JPH02255618A - Remedy for glaucoma - Google Patents

Abstract

PURPOSE:To obtain the subject agent effective in remarkably lowering the intraocular tension and useful as a remedy for glaucoma by using an isoquinolinone derivative and its acid addition salt as active component. CONSTITUTION:The objective agent contains an isoquinolinone derivative of formula (R1 is H or lower alkyl; R2 is lower alkyl) and its acid addition salt as active component. The acid of the acid addition salt is e.g. HCl, H2SO4, nitric acid or hydrobromic acid. An example of the compound of formula is 4-(3-t-butylamino-2-hydroxypropoxy)-1-isoquinolinone. The active component of the remedy is administered at a rate of 0.005-2.5mg, preferably 0.025-1.0mg per day for adult in 1 to several divided doses.

Description

[Detailed description of the invention] The present invention relates to a therapeutic agent for glaucoma.

Glaucoma is a group of diseases that cause functional and organic damage to the eye due to persistent or repeated increases in intraocular pressure.The treatment involves lowering the intraocular pressure to normal levels to preserve visual function. (Masayoshi Mikuni, Kazuo Iwata, Glaucoma, Kanehara Publishing Co., Ltd., 1968)
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Pilocarbine eye drops have been widely used as a therapeutic agent for glaucoma. However, pilocarbin eye drops not only lower intraocular pressure but also act on the pupillary sphincter and ciliary body, and are known to cause side effects such as a feeling of darkness due to miosis, accommodative disorders, and conjunctival hyperemia. . Such side effects pose an extremely serious danger to those working in the transport and traffic-related industries.
In the case of elderly patients with cataracts, miosis will exacerbate visual impairment. For these reasons, it has been desired to develop a therapeutic agent for glaucoma to replace pilocarbin eye drops.

Epinephrine ophthalmic solutions were born from this demand, but these ophthalmic solutions also have side effects such as conjunctival hyperemia, B hair pain, and allergic blepharoconjunctivitis, and can sometimes lead to increased intraocular pressure due to mydriasis. Yes, but not used much.

In addition, surface anesthetics, psychotropic agents, and other drugs have been clinically tried as therapeutic agents for glaucoma, but none of them have yet been put into practical use.

Recently, β-receptor blockers have been shown to be promising in this field, and timolol maleate, carteolol hydrochloride, and befunolol hydrochloride are already on the market as therapeutic agents for glaucoma.

The present inventors have discovered that an isoquinolinone derivative, which is a type of β-receptor blocker and is being evaluated as a therapeutic agent for hypertension, arrhythmia, and angina pectoris, is also useful as a therapeutic agent for glaucoma, and has hereby completed the present invention. It arrived.

That is, the present invention is based on the general formula [wherein R represents a hydrogen atom or a lower alkyl group, R2
represents a lower alkyl group] The present invention relates to a therapeutic agent for glaucoma containing an isoquinolinone derivative or an acid addition salt thereof as an active ingredient.

The lower alkyl group in the group represented by R and R8 in the above general formula CI) includes a straight chain or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group. group, isopropyl group, butyl group, tert-butyl group, and the like. The acid addition salts of the isoquinolinone derivatives represented by the above general formula CI) include conventional pharmaceutically acceptable acid addition salts of the derivatives, such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, oxalic acid, and maleic acid. , fumaric acid, citric acid, citric acid, malic acid, and other inorganic or organic acids.

The compound represented by the above general formula (I) is, for example,
It can be produced according to the method described in No. 3-41673 and Japanese Patent Publication No. 63-55512.

Representative examples of the active ingredient compound of the glaucoma therapeutic agent of the present invention represented by the above general formula (1) include the following.

04-(3-tert-butylamino-2-hydroxypropoxy)-1-inquinolinone o4 (3-tert-butylamino-2-hydroxypropoxy)-2-methyl-1-isoquinolinone 0 4-(3-isopropylamino- 2-Hydroxypropoxy)-1-inquinolinone 0 4-(3-isopropylamino-2-hydroxypropoxy)-2-methyl-1-inquinolinone 0 4-(3-ethylamino-2-hydroxypropoxy)-1-inquinolinone 0 4-(3-ethylamino-2-hydroxypropoxy)-2-methyl-1-isoquinolinone 0 4-(3-ethylamino-2-hydroxypropoxy)-2-ethyl-1-inquinolinone Glaucoma treatment of the present invention The agent is prepared in a suitable dosage unit form by mixing the derivative represented by general formula CI) or its acid addition salt with a conventional ophthalmic pharmaceutical carrier.

As the dosage unit form, any of the usual various forms can be adopted. For example, for topical administration, eye ointments, eye drops, etc.
Examples of systemic administration include tablets, granules, and injections. In particular, the therapeutic agent of the present invention is preferably in the form of eye drops.

There is no particular restriction on the dosage of the therapeutic agent of the present invention, but the amount of active ingredient in the usual therapeutic agent is 0.005 to 2.5 cm per adult per day.
The dosage is preferably 0,0'25 to 1.0+mg, and administration is preferably carried out in one to several times a day. Also, the amount of active ingredient in the therapeutic agent is preferably in the range of about 0.01 to 5% by weight.

