JP7197112B2 - Pharmaceutical composition for treating bullous keratopathy - Google Patents

Description

The present invention relates to a pharmaceutical composition for treating bullous keratopathy.

Bullous keratopathy is a disease in which corneal edema/opacity occurs due to dysfunction of corneal endothelial cells (corneal endothelial disorder). Corneal edema/opacity is also caused by various factors such as dryness, trauma, infection, ocular inflammatory disease, glaucoma, and tumor. Corneal opacification is caused by an increase in water content between aligned collagen fibers present in the corneal stroma. In a normal clear cornea, the water content in the corneal stroma is regulated by corneal epithelial cells and corneal endothelial cells. corneal edema/opacity due to excess water in the corneal stroma. For corneal edema/opacity, a treatment method is generally performed in which the corneal edema/opacity is alleviated by draining water from the corneal stroma by the osmotic action of hypertonic saline solution. Attempts to alleviate corneal edema and opacity using water did not yield satisfactory results.

Full-thickness or partial corneal transplantation has been performed as an actual treatment method, and treatment of bullous keratopathy using eye drops and regenerative medicine has also been attempted. For example, Patent Document 1 discloses that a Rho kinase inhibitor has a corneal endothelial cell adhesion-promoting effect and is useful as a preventive or therapeutic agent for corneal endothelial disorders. In addition, regenerative medicine has been attempted in which an endothelial cell sheet cultured in vitro is transplanted into the eye, or endothelial cells are directly injected into the eye.

On the other hand, local anesthetic eye drops are mainly used for topical anesthesia in the ophthalmic area. It is used during examinations and treatments that require contact with the inside and outside of the eye. It is an eye drop that is also used in cases of blepharospasm and pain relief during ophthalmic surgery. Local anesthetic eye drops have a maximum effect in dogs 15 minutes after instillation and have an action time of about 45 minutes.

JP 2016-026199 A

Thus, bullous keratopathy accompanied by corneal edema/opacity is treated only by surgical therapy such as corneal transplantation. There is a need for a less burdensome treatment. An object of the present invention is to provide a novel pharmaceutical composition for treating bullous keratopathy that is less burdensome to patients.

The inventor of the present invention visited a hospital complaining of corneal edema and opacity, and applied local anesthetic eye drops during intraocular pressure examination. completed. The present invention
[1] A pharmaceutical composition for treating bullous keratopathy containing a local anesthetic as an active ingredient,
[2] The pharmaceutical composition for treating bullous keratopathy of [1], wherein the local anesthetic is oxybuprocaine, bupivacaine, or lidocaine, or a pharmaceutically acceptable salt thereof;
[3] A method of treating bullous keratopathy, comprising administering an effective amount of a local anesthetic to a subject in need of treatment for bullous keratopathy;
[4] Use of a local anesthetic for manufacturing a therapeutic agent for bullous keratopathy,
[5] It relates to a local anesthetic for treating bullous keratopathy.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide drug therapy with less burden on patients.

corneal edema and opacity before and after instillation of a pharmaceutical composition containing oxybuprocaine hydrochloride as an active ingredient (Benoxil (registered trademark) ophthalmic solution 0.4%; Santen Pharmaceutical Co., Ltd.) in cases 1 to 4; It is a photograph instead of a drawing. Fig. 10 is a photograph, instead of a drawing, showing hourly changes in corneal edema/suspension with respect to benoxil ophthalmic solution 0.4% in case 1; FIG. 10 is a photograph, instead of a drawing, showing the results of a slit lamp examination and an OCT examination before and after instillation of 0.4% benoxil ophthalmic solution in Case 4. FIG.

The local anesthetic used in the present invention is not particularly limited as long as it is a drug capable of improving corneal edema/opacity. buprocaine hydrochloride), bupivacaine or a pharmaceutically acceptable salt thereof (e.g. bupivacaine hydrochloride hydrate), lidocaine or a pharmaceutically acceptable salt thereof (e.g. lidocaine hydrochloride), or these Pharmacologically related compounds and the like can be mentioned.

