JPH03106816A - Instillation for glaucoma therapy - Google Patents

Abstract

PURPOSE:To provide the title instillation containing an isoquinolinone derivative and, as stabilizer, a phenolic hydroxyl group-contg. compound and/or glycol. CONSTITUTION:The objective instillation can be obtained by dissolving in an appropriate base (A) as active ingredient, an isoquinolinone derivative of the formula (R1 is H or lower alkyl; R2 is lower alkyl) or its acid-added salt so as to be 0. 1-5w/v% in the content and (B) as stabilizer, a phenolic hydroxyl group-contg. compound (e. g. phenol) and/or glycol so as to be 0. 02-10w/v% in the content, followed by sterilization treatment. The present instillation can be additionally incorporated with such ingredient(s) as dissolution aid, thickening agent, buffering agent, antioxidant or preservative. For the present instillation, 0. 005-2.5mg per adult/day of the active ingredient should be administered once or in several portions a day.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a therapeutic agent for glaucoma, particularly a therapeutic agent for glaucoma for use in eye drops, which uses isoquinolinone derivatives or acid addition salts thereof as effective ingredients.

[Prior art]

Pilocarpine eye drops have been widely used as a therapeutic agent for glaucoma. However, pilocarpine eye drops not only lower the intraocular pressure but also act on the pupillary sphincter and ciliary body, resulting in w1l! It is known that i1 causes side effects such as a feeling of darkness, accommodative disorder, and conjunctival hyperemia.

Such side effects pose an extremely serious danger to those working in transportation and traffic-related fields in particular. In the case of elderly patients with cataracts, miosis will aggravate visual impairment. For these reasons, there has been a desire to develop a therapeutic agent for glaucoma to replace pilocarbin eye drops.

Ebine 7-phosphorus ophthalmic solution was born from such a request, but this ophthalmic solution also has side effects such as conjunctival congestion, eyebrow pain, and allergic blepharoconjunctivitis, and can sometimes lead to increased intraocular pressure due to mydriasis. There is, but it is not used much. Other surface anesthetics, psychotropic agents, and other drugs have been clinically tried as therapeutic agents for green naishin, but none of them have yet been put to 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.

Under such circumstances, the present inventors have developed an isoquinolinone derivative (incarpostyryl derivative: Japanese Patent Publication No. 53-4-1983) which is known to have an action as a β-receptor blocker.
1673 and Japanese Patent Publication No. 63-55512), it was discovered that this product was useful as a therapeutic agent for ocular hypertension and glaucoma.
A patent application has been filed as Japanese Patent Application No. 1-73866).

[Problem to be solved by the invention]

The above-mentioned therapeutic agent for glaucoma containing an isoquinolinone derivative or an acid addition salt thereof according to the invention of the present inventors is an extremely effective drug, and can be administered by various administration methods including oral and parenteral administration. From the viewpoint of effectiveness, such as rapid onset of effect, ease of administration, and small dosage, it is preferable to use eye drops. When making eye drops, this isoquinolinone derivative or its acid addition salt is used by dissolving it in water as a base, but since isoquinolinone derivatives or its acid addition salt are insufficiently stable in water, The problem with these eye drops is that they are difficult to store for a long period of time.

Therefore, there is a need for eye drops containing an effective isoquinolinone derivative or its acid addition salt that has improved long-term storage stability.

[Means to solve the problem]

As a result of intensive research by the present inventors to solve the above problems, it was found that an aqueous solution as an eye drop containing an isoquinolinone derivative or an acid addition salt thereof may contain a compound having a heptenolic hydroxyl group, glycols, or They completed the present invention by discovering that stability is significantly improved by incorporating both a compound having a phenolic hydroxyl group and glycols as stabilizers.

That is, the present invention relates to the following general formula (1) [wherein R. represents a hydrogen atom or a lower alkyl group, R
, represents a lower alkyl group] The present invention relates to an eye drop characterized by containing an isoquinolinone derivative represented by the following formula or an acid addition salt thereof, and a compound having a phenolic hydroxyl group and/or glycols as a stabilizer.

