Title:  Drug of improving optic nerve head circulation disorder

United States Patent:  6,387,910

Assignee:  Akzo Nobel N.V. (Arnhem, NL)

Filed:  October 2, 2000

PCT NO:  PCT/JP99/00202

102(e) Date:  October 2, 2000

PCT PUB. Date:  August 5, 1999

Foreign Application Priority Data:  Jan 29, 1998[JP] (10-016831); Sep 07, 1998[JP] (10-252375)

A novel drug for improving the circulation in the optic nerve head, which comprises as an active ingredient Lomerizine (I) or a pharmaceutically acceptable acid addition salt. The optic nerve head circulation improving drug of this invention can increase the blood flow in the optic nerve head with no or little systemic side effects such as hypotensive activity or heart rate increasing activity and is useful particularly for the treatment of normal tension glaucoma.

DETAILED DESCRIPTION OF THE INVENTION

The drug for improving the optic nerve head circulation of this invention comprises as an active ingredient Lomerizine or a pharmaceutically acceptable acid addition salt thereof. These compounds are prepared by a process as disclosed, for example, in the above-mentioned JP-A-60-222472.

The pharmaceutically acceptable acid addition salt includes a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or a salt with an organic acid such as maleic acid, fumaric acid, succinic acid, citric acid, and particularly preferable salt is dihydrochloride salt.

Besides, it is known that the pharmaceutically acceptable acid addition salt of Lomerizine is present also as in the form of polymorph or of a hydrate, and the active ingredient in the present invention includes also those polymorph or hydrate.

The drug for the improvement of the optic nerve head circulation of this invention can be administered to the patients suffering from the normal tension glaucoma in the form of a preparation suitable for oral administration or for injection, preferably in the preparation for oral administration.

The preparation for oral administration includes tablets, granules, fine granules, powders, etc. and these preparations can be prepared by conventional methods by admixing Lomerizine or a pharmaceutically acceptable acid addition salt thereof with conventional pharmaceutically acceptable additives such as lactose, corn starch, crystalline cellulose, magnesium stearate, carboxymethyl-cellulose calcium, hydroxypropyl cellulose, talc, and the like.

The preparation for injection can be prepared by dissolving Lomerizine or a pharmaceutically acceptable acid addition salt thereof in a distilled water for injection, which may optionally be incorporated with isotonic agents (e.g. mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose, etc.), stabilizers (e.g. sodium sulphite, albumin, etc.), preservatives (e.g. benzyl alcohol, methyl p-hydroxy-benzoate, etc.). The preparation may also optionally be incorporated with a pH adjusting agent such as an acid (e.g. hydrochloric acid, methanesulfonic acid, citric acid, etc.) or a base (e.g. sodium hydroxide, diisopropanolamine, etc.).

The injection preparation may be in the form of a lyophilized preparation which is dissolved in a solvent when used. The lyophilized preparation can be prepared by lyophilizing an aqueous solution of the above active ingredient, and may optionally be incorporated with the above-mentioned isotonic agents, stabilizers, preservatives, pH adjusting agents, and the like.

The drug of this invention can increase the blood flow in the optic nerve head and can improve the optic nerve head circulation, and hence is useful particularly for the treatment of the normal tension glaucoma.

The dose of the optic nerve head circulation improving drug of this invention may vary depending on the administration routes, the severity of diseases, age, weight of patients, and the like, but is usually in the range of 0.1 mg to 100 mg as Lomerizine or a pharmaceutically acceptable acid addition salt thereof, which is administered one to three times per day.

Among the above, in case of a optic nerve head circulation improving drug comprising as an active ingredient Lomerizine hydrochloride, it is particularly preferable to administer by oral route, where the dose thereof may vary depending on the severity of diseases, age and weight of the patients, but may usually be in the range of 1 mg to 40 mg as Lomerizine hydrochloride which is administered one to three times per day. Preferably it is administered at a dose of 2 mg to 10 mg, twice or three times per day.

Lomerizine or a pharmaceutically acceptable acid addition salt thereof can increase the blood flow in the optic nerve head with little systemic side effects such as hypotensive activity or increase of heart rate. The optic nerve head circulation improving drug of this invention has also less manifestation of other side effects (objective and subjective symptoms). Moreover, the side effect-manifestation in aged persons (65-85 years old) is not so different from that in younger persons (15-64 years old).

Accordingly, the optic nerve head circulation improving drug of this invention has high safety and can safely be used even in an aged patient, particularly for the treatment of the normal tension glaucoma.

Besides, the optic nerve head circulation improving drug of this invention is effective by oral administration.

The above excellent effects of the optic nerve head circulation improving drug of this invention could be confirmed by the following experiments.

That is, Lomerizine hydrochloride 20 mg (5 mg.times.4 tablets) was administered to healthy male volunteers (6 men) with normal intraocular pressure, and the blood flow in the central retinal artery and ophthalmic artery were measured by a ultrasonic color Doppler's method at 1.5, 3.0, 4.5 and 6.0 hours after administration of the drug. Simultaneously, the blood pressure, heart rate and intraocular pressure were also measured.

As a result, Lomerizine hydrochloride could significantly increase the blood flow in the central retinal artery at a dose which did not affect on the blood pressure and intraocular pressure. Since the central retinal artery is correlative with blood flow in the retina and the optic nerve head, it is considered that Lomerizine hydrochloride is effective for the improvement of circulation dysfunction in the retina and in the optic nerve head at a dose at which it does not affect on the blood pressure and the intraocular pressure. Besides, Lomerizine hydrochloride showed no significant action on the blood flow in the ophthalmic artery. Further, four and half hours after administration, it showed a temporary lowering of the heart rate.

When the effects of Lomerizine hydrochloride on the blood flow lowering in the optic nerve head induced by administration of Endothelin-1 was observed by the method of Sugiyama et al. [cf. Tetsuya SUGIYAMA and Ikuo AZUMA, "Atarashii Ganka" (Journal of the Eye), Vol. 14, No. 5, pp. 745-748, 1997]. As a result, it showed dose-dependent inhibition of lowering of blood flow in the optic nerve head.

Moreover, it is expected from the following experimental results that the optic nerve head circulation improving drug of this invention can inhibit the death of neurocytes in retina which is usually observed in patients suffering from glaucoma.

That is, in view of the facts that within the vitreous body of glaucoma patients glutamic acid is contained in so high concentration as to induce death of neurocyte and that the neurocytes in retina disappear by exposing to glutamic acid in experimental models, the following experiments have been done.

From an embryo of a pregnant rat (18th days after confirmation), the neurocytes in retina were isolated and cultivated for 10 days, and were treated with glutamic acid (500 .mu.M) for 10 minutes. The resultant was incubated in a medium containing no glutamic acid for one hour, and then was subjected to examine the neurotoxicity with glutamic acid by a Trypan blue-exclusion method. Lomerizine hydrochloride was applied to the neurocytes to be tested from 30 minutes prior to the treatment with glutamic acid till one hour after the evaluation of the survival rate of the cells.

As a result, Lomerizine hydrochloride showed dose-dependently inhibitory activity against the death of neurocytes induced by glutamic acid, and showed significant inhibitory activity in an amount of 0.01, 0.1 and 1 .mu.M.

Claim 1 of 18 Claims

What is claimed is:

1. A method for improving the circulation in the optic nerve head, which comprises administering orally an effective amount of Lomerizine or a pharmaceutically acceptable acid addition salt thereof to a subject in need thereof.

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