JP2002179573A - Therapeutic agent for glaucoma and therapeutic agent for ocular hypertension - Google Patents

Abstract

PROBLEM TO BE SOLVED: To create an agent useful for prophylaxis or treatment of glaucoma and ocular hypertension. SOLUTION: This prophylactic or therapeutic agent for the glaucoma and ocular hypertension comprises a compound represented by formula (1) and capable of exhibiting excellent hypotensive actions on ocular tension and excellent effects thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel intraocular pressure reducing agent effective for treating glaucoma and ocular hypertension. More specifically, the present invention relates to the formula (1)

Embedded image 4 '-[(2-methyl-1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepin-6-yl) carbonyl] -2-phenylbenzanilide hydrochloride represented by Hereinafter, the present invention relates to a therapeutic agent for glaucoma and a therapeutic agent for ocular hypertension containing (compound (1)) as an active ingredient.

[0002]

2. Description of the Related Art Glaucoma is a disease that is based on a sustained or repeated increase in intraocular pressure exceeding a normal range, and causes visual impairment such as organic disorder of the eye and visual field abnormality. Ocular hypertension is an example in which high intraocular pressure exceeding normal values is observed, but visual field dysfunction is not observed, and may develop into glaucoma after a long course. The goal of pharmacotherapy for ocular hypertension or glaucoma is to lower and maintain intraocular pressure to the level of a healthy individual without visual impairment.

Conventionally, as a therapeutic agent for ocular hypertension or glaucoma, a carbonic anhydrase inhibitor (oral), a hypertonic osmotic agent (injection), pilocarpine (ophthalmic solution), epinephrine and its prodrug dipivefrin (ophthalmic solution) ) And isopropyl unoprostone (ophthalmic solution) are known, and recently β-receptor blockers are frequently used, but all have many disadvantages. For example, carbonic anhydrase inhibitors can cause gastrointestinal disorders, urolithiasis, and electrolyte abnormalities. The application of sympathomimetics such as epinephrine and dipivefrin is also limited to open-angle glaucoma, rebound hyperemia due to vasoconstriction, eye pain, mydriasis, blepharitis, and systemic heart rate May cause an increase in blood pressure and blood pressure. In addition, eye drops containing a β-receptor blocker as an active ingredient act systemically on the central nervous system to cause headache and depression symptoms, asthma-like symptoms for the respiratory system, and circulatory system-related symptoms. Side effects such as bradycardia and hypotension have been reported (Pharmaceutical Journal, 28 , 705, 199).
2). As described above, currently used intraocular pressure lowering agents each have problems, and there is still no satisfactory drug that effectively lowers intraocular pressure and has few side effects.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel therapeutic agent for glaucoma and a therapeutic agent for ocular hypertension, which has an excellent intraocular pressure lowering action and has few side effects.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies to find excellent therapeutic agents for glaucoma and ocular hypertension. The known compound (1) has a known effect (Journa
l of Pharmacology and Experimental Therapeutics, 2
82 (1), 301-308, 1997; Eur. J. Pharmacol., 321 (2), 225.
-230, 1997)
The present inventors have found that they are useful as therapeutic agents for expected ophthalmic diseases such as glaucoma and ocular hypertension, and also as therapeutic agents for normal-tension glaucoma, and have completed the present invention. That is, the present invention provides a therapeutic agent for glaucoma and ocular hypertension containing the compound (1) as an essential component.

The production of compound (1) is described, for example, in WO 95 /
The method can be performed by the method described in Example 18 of No. 03305.

When the therapeutic agent for glaucoma and the therapeutic agent for ocular hypertension of the present invention is administered as a medicament, the compound to be used may be used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, from 0.1 to 99%. 0.5%, preferably 0.5-9
It is administered to animals including humans as a pharmaceutical composition containing 0%.

As the carrier of the pharmaceutical composition for treating glaucoma and ocular hypertension of the present invention, one or more solid, semi-solid or liquid diluents, fillers and other prescription auxiliaries are used. Can be The pharmaceutical composition is desirably administered in a unit dosage form. As the administration unit form, various usual forms can be arbitrarily adopted. For example, for systemic administration, injections and oral preparations, and for local administration, eye drops, eye ointments,
Examples include nasal drops and the like, and they can be administered rectally. As shown in Test Example 2, compound (1) exhibits excellent drug efficacy by intravenous administration, and has excellent oral absorbability, and thus can be expected to exhibit excellent drug efficacy as an oral preparation.

