OCULAR ANTIHYPERTENSIVE COMPOSITION FOR TOPICAL USE

Abstract: An ocular antihypertensive composition for topical use which contains an effective amount of a compound represented by the formula or a salt thereof has, in low concentrations, intraocular pressure lowering activity in mammals, is low toxicity and has no influence on the pupil size and, therefore, is useful as a therapeutic agent for glaucoma, for instance. Furthermore, since the compound is effective in low concentrations, the possibility of tolerance development therefor is considered to be scarce.

Description: This invention relates to the use of a compound of the formula or a salt thereof for the manufacture of a topical medicament for the treatment of ocular hypertension. Heretofore various drugs have been used for the purpose of inhibiting intraocular pressure increase or lowering increased intraocular pressure. Thus, epinephrine, for instance, is known as an ocular antihypertensive agent. When epinephrine is used in patients with narrow-angle glaucoma, however, it intensifies angle closure because of its mydriatic activity and may possibly cause acute intraocular pressure rise and, furthermore, blood pressure increase and/or conjunctival pigmentation is often observed. Parasympathomimetic drugs such as pilocarpine induce visual field deterioration or abnormal accomodation, among others. Beta-blockers such as timolol, which are recently in wide use in the treatment of glaucoma, are reported to produce adverse systemic effects, inducing bradycardia, heart failure and asthmatic attack. Therefore, beta-blockers cannot be used in patients with such symptoms. On the other hand, beta-stimulators are expected to be usable in such patients. However, salbutamol, which is a conventional beta-stimulator, can produce a satisfactory effect only when it is used in high concentrations in which it might cause marked conjunctival hyperemia. Therefore, salbutamol is said to be unsuited for prolonged administration. As mentioned hereinabove, a drug which would be effective in low concentrations in the prevention or treatment of increased intraocular pressure, typically in glaucoma, with the slightest adverse effects has not been available as yet. Accordingly, the present inventors attempted a search for an agent which would be safe and have satisfactory intraocular pressure-lowering activity. Drugs of the Future, Vol. 5, no. 12, 1980 discloses that the compounds of the present invention can be used as β₂-adrenoceptor stimulant. From Graefe's Archive for Clinical and Experimental Ophthalmology, Vol. 218, 1982, page 297 it is known that β₂-adrenoceptor stimulation is an effective mechanism for lowering intraocular pressure. The present inventors conducted an intensive research to develop a compound which would be effective at low concentration and be free of the above-mentioned disadvantages, and have ultimately accomplished the present invention. The present invention is concerned with the use of a compound of the formula or a salt thereof for the manufacture of a topical medicament for the treatment of ocular hypertension. Fig. 1, Fig. 2 and Fig. 3 show the results of the tests for intraocular pressure lowering activity as conducted in the test example. Fig. 4 shows the dose-response curve derived from the results obtained in the test example, and Fig. 5 shows the dose-response curve for the compound and salbutamol. The ocular antihypertensive composition for topical use according to the present invention comprises the above compound or salt as an active ingredient thereof. The salt may be an inorganic salt such as hydrochloride, sulfate or nitrate, or an organic acid salt such as oxalate or citrate. In terms of solubility in water, the hydrochloride is preferred. This compound can be produced by the method described in U.S. Patent No.4035512, for instance. The compound of this invention may be used in trans-form , cis-form or their mixture, and particularly trans-form is preferred. The above compound included as an active ingredient in the ocular antihypertensive composition for topical use according to the present invention has activity to lower the intraocular pressure of mammalian animals at low concentration, is low in toxicity, and has no influence on pupil size and, therefore, can be used with advantage in the pharmacotherapy for glaucoma. The ocular antihypertensive composition according to the present invention is preferably manufactured in dosage forms suitable for local administration, such as eye-drops and ophthalmic ointment. The eye-drops preferably contain the active compound in a concentration of 0.0001 to 1.0 percent, preferably 0.001 to 0.1 percent in an aseptic aqueous medium. The pH of the eye-drops of this invention is 4-10, preferably 5-9. For administration, one to a few drops per dose is instilled in the eye with a frequency of 1 to 4 times a day according to the patient's condition. Such eye-drops may further contain pharmacologically acceptable addenda such as buffers for pH adjustment, e.g. phosphate buffer, borate buffer, citrate buffer, tartrate buffer and acetate buffer; isotonizing agents, e.g. sorbitol, glycerol, polyethylene glycol, propylene glycol, glucose and sodium chloride; preservatives, e.g. parahydroxybenzoic acid esters, benzyl alcohol, parachloro-meta-xylenol, chlorocresol, phenethyl alcohol, sorbic acid, sorbic acid salts, thimerosal and chlorobutanol; chelating agents, e.g. edetate sodium and condensed sodium phosphate; and thickening agents e.g. carboxypropylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol and sodium polyacrylate. An eye ointment is produced by admixing the active ingredient in a concentration of 0.0001-1.0%, preferably 0.001-0.1%, with a conventional eye ointment base. The eye ointment is administered 1 to 4 times a day depending on the patient's condition. As the eye