The therapeutic agent of the present invention can be manufactured by conventional methods. Specifically, it is produced by using an isoquinolinone derivative represented by the general formula CI) or an acid addition salt thereof as an active ingredient, and shaping the same with an appropriate base using a mixer as necessary. When the therapeutic agent is an eye ointment, eye drops, injection, etc., it is manufactured by further sterilization. In the above, the base may be appropriately determined depending on the form of the therapeutic agent. For example, when manufacturing an eye ointment, a conventional emulsion base, water-soluble base, suspendable base, etc. Can be used. Representative examples of these bases include white petrolatum, purified lanolin, liquid paraffin, and the like. Furthermore, in producing eye drops, for example, sterile distilled water can typically be used as a base.

The therapeutic agent of the present invention may further contain, for example, solubilizing agents, stabilizers, buffers, antioxidants, preservatives, and the like. Examples of solubilizing agents include sodium carboxymethyl cellulose, polyoxyethylene glycol ethers such as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether, and higher grade polyethylene glycols such as polyethylene glycol monolaurate and polyethylene glycol monooleate. Examples include fatty acid esters, polyoxyethylene fatty acid esters such as polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monooleate. Specifically, the stabilizers include sodium benzoate, ethanol, benzyl alcohol, D-mannitol, glucose, hydroxypropylmethylcellulose, polyvinyl alcohol, carboxymethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, glycerin, and EDT.
Examples include A. Buffers include sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate,
Examples include boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate, and sodium acetate.

Examples of the antioxidant include sodium bisulfite, sodium sulfite, sodium thiosulfite, sodium pyrosulfite, oxyquinoline sulfate, and ascorbic acid. Preservatives include chlorobutanol, penzatonium chloride,
Examples include cetylpyridium chloride, thimerosal, and 7-enethyl alcohol.

Furthermore, when the therapeutic agent of the present invention is in the form of eye drops, the eye drops are preferably made isotonic with lachrymal fluid, and therefore, an isotonic agent such as common salt can be added if necessary. Furthermore, the eye drops have a pH
It is desirable to adjust it to 5.5 to 9.0, preferably 6.5 to 8.5.

The therapeutic agent for glaucoma of the present invention thus obtained is administered by various administration methods depending on its dosage unit form. For example, in the case of eye drops, they are dropped into the eye from a suitable drop container or sprayed into the eye from a spray device. In the case of eye ointment, it is applied to the eye. In the case of tablets, granules, etc., they are administered orally; in the case of injections, they are administered subcutaneously, intramuscularly, or intravenously; in either case, the desired therapeutic effect can be achieved.

Formulation examples and drug efficacy tests are listed below to explain the present invention in more detail, but the present invention is not limited thereto.

Formulation example l Penzatonium chloride 0.1 mg Sodium chloride mg Sodium dihydrogen phosphate 5 mg Sodium hydrogen phosphate 12H! 0
11.8119 total 1
mI2 Each of the above ingredients was dissolved in distilled water and sterilized and filtered using an appropriate filter paper to produce a therapeutic agent for glaucoma of the present invention in the form of eye drops.

Formulation example 2 4-(3-tert-butylamino-2-hydroxypropoxy)-1-isoquinolinone hydrochloride Penzatonium chloride Sodium chloride Sodium dihydrogen phosphate Sodium hydrogen phosphate ・12H,0 0rny O,1 Mayuzhi 9 m19 u 11.8 Field Total Each of the above ingredients was dissolved in distilled water and sterilized and filtered using an appropriate filter paper to prepare a therapeutic agent for glaucoma of the present invention in the form of eye drops.

Efficacy test The effect of the eye drops obtained in the above formulation example on normal intraocular pressure was investigated using male Japanese white rabbits weighing 2.2 to 2.9 kg. Alcon pneumaticap for intraocular pressure
It was measured using a planation tonometer (Nippon Alcon).

A drug solution xooaa was instilled into one eye, and changes in intraocular pressure over time were measured. Note that the intraocular pressure 1 hour before the point was taken as the previous value. In addition, as a control example, a solution obtained by removing the medicinal drug from the formulation example was used. The control example and the formulation example were evaluated in the same rabbit after a one-week period of physical therapy. The results obtained from Formulation Example 1 are shown in Table 1 below, and the results obtained from Formulation Example 2 are shown in Table 2 below.

Table Comparative Example Formulation Example 1 Intraocular pressure (Hg) Leak □111r! ! 23 Sat 1 Sat 3 17.8 19.0 17.8 18.0 17
．． 8 19.9 20.73 19.8 16.0
16.8 15.7 17.2 16.8 18.2 (
Average value of 3 cases) No. 1 Intraocular pressure (related to) 1g) Ike □□ Upper soil 11 Control case 3 18.9 19.2 18.0 1?
, 6 18.5 17.8 19.0 Formulation example 2 3
19.1 15.2 16.0 16.6 17.3
18.1 17.9 (average value of 3 cases) As is clear from Tables 1 and 2, this formulation example was able to significantly lower intraocular pressure.

Acute toxicity test 4-(3-tart-butylamino-2-hydroxypropoxy)-2-methyl-1-isoquinolinone hydrochloride and 4-(3-tert-butylamino-2-hydroxypropoxy)-1-isoquinolinone hydrochloride The LD values determined by administering the drug to mice are shown in Tables 3 and 4 below, respectively.

Table 3 Administration method Gender LD. Value (mg/kg) Male 1393 Male 578 Intraperitoneal administration Administration method Oral administration Intraperitoneal administration Female Gender LDmo value (waste y/by”) 8I0

Claims (1)

[Claims] The following general formula▲ includes mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 represents a hydrogen atom or a lower alkyl group,
_2 represents a lower alkyl group] A therapeutic agent for glaucoma containing an isoquinolinone derivative or an acid addition salt thereof as an active ingredient.