The dose of the compound used for the therapeutic agent for glaucoma and the therapeutic agent for ocular hypertension of the present invention is determined in consideration of the patient's condition such as age and weight, the administration route, the symptoms and severity of the disease, and the like. It is preferable that the amount of the active ingredient of the present invention is generally 5
~ 1500 mg / human, preferably 10-300
The range of mg / human is common. In the case of intravenous administration, the dose is in the range of 0.1 to 1000 mg / human, preferably 1 to 1000 mg / human.
The range is generally from 600 to 600 mg / human, and moreover, in the case of topical administration, for example, in the case of ophthalmic administration, 0.001 to 1
0% (V / W) concentration, preferably 0.01 to 2
% (V / W). In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in divided doses 2 to 4 times a day.

Oral administration is carried out in solid or liquid dosage units such as powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets and other forms. Can be. Powders are prepared by comminuting the active substance to a suitable fineness and then mixing with a similarly comminuted pharmaceutical carrier such as starch, edible carbohydrates such as mannitol, and the like. Flavoring agents as needed,
Preservatives, dispersants, coloring agents, fragrances and the like may be mixed.

[0011] Capsules are prepared by first filling the powdered powder or tablets granulated as described above in the form of a capsule as described in the section of the powder into a capsule shell such as a gelatin capsule. Is done. Lubricants and fluidizers, such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, and the like may be mixed with the powdered state, and then the filling operation may be performed. it can. Disintegrators and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxystarch sodium, calcium carbonate,
Addition of sodium carbonate can improve the effectiveness of the medicament when the capsule is ingested.

Further, a fine powder of the compound used for the therapeutic agent for glaucoma and ocular hypertension of the present invention is suspended and dispersed in vegetable oil, polyethylene glycol, glycerin and a surfactant, which is wrapped in a gelatin sheet and softened. It can be a capsule. Tablets are made by preparing a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and pressing. Powder mixtures are obtained by mixing an appropriately powdered material with the diluents and bases described above and, if necessary, a binder (e.g., sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin,
Polyvinyl pyrrolidone, polyvinyl alcohol, etc.), dissolution retardant (eg, paraffin, wax, hydrogenated castor oil, etc.), resorbent (eg, quaternary salt) and adsorbent (eg, bentonite, kaolin, dicalcium phosphate, etc.) )
May also be used in combination. The powder mixture can be moistened with a binder such as syrup, starch paste, acacia, cellulose solution or macromolecular solution and then forced through a sieve to form granules. Instead of granulating the powder in this way, it is also possible to first apply a tableting machine and then crush the imperfect slag obtained into granules.

The granules thus prepared can be prevented from adhering to each other by adding stearic acid, stearic acid salt, talc, mineral oil or the like as a lubricant. The mixture thus lubricated is tableted. The uncoated tablets thus produced can be coated with a film or coated with sugar. Alternatively, the drug may be directly tableted after mixing with a fluid inert carrier without going through the granulating or slagging steps as described above. Transparent or translucent protective coatings consisting of a shellac hermetic coating, coatings of sugar or polymeric materials, and polish coatings of wax can also be used.

[0014] Other oral dosage forms, such as solutions, syrups, elixirs and the like can also be presented in dosage unit form so that a given quantity contains a fixed amount of the drug. Syrups are prepared by dissolving the compound in a suitable aqueous flavor solution, and elixirs are prepared through the use of a non-toxic alcoholic carrier. Suspensions are formulated by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohols,
Polyoxyethylene sorbitol esters), preservatives, flavor enhancers (eg, peppermint oil, saccharin)
Others can also be added as needed.