The lower alkyl group in the group represented by R and R2 in the above general formula (I) includes a straight or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group or an ethyl group. , probyl 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, tartaric 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 methods described in No. 3-41673 and Japanese Patent Publication No. 63-55512.

The above-mentioned compound having a phenolic hydroxyl group, which is one of the stabilizers, has the following general formula CI (alkyl group, lower alkoxy group, carpoxyl group, lower alkoxyl group).

In the above general formula (II), R. , R4 and R. The halogen atom in the group represented by is F, CQ1Br and I, and the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group or an ethyl group. , probyl group, inglovir group, butyl group, tert-butyl group, etc., and lower alkoxy groups include linear or branched alkoxy groups in which the alkyl moiety has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methoxy group. , ethoxy group, propoxy group, impropoxy group, butoxy group, tert-butoxy group, etc., and lower alkoxy carbonyl group has an alkyl moiety of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, straight chain or branched chain. Examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isoproboxycarbonyl, butoxycarbonyl, and tert-butoxycarbonyl groups.

Specific examples of the compound represented by the general formula (I[) include phenol, o-, m-p-cresol, methoxy 7-enol, hydroxybenzoic acid, methyl hydroxybenzoate, ethyl hydroxybenzoate, and hydroxybenzoic acid. Brovil, imbrovir hydroxybenzoate, butyl hydroxybenzoate, isobutyl hydroxybenzoate, butylated hydroxyanisole, butylated hydroxytoluene, 4-chloro-m-cresol, and the like.

The above-mentioned glycols, which are other stabilizers, have the following general formula (I[I) HO-((CH*)m O)n-H (where m is an integer of 2 to 4, n is an integer up to 1 or 30).

Specific examples of the compound represented by the general formula (I[I) include ethylene glycol, propylene glycol, butylene glycol, polyethylene glycol, and polypropylene glycol.

These stabilizers are used singly or in a mixture of two or more, and the mixing amount can be used up to the maximum amount dissolved in the base, but it is usually 0.02 to 10.00% (w/v).
A range of is preferred. The effective amount of the compound of formula (I) in eye drops is usually preferably in the range of about 0.1 to 5% (v/v). The dosage varies depending on various conditions, but it is usually 0.005 to 2.5 mg per day, preferably 0.025 to 1.011!9, as an eye drop once to several times a day. Preferably, it is administered in separate doses.

The eye drops of the present invention can be manufactured by conventional methods. in particular,
It is produced by sterilizing a solution of the compound of formula (I), which is an effective ingredient, and the above-mentioned stabilizer in a suitable base.

In the above, the base may be appropriately determined according to need; for example, sterile distilled water can be typically used.

The eye drops of the present invention may further contain, for example, a solubilizing agent, a thickener, a buffering agent, an antioxidant, a preservative, and the like. Examples of solubilizing agents include polyoxygenates such as sodium carboxymethyl cellulose, polyoxyethylene lauryl ether, and polyoxyethylene oleyl ether.
polyethylene glycol higher fatty acid esters such as polyethylene glycol ethers, polyethylene glycol monolaurate, polyethylene glycol monooleate, polyoxyethylene fatty acid esters such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, etc. I can give an example. Examples of the thickener include hydroxybutylene methylcellulose, polyvinyl alcohol, carboxymethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, glycerin, and carboxyvinyl polymer. Buffers include sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium hydrogen phosphate, boric acid, sodium borate,
Examples include citric acid, sodium citrate, tartaric acid, sodium tartrate, and sodium acetate. Examples of the antioxidant include sodium bisulfite, sodium sulfite, sodium thiosulfite, sodium birosulfite, oxyquinoline sulfate, and ascorbic acid. Examples of preservatives include chlorobutanol, penzatonium chloride, cetylpyridium chloride, thimerosal, and phenethyl alcohol.