Pharmaceutical compositions containing oxybuprocaine or a pharmaceutically acceptable salt thereof include, for example, oxybuprocaine hydrochloride ophthalmic solution, which is an ophthalmic surface anesthetic, Benoxil (registered trademark) ophthalmic solution 0.4 % (Santen Pharmaceutical Co., Ltd.) and 0.4% oxybuprocaine hydrochloride Minimus (registered trademark) ophthalmic solution "Senju (registered trademark)" (Senju Pharmaceutical Co., Ltd.). Alternatively, it can be used by appropriately diluting or concentrating and/or adding one or more pharmaceutically acceptable pharmaceutical additives.

The Benoxil ophthalmic solution 0.4% contains, as additives, sodium edetate hydrate, sodium chloride, benzalkonium chloride, polyvinyl alcohol (partially saponified product), and a pH adjuster. The 0.4% oxybuprocaine hydrochloride minimus ophthalmic solution "Senju" contains sodium edetate hydrate, polyvinyl alcohol, sodium acetate hydrate, sodium chloride and hydrochloric acid as additives. The pharmaceutical composition of the present invention can contain one or more compounds selected from these additives in addition to oxybuprocaine or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions containing bupivacaine or a pharmaceutically acceptable salt thereof include, for example, bupivacaine hydrochloride hydrate injection, which is a long-acting local anesthetic, Marcaine (registered trademark) 0.125% , 0.25%, and 0.5% (Aspen Japan) are commercially available, and in the present invention, the commercially available product is used as it is, or by appropriately diluting or concentrating it, and/or a pharmaceutically acceptable drug One or more additives can be added and utilized.

The Marcaine Injection 0.125%, 0.25%, and 0.5% contain sodium chloride, methylparaben, propylparaben, and a pH adjuster as additives. The pharmaceutical composition of the present invention can contain one or more compounds selected from these additives in addition to bupivacaine or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions containing lidocaine or a pharmaceutically acceptable salt thereof include, for example, lidocaine hydrochloride injection, which is a local anesthetic, Xylocaine (registered trademark) injection 0.5%, 1%, 2 % (Aspen Japan) is commercially available, and in the present invention, the commercially available product is used as it is, or diluted or concentrated as appropriate, and / or 1 or more pharmaceutically acceptable pharmaceutical additives are added. can be used.

The 0.5%, 1%, and 2% xylocaine injection solutions contain sodium chloride, methylparaben, and a pH adjuster as additives. The pharmaceutical composition of the present invention can contain one or more compounds selected from these additives in addition to lidocaine or a pharmaceutically acceptable salt thereof.

The oxybuprocaine or a pharmaceutically acceptable salt thereof is an aminobenzoic acid ester compound, and pharmacologically related compounds such as procaine or a pharmaceutically acceptable salt thereof (e.g. , hydrochloride), tetracaine or a pharmaceutically acceptable salt thereof (eg, hydrochloride), etc. (Benoxil ophthalmic solution 0.4% pharmaceutical interview form).
The bupivacaine or a pharmaceutically acceptable salt thereof is an amide-type local anesthetic, and pharmacologically related compounds such as lidocaine, mepivacaine, ropivacaine, or their pharmaceutically acceptable Salts, etc. (from drug interview form for Marcaine Injection 0.125%, 0.25%, 0.5%).
Lidocaine or a pharmaceutically acceptable salt thereof is an amide-type local anesthetic, and pharmacologically related compounds include, for example, bupivacaine, mepivacaine, propitocaine, ropivacaine, etc. (xylocaine injection 0 .5%, 1%, 2% drug interview forms).
These local anesthetics can also be used as active ingredients of the pharmaceutical composition of the present invention as long as they are drugs capable of improving corneal edema/opacity.

