Therapeutic agent for glaucoma

The present invention provides a novel drug for treating glaucoma. The present invention relates to a therapeutic agent for glaucoma which comprises an aminoalkoxybibenzyl represented by the formula (I): ##STR1## or a hydrate or pharmaceutically acceptable salt thereof as an active ingredient.

FIELD OF THE INVENTION 
The present invention relates to a therapeutic agent for glaucoma. 
BACKGROUND OF THE INVENTION 
Glaucoma is considered to be a group of diseases wherein the entoptic 
tissue (particularly function of optic nerve cell) is damaged from lesions 
causing an abnormal ocular tension. Normally, the principal factors of the 
mechanism causing lesions are considered to be ischemic symptoms and 
disorder of optic nerve axonal flow due to mechanical compression in the 
lamina cribrosa caused by an increase in ocular tension. However, the 
mechanism of the increase in ocular tension is not clear at present. 
For the treatment of the disease, glaucoma, a drug or surgical therapy has 
been mainly performed aiming at returning the increased ocular tension to 
a normal level. There are few treatments for protecting an optical nerve 
function directly. For instance, a vitamin B12 formulation can be used as 
a nutrient agent for protecting the optical nerve, and a calcium 
antagonist or an enzyme formulation can be used for the purpose of 
improving blood flow in the optic disc to protect the optical nerve cells. 
However, effectiveness of these agents on the disorder of the visual field 
caused by glaucoma is not clear. Besides, there is a problem that side 
effects can occur during a long-term usage thereof. 
Therefore, the purpose of the present invention is to provide a therapeutic 
agent enabling an effective drug therapy for glaucoma. Further purpose of 
the present invention is to provide a therapeutic agent for glaucoma which 
has reduced side effects related to a long-term usage thereof. 
SUMMARY OF THE INVENTION 
In order to solve the above problems, the present inventors have studied 
intensively. As a result, it has been found that 2-(4-methylaminobutoxy) 
diphenylmethane or a hydrate or pharmaceutically acceptable salt thereof 
is useful for treating glaucoma, and the present invention has been 
accomplished. 
The present inventors have found that 
2-(4-methylaminobutoxy)diphenylmethane, which is disclosed in Japanese 
Patent Publication (Kokoku) No. Hei 60-6349 specification, is useful for 
treating infantile hyperkinetic disorders. The present invention has been 
established based on such finding. 
It is reported in GB 1512880 publication that 
2-(4-methylaminobutoxy)diphenylmethane possesses an antidepressant 
activity, and it is also known from EP 103897 publication that this 
compound is useful as an agent for improving and treating pathergasia 
caused by intracranial organic disease such as cerebral hemorrhage or the 
like. A medicine containing 2-(4-methylaminobutoxy) diphenylmethane 
hydrochloride as an effective ingredient, which has a generic name of 
"bifemelane hydrochloride", is commercially available and has been used 
for improving cerebral nerve function, in particular, for treating 
aftereffect of cerebral occlusion or hemorrhage accompanied by volition 
lowering and emotional disorder. 
According to the present invention, a therapeutic agent for glaucoma, which 
contains as an essential component 2-(4-methylaminobutoxy) diphenylmethane 
of the formula (I): 
##STR2## 
or a hydrate or pharmaceutically acceptable salt thereof, is provided. 
The compound of the formula (I) can be easily prepared according to the 
method as described, for example, in Japanese Patent Publication Kokoku) 
No. Sho 60-6349 specification (Example 1) or Japanese Patent Publication 
(Kokoku) No. Hei 2-33689 (Column 4 -5). A free form of said compound, its 
hydrate or a physiologically acceptable acid addition salt thereof may be 
used as an active ingredient of the pharmaceutical. composition of the 
present invention. 
