value in (left eye)

As an example of the test results, the test drugs (rat α-ANP, rat BNP-32 and human CNP-2
2; both purchased from Peptide Institute) Table 1 shows the amount of increase in tears (mm) 1 hour after instillation of the solution.

[0028]

[Table 1] The numerical values in the table each represent the average value of 6 cases per group.

As can be seen from Table 1, the test drug (rat α
-ANP, rat BNP-32 and human CNP-2
2) was found to have an excellent lacrimation promoting action.

[0030]

Industrial Applicability According to the present invention, it is possible to provide an ophthalmic solution containing a natriuretic peptide, which has an excellent lacrimation promoting action and is useful as a lacrimation promotion and therapeutic agent for keratoconjunctival disorders.

Claims (3)

[Claims] 1. An eye drop for promoting lacrimal secretion, comprising a natriuretic peptide as an active ingredient. 2. An ophthalmic solution for treating keratoconjunctival disorders, comprising a natriuretic peptide as an active ingredient. 3. The ophthalmic preparation according to claim 2, wherein the corneal conjunctival disorder is dry eye, corneal epithelial detachment and / or corneal ulcer.