Improvement of corneal edema/opacity is observed with the naked eye or with an ophthalmologic examination instrument such as a slit lamp after administration of the evaluation drug (e.g., after instillation). It can be confirmed by intraperispective examination, thinning of the cornea, and the like. In addition, for example, it can be confirmed by measuring the thickness of the cornea with an optical coherence tomography (OCT).

The dosage of the local anesthetic is appropriately determined on a case-by-case basis, taking into account, for example, the route of administration, symptoms of disease, age, race, and sex of the subject to be administered. In the case of eye instillation for a normal adult, for example, 1 to 4 drops of 0.01 to 1000 mg/mL, preferably 0.1 to 100 mg/mL, more preferably 1 to 10 mg/mL can be instilled into the eye. can be administered once or multiple times. In the case of multiple administrations, the interval may be selected regularly or irregularly, for example, 10 minutes to 6 hours, preferably 30 minutes to 4 hours, more preferably 1 to 2 hours. . In addition, each said minimum and each upper limit can be combined arbitrarily as desired.

Dosage forms of the pharmaceutical composition of the present invention include oral agents such as powders, fine granules, granules, tablets, capsules, suspensions, emulsions, syrups, extracts, and pills; Alternatively, parenteral agents such as injections, external solutions, ointments, suppositories, creams for topical administration, and eye drops, preferably eye drops.

The pharmaceutical composition of the present invention contains, in addition to the active ingredient, a local anesthetic, optionally pharmaceutically acceptable pharmaceutical additives such as buffers, tonicity agents, thickening agents, and stabilizing agents. agents, antioxidants, preservatives, excipients, binders, disintegrants, acidulants, effervescent agents, artificial sweeteners, flavors, lubricants, colorants, and the like. These pharmaceutical additives may be added singly or in combination of two or more in an appropriate amount.

EXAMPLES The present invention will be specifically described below with reference to Examples, but these are not intended to limit the scope of the present invention.

<<Example 1: Case 1>>
Case 1 is a Chihuahua, female, 8 years old, weighing 3.6 kg. He was diagnosed with corneal dystrophy in both eyes by a nearby doctor and visited the Department of Ophthalmology, Animal Medical Center, Faculty of Agriculture, Tottori University. A medical examination at this center revealed corneal edema and opacity in both eyes.

In order to observe the effect of oxybuprocaine hydrochloride, Benoxil (registered trademark) ophthalmic solution 0.4% (Santen Pharmaceutical Co., Ltd.) (hereinafter referred to as Benoxil unless otherwise specified) was applied to the right eye at hourly intervals. Corneal edema/opacity was observed before and immediately after each eye drop. Unless otherwise specified, about 1 to 4 drops were used for one eye drop.
FIG. 1 shows the state of corneal edema/opacity before instillation and 4 hours after the first instillation (immediately after the fifth instillation). Observation is performed using diffused light and a slit lamp. The left side of FIG. 1 is an observed image by diffused light, and the right side of FIG. 1 is an observed image by a slit lamp. In addition, observation with a slit lamp microscope was performed by photographing at an incident light of 45 degrees. Fig. 2 shows changes in corneal edema/opacity before instillation and hourly.
Edema and opacity were observed over the entire cornea of the right eye before instillation, but improvement of corneal edema and opacity in the right eye was observed after instillation of oxybuprocaine hydrochloride.

<<Example 2: Case 2>>
Case 2 is a miniature schnauzer, castrated male, 8 years and 3 months old, weighing 10.0 kg. He was diagnosed with cataracts in both eyes by a nearby doctor, and visited the Department of Ophthalmology, Animal Medical Center, Faculty of Agriculture, Tottori University for cataract surgery. Right eye cataract surgery was performed at this center. After that, the follow-up after the operation of the right eye was good, but about half a year after the operation, ocular swelling, conjunctival hyperemia, and corneal opacity were observed in the right eye, and the patient visited our center again.

In case 2, benoxil was instilled into the right eye at 1-hour intervals, and corneal edema/opacity was observed before and immediately after each instillation.
FIG. 1 shows the state of corneal edema/opacity before instillation and 4 hours after the first instillation (immediately after the fifth instillation). Improvement of corneal edema/opacity in the right eye was observed.