ointment base, there may be mentioned petrolatum, Macrogol® and carboxymethylcellulose sodium, among others. In each dosage form, the ocular antihypertensive composition according to the invention may contain any other pharmacologically active ingredients unless they are unsuited for the purpose of the present invention. The test results given below are illustrative of the effect of the ocular antihypertensive composition according to the invention. In the test, trans -2,5-dihydroxy-6-isopropylamino-5,6,7,8-tetrahydro-1-naphthylmethanol hydrochloride (hereinafter referred to as "the Compound") was used. Experimental example The ocular antihypertensive effect of this compound was evaluated in male white rabbits weighing about 2 kg and having no ocular abnormality. The animals were kept in a vivarium controlled at 20-28°C and 40-70% R.H. Food intake was restricted, while water was made available ad libitum . The test substance was dissolved in 20 mM phosphate buffer to concentrations of 0.0001, 0.0003, 0.001, 0.003, 0.01, 0.03, and 0.1%. The pH of the solutions was adjusted to 7.0-7.2 and the osmotic pressure to about 300 mOsm/kg·H₂O. Four animals were used. Fifty microliters of each test substance solution was instilled into one eye and 50µl of phosphate buffer adjusted to pH 7.0-7.2 and about 300 mOsm/kg·H₂O (osmotic pressure) into the fellow eye. Immediately before and 0.5, 1, 2 and 4 hours (6 and 8 hrs. for 0.03% and higher concentrations) after instillation, the intraocular pressure was measured with a PTG (pneumatograph, Alcon) and the pupillary diameter was measured with a Mita universal gauge. Prior to measurement, a local anesthetic (0.4% Anelocal Eyedrops, Senju Pharmaceutical Co. Ltd.) was instilled into the eyes. The intraocular pressure lowering effects thus produced are shown in Figs. 1-3. In Figs 1-3, the data represented by open circles are for Compound, those by solid circles are for the base composition. The marks *, ** and *** indicated that the differences between the data and the initial value are statistically significant at the levels of P<0.05, P<0.01 and P< 0.001, respectively. Each data is presented in terms of mean ± standard error (4 animals). These figures indicate that the Compound developed tendency toward intraocular pressure decrease even at 0.0001% and, at 0.001% and higher concentrations, produced statistically significant intraocular pressure decrease in a concentration-dependent manner. In each concentration, the intraocular pressure lowering effect was maximal at 2 hours after administration. At the concentration of 0.01%, the Compound produced a maximum intraocular pressure lowering effect; the pressure drop was as great as 1133.2 ± 133.32 Pa (8.5 ± 1.0 mmHg) (mean ± standard error for 4 animals) and statistically significant intraocular pressure decrease was noted even at 8 hours after administration. A dose-response curve was constructed based on the results shown in Figs. 1-3 (Fig. 4). Thus, the area between the base line set at the initial intraocular pressure and the intraocular pressure curve after administration of the Compound (for the period of hours 0-8) was plotted along the ordinate and the concentration of the Compound the abscissa. As a result, it became apparent that the Compound exhibits concentration-dependent intraocular pressure-lowering activity in the concentration range of up to 0.01%. As the pupil size measurement results given in Table 1 indicate, the Compound had no influence on the pupil size. For comparison, salbutamol, which is also a beta-stimulator, was tested in the same manner. The dose-response curve for salbutamol is shown in Fig. 5 in comparison with that for Compound. The data indicated by open circles are for the Compound and those by open triangles are for salbutamol. It was thus established that the Compound produces by far more potent intraocular pressure lowering effect in lower concentrations as compared with salbutamol. Accordingly the possibility of tolerance development for the Compound is considered to be less and slight. Dosage Form Example 1 (Eye-drops) The Compound 0.01 g Disodium phosphate 0.26 g Monosodium phosphate 0.12 g Sodium chloride 0.65 g Benzalkonium chloride 0.005 g Sodium hydroxide Sufficient quantity Sterile purified water Sufficient quantity Total 100 ml The above ingredients were made up into eye-drops in the conventional manner, the pH being adjusted to 7.0. and pasteurized. Dosage Form Example 2 (Eye-ointment) The Compound 0.01 g White petrolatum Sufficient quantity Total 100 g The above ingredients were made up into an eye ointment in the conventional manner and pasteurized.

Claims: Claims for the following Contracting States : CH, DE, FR, GB, IT, LI, SE Use of a compound of the formula or a salt thereof for the manufacture of a topical medicament for the treatment of ocular hypertension. Use according to claim 1 wherein the compound or its salt is incorporated in an amount of from 0.0001-1.0%. Use according to claim 1 or 2 wherein the compound or its salt is in eye-drops form. Use according to claim 1 or 2 wherein the compound or its salt is in eye ointment form. Use according to claims 1-3 wherein the pH of the solution is from 4-10 and the aqueous medium is pasteurized. Claims for the following Contracting States : ES, GR A process for preparing of eye-drops which comprises adding and dissolving a compound representing by the formula or a salt thereof into an aqueous medium and adjusting the pH of the solution to 4-10 and pasteurizing. A process for preparing an eye ointment which comprises adding and admixing a compound represented by the formula into a eye ointment base and pasteurizing.

Inventors: KURIBAYASHI, YOSHIKAZU, OGAWA, TAKAHIRO, YAMAMOTO, YUJIRO
Applicants: SENJU PHARMACEUTICAL CO., LTD.
Application year: 1987
Main classification: A61K31
IPC codes: C07C215, A61K31, A61P27