Furthermore, the eye drops of the present invention are preferably isotonic with lachrymal fluid,
Therefore, an isotonizing agent such as common salt can be added if necessary. Furthermore, the eye drops have a pH of 5.5 to 9.0, preferably 6.5 to 8.
．． It is desirable that the temperature is adjusted to 5.

The thus obtained eye drops of the present invention are dropped into the eyes from a suitable eye drop container or sprayed into the eyes from a spray device.

Hereinafter, in order to explain the present invention in more detail, 4-(3
tert-butylamino-2-hydroxypropoxy)
The following examples are given using -2-methyl-1-isoquinolinone hydrochloride (hereinafter abbreviated as tyrinrol hydrochloride) as an example, but the present invention is not limited thereto.

Example 1 After dissolving 1.09 of tisolol hydrochloride as an active ingredient and 0.10 g of phenol as a stabilizer in a 0.2M disodium monohydrogen phosphate solution, 0.2M phosphorus was added to adjust the pH to 7.4. A monosodium acid dihydrogen solution was added as a buffer to bring the total volume to lOOmrl. Next, the obtained solution was sterilized and filtered using an appropriate filter paper, and then 5 mQ each was dispensed into PET containers for eye drops.

After storing the above solution in a constant temperature bath at 50° C. for 60 days while shielding from light, the remaining percentage of tisolol hydrochloride was determined by HPLC analysis. At the same time, the degree of coloring was examined. The stability as an eye drop solution was compared based on the residual rate and the degree of coloring.

Examples 2 to 19 The procedure was similar to that of Example 1, using one or a mixture of various stabilizers instead of phenol. In Examples 14 to 15, the content of tisolol hydrochloride was also changed.
;.

Examples 20-22 It is carried out in a manner analogous to Example 1, but using one or a mixture of two of various stabilizers instead of phenol and (0.2 M sodium hydrogen phosphate as buffering agent). (instead of solution) suitable! (7) After dissolving in 0.05M borax solution, 0.2M boric acid solution was added to adjust the pH to 7.4 to make the total volume 100ml2, but the same process as in Example 1 was carried out.

Control example l Tirisolol hydrochloride l. After Og was dissolved only in distilled water to make the total amount 100 mQ, the same treatment as in Example 1 was carried out. The pH at this time was 5.9.

Control Example 2 The same procedure as in Example 1 was carried out, except that no phenol was added.

Control Example 3 This was carried out in the same manner as in Example 20, except that no stabilizer was added.

Control Example 4 Performed in the same manner as in Example 14, but without containing a stabilizer I; otherwise treated in the same manner.

Control Example 5 This was carried out in the same manner as in Example 15, except that no stabilizer was added.

The formulations of the liquids prepared in the Examples and Control Examples described above are summarized in Table 1 below.

-95- Two copies of each of the solutions prepared in the above Examples and Control Examples were tested for the residual rate of tisolol hydrochloride and the degree of coloration of the solutions using the method described in Example 1. The results are shown in Table 2 below. show.

Table 2 Stability of Tirisolol Hydrochloride after 60 days in a 50°C constant temperature bath Preparation solution number Tirisolol Hydrochloride residual rate (%) 84.85 76.29 95.92 99.00 B1.82 96.97 100.00 102.92 106.12 84.16 97.96 105.10 106.12 107.27 Coloring degree + ++ 10+ ++ 10+ + 1095.05 102.02 81.63 101.05 103.06 91.74 79.38 93.33 0.00 53.06 0,O0 53.33 + + Ten++++ +++ +++10+10+ +++10; Significantly colored +++; Quite colored + 10; Slightly colored +; Slightly colored; Results better than no coloring Therefore, compared to the control example, the eye drops of the present invention have
It was shown that its stability was dramatically improved.

hand control Supplementary Orthography Hiraga 2 year t month nog day

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,
A glaucoma treatment comprising an isoquinolinone derivative represented by (R_2 represents a lower alkyl group) or an acid addition salt thereof as an active ingredient, and a compound having a phenolic hydroxyl group and/or glycols as a stabilizer. eye drops.