<<Example 3: Case 3>>
Case 3 is a pug, female, 8 years and 1 month old, weighing 6.2 kg. He was diagnosed with keratitis by a nearby doctor. As clouding of the cornea progressed, he visited the Department of Ophthalmology, Animal Medical Center, Faculty of Agriculture, Tottori University.

In case 3, benoxil was instilled into the right eye at 1-hour intervals, and corneal edema/opacity was observed before and immediately after each instillation.
FIG. 1 shows the state of corneal edema/opacity before instillation and 4 hours after the first instillation (immediately after the fifth instillation). Improvement of corneal edema/opacity in the right eye was observed.

<<Example 4: Case 4>>
Case 4 is a toy poodle, female, 9 years and 3 months old, weighing 4.2 kg. There was no response in the left eye, and the whites of the eyes were noticed to be red. As a result of an ophthalmologic examination, the patient was diagnosed with left eye lenticular dislocation, uveitis, and glaucoma, and left eye intracapsular cataract extraction was performed. Although the postoperative intraocular pressure was controlled, the expansion of the corneal opacity area near the incision and the progression of the degree of opacification were observed.

In case 4, benoxil was instilled into the left eye at 1-hour intervals, and corneal edema/opacity was observed before instillation and 5 hours after the first instillation (immediately after the sixth instillation).
FIG. 1 shows the state of corneal edema/turbidity (images observed with diffuse light and images observed with a slit lamp) before instillation and 5 hours after the first instillation (immediately after the sixth instillation). Improvement of corneal edema/opacity in the left eye was observed.
In addition, before instillation and 5 hours after the first instillation (immediately after the sixth instillation), the cornea was observed with an optical coherence tomography (OCT; SANTEC CORPORATION). An image observed by the OCT examination is shown in FIG. 3 together with an image observed by the slit lamp examination. An OCT examination showed marked thinning compared to before eye drops.

Next, in case 4, oxybuprocaine hydrochloride Minimus (registered trademark) ophthalmic solution 0.4% "Senju (registered trademark)" (Senju Pharmaceutical Co., Ltd.) was used instead of benoxil as oxybuprocaine hydrochloride. We confirmed the effect. When instilled into the eyes at 1-hour intervals and observed for 7 hours and 30 minutes, the same effect as benoxil was observed.

Furthermore, in case 4, Marcaine (registered trademark) injection 0.5% (Aspen Japan) as bupivacaine hydrochloride hydrate, and Xylocaine (registered trademark) injection 2% (Aspen Japan) as lidocaine hydrochloride were used as comparative examples. , 5% physiological saline (5% Sodiumu Chloride Ophthalmic Solution, USP (Akorn, USA)), respectively, to confirm the effect.
For bupivacaine hydrochloride hydrate, 0.5% marcaine injection diluted with physiological saline to a concentration of 0.4% was instilled into the eye at 1 hour intervals and observed for 6 hours. As for lidocaine hydrochloride, 2% xylocaine injection diluted with physiological saline to a concentration of 0.4% was instilled into the eye at intervals of 1 hour and observed for 7 hours. 5% physiological saline was instilled into the eyes at 1 hour intervals and observed for 6 hours.
5% physiological saline had almost no ameliorative effect on corneal edema/opacity, but bupivacaine hydrochloride hydrate and lidocaine hydrochloride ameliorated corneal edema/opacity.

INDUSTRIAL APPLICABILITY The present invention can be used to treat bullous keratopathy.

Claims (1)

A pharmaceutical composition for treating bullous keratopathy, containing as an active ingredient a local anesthetic selected from the group consisting of oxybuprocaine, bupivacaine, lidocaine, and pharmaceutically acceptable salts thereof (provided that excluding therapeutic mixtures for the treatment of post-inflammatory bullous keratopathy containing lidocaine, dexazone, taufone, daragin, and lidase) .

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