The pharmacologically acceptable acid addition salts include mineral acid 
salts such as hydrochloride, hydrobromide, hydroiodide, suifate, nitrate 
and phosphate; or organic acid salts such as acetate, maleate, fumarate, 
citrate, oxalate, succinate, tartarate, malate, mandelate, 
methanesulfonate, p-toluenesulfonate and 10-camphor sulfonate, with the 
hydrochloride of said compound being preferred, which is commercially 
available as a substance having generic name "bifemetane hydrochloride". 
Route of administration of the therapeutic agent is not particularly 
limited, and it may be administered by oral and parenteral routes, with 
oral used alone for treating said disorder, but ordinarily, a conventional 
pharmaceutical formulation comprising the compound of the formula (I) 
together with pharmacologically and pharmaceutically acceptable additives 
may be prepared. The pharmacologically and pharmaceutically acceptable 
additives include, for example, excipients, disintegrators or 
disintegration aids, binders, lubricants, coating agents, pigments, 
diluents, bases, dissolving agents or solubilizers, isotonic agents, pH 
regulators, stabilizers, propellants, adhesives, and the like. 
Appropriate formulations for oral administration include, for example, 
tablets, capsules, powders, fine granules, granules, solutions, syrups and 
the like. Appropriate formulations for parenteral administration include, 
for example, injections, drops, suppositories, inhalants, plasters, and 
the like. 
The formulations suitable for oral, percutaneous or transmucosai 
administration may contain pharmaceutically acceptable additives including 
excipients such as glucose, lactose, D-mannitol, starch or crystalline 
cellulose; disintegrators or disintegration aids such as carboxymethyl 
cellulose, starch or calcium carboxymethyl cellulose, etc.; binders such 
as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, 
polyvinylpyrrolidone or gelatin; lubricants such as magnesium stearate or 
talc; coating agents such as hydroxypropyl methyl cellulose, saccharose, 
polyethylene glycol or titanium oxide; and bases such as vaseline, liquid 
paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water 
or hard fat. Further, such formulations may be prepared by adding 
pharmaceutical additives including propellants such as fron, diethyl ether 
or compressed gas; adhesives such as sodium polyacrylate, polyvinyl 
alcohol, methyl cellulose, polyisobutylene or polybutene; basic cloth such 
as cotton cloth or plastic sheet; and the like. 
The formulations appropriate for injection or drip infusion may contain 
pharmaceutical additives including dissolving agents or dissolution aids 
which can form aqueous injections or those of the dissolving type-in use 
such as distilled water for injection, physiological brine or propylene 
glycol; isotonic agents such as glucose, sodium chloride, D-mannitol or 
glycerin; pH regulators such as inorganic acids, organic acids, inorganic 
bases or organic bases; and the like. 
Since pharmaceutical formulations for treating cerebral nerve function 
which contain the compound of the formula (I) as an active ingredient are 
already commercially available under the generic name "bifemelane 
hydrochloride" and trade names "Alnert" and "Celeport" by Fujisawa 
Pharmaceutical Chemical Industries, Co., Ltd. and Eisai Co., Ltd., 
respectively. Said commercially available formulations may be used as a 
pharmaceutical composition of the present invention for treating 
hyperkinetic disorders. 
Appropriate dosage of said agent is not limitative and can be appropriately 
determined depending upon administering route, age or body weight of 
patients, symptoms of the disease, and the like. For example, for oral 
administration, the daily dosage for adult, which corresponds to about 
5-300 mg. preferably about 50-200 mg, particularly preferably 150 mg of 
the active ingredient can be used as a basis for calculating the daily 
dosage for infants. The pharmaceutical composition of the present 
invention may be administered once a day or for several times at devided 
daily dose, and the period of administration may be appropriately 
determined, depending upon the age of particular infant and degree of the 
symptoms. Further, 2-(4-methylaminobutoxy)diphenylmethane incorporated 
into the composition of the present invention is almost nontoxic as will 
be noted from the acute toxicity value listed in Table 1 of Japanese 
Patent Publication (Kokoku) No. Hei 2-33689 specification. Since the 
pharmaceutical composition aims at applying to infants, it may be easily 
understood that such characteristics of said composition is very 
advantageous to this invention.

EXAMPLE 
Pharmaceutical formulations of the present invention are shown below, but 
the formulations of the present invention are not limited to those 
examples. 
______________________________________ 
Formulation 1. 
______________________________________ 
2-(4-Methylaminobutoxy)diphenylmethane hydrochloride 
100 g 
Mannit 300 g 
Corn starch 450 g 
Lactose 300 g 
Hydroxypropyl cellulose 38 g 
Calcium stearate 12 g 
______________________________________ 
The above ingredients are admixed in a conventional manner to give capsules 
weighing 120 mg per capsule. 
______________________________________ 
Formulation 2. 
______________________________________ 
2-(4-Methylaminobutoxy)diphenylmethane hydrochloride 
100 g 
Corn starch 200 g 
Lactose 500 g 
Calcium carboxymethyl cellulose 
150 g 
Polyvinylpyrrolidone 75 g 
Talc 75 g 
Microcrystalline cellulose 250 g 
______________________________________ 
The above ingredients are admixed in a conventional manner and granulated 
and subjected to a tableting machine to give tablets weighing 120 mg per 
tablet. 
______________________________________ 
Formulation 3. 
______________________________________ 
2-(4-Methylaminobutoxy)diphenylmethane 
50 mg 
hydrochloride 
Hydroxypropyl cellulose 4 mg 
Hydroxypropylmethyl cellulose 
50 mg 
Sodium citrate 50 mg 
Sodium saccharin 3 mg 
Saccharose optimum dose 
Corn starch 29 mg 
D-Mannitol 67 mg 
Glycerin monostearate 200 mg 
Eudragit L-30D55 71 mg 
Macrogoal 6000 7 mg 
Talc 21 mg 
Sodium laurylsulfate trace 
Perfume trace 
1000 mg 
______________________________________ 
The above ingredients are admixed in a conventional manner to give dry 
syrup. 
______________________________________ 
Formulation 4. 
______________________________________ 
2-(4-Methylaminobutoxy)diphenylmethane 
50 mg 
hydrochloride 
Hydroxypropyl cellulose 70 mg 
Corn starch 50 mg 
D-Mannitol optimum dose 
Aminoalkyl methacrylate copolymer E 
85 mg 
Talc 60 mg 
Calcium stearate 5 mg 
1000 mg 
______________________________________ 
The above ingredients are admixed to give granules. 
Clinical Tests 
Case 1 
Twenty-five patients with primary open-angle glaucoma, whose ocular tension 
is kept at 20 mmHg by eye drops and who have a progressive constriction in 
the visual field, detected by perimetry using Humphrey's Ocular Field Stat 
Pack II, were orally administered a tablet containing 50 mg of bifemelane 
hydrochloride for 3 times a day for 24 months, and therapeutic effects 
thereof on the progressive constriction in the visual field Was examined. 
The visual field was measured using Humphrey's static quantitative 
perimeter before and 6, 12, 18 and 24 months after administration of 
bifemelane hydrochloride. The therapeutic effects on the visual field were 
determined by comparing mean sensitivities in time-course. As a result, 
50% of the patients was judged as "improved" and 12% as "unchanged", when 
compared with the visual field before administration of bifemelane 
hydrochloride. 
Case 2 
In sixteen patients, who have glaucoma with normal ocular tension as well 
as progressive constriction in the visual field, and who have not received 
eye drops treatment, therapeutic effects of bifemelane hydrochloride on 
the changes in the visual field were examined in the same method as 
described above. As a result, 47% of the patients was judged as improved 
and 16% as unchanged, when compared with the visual field before 
administration. 
The above results demonstrated that, for glaucoma with progressive 
constriction in the visual field, bifemelane hydrochloride exhibited 
therapeutic effects for 62% of the patients having open-angle glaucoma and 
63% of the patients who had glaucoma with normal ocular tension. 
These results clearly suggest that bifemelane enables an effective new drug 
therapy for glaucoma, since at present time there are few drugs effective 
on progressive constriction in the visual field accompanying glaucoma.