[0015] If desired, dosage unit formulations for oral administration may be microencapsulated. The formulation can also provide an extended period of action or sustained release by coating or embedding in polymers, waxes, and the like. Administration into tissues can be carried out by using liquid dosage unit forms for subcutaneous / muscular or intravenous injection, for example, in the form of solutions and suspensions. These things are
A quantity of the compound is prepared by suspending or dissolving a non-toxic liquid carrier suitable for the purpose of injection, such as an aqueous or oily medium, and then sterilizing the suspension or solution. Alternatively, an aliquot of the compound may be placed in a vial and the vial and its contents sterilized and sealed thereafter. Spare vials or carriers may be provided with the powdered or lyophilized active ingredient for dissolving or mixing immediately prior to administration. Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Further, stabilizers, preservatives, and emulsifiers can be used in combination.

For rectal administration, the compound used in the therapeutic agent for glaucoma and ocular hypertension of the present invention is soluble or insoluble in water having a low melting point, for example, polyethylene glycol, cocoa butter, higher esters (for example, palmitin). Acid myristyl ester) and mixtures thereof.

The ophthalmic administration can be carried out by using a form such as eye drops, eye ointment and the like. For eye drops,
Isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl stearate 40, and polyoxyethylene hydrogenated castor oil , Sodium citrate, sodium edetate and the like; and preservatives such as benzalkonium chloride, paraben and the like.
H may be within the range acceptable for ophthalmic preparations,
A range of 8 is preferred.

The usage and dosage of the eye drops of the present invention cannot be determined unconditionally depending on the condition and age of the patient. In the case of eye drops, however, they are usually 2 to 4 times a day, 1 to 5 drops per time. In the case of eye ointments, an appropriate amount is usually applied to the conjunctival sac once to three times a day for use.

[0019]

The present invention will be described in more detail below with reference to Test Examples and Preparation Examples, but the present invention is not limited thereto.

Test Example 1 : Intraocular pressure lowering effect (application of ophthalmic solution) Using rabbits, the intraocular pressure lowering effect of applying the ophthalmic solution of the present invention was examined. Method: 1. Preparation method: Compound (1) was added to 0.5% HCO60 solution in 0.3%
Dissolved and prepared. 2. Test content: Male white rabbits with normal intraocular pressure (weight 2.5-3k)
g) Twelve birds were set as one group, and a test solution or a control solution (an eye drop containing no compound) was instilled in the left eye in an amount of 50 μL each.
After corneal surface anesthesia with 20 μL of 0.4% oxybuprocaine hydrochloride ophthalmic solution, Alcon Pneumatic Applanation Tonograph (Alco
Intraocular pressure was measured before and up to 4 hours after instillation. The negative control was compared with the ophthalmic solution of the present invention using a solvent.

Results: The above test results (difference from intraocular pressure before administration) of Compound (1) ophthalmic solution are shown in FIG. In the figure, the horizontal axis represents the time (hour) after instillation, and the vertical axis represents the intraocular pressure difference (ΔmmHg). Each value represents the mean value ± standard deviation (12 cases). * 1 indicates p <0.05 (solvent group), and these were analyzed by an Aspin-Welch's t test. 0.3
% Compound (1) ophthalmic solution showed a significant intraocular pressure lowering effect 3 hours after instillation compared to the vehicle group.

Test Example 2 : Intraocular pressure lowering effect (intravenous application) The intraocular pressure lowering effect of the intravenous administration of the present invention was examined using rabbits. Method: 1. Preparation method; Compound (1) was prepared with N, N-dimethylformamide to a concentration of 15 mg / mL. 2. Test content: Male white rabbit with normal intraocular pressure (weighing 2.8-3.3k)
g) 5 to 6 birds were set as one group, and 3 mg / kg of the compound (1) was intravenously administered. After corneal surface anesthesia with 20% of 0.4% oxybuprocaine hydrochloride ophthalmic solution, Alcon Pneumatic Applanation To
Using nograph (Alcon), intraocular pressure was measured before intravenous administration and up to 6 hours after intravenous administration. The negative control was compared with the intravenous injection of the present invention using a solvent.

Results: FIG. 2 shows the test results (difference from intraocular pressure before administration) by intravenous administration of compound (1) at 3 mg / kg. In the figure, the horizontal axis represents the time (hour) after intravenous administration, and the vertical axis represents the intraocular pressure difference (ΔmmHg). Each value represents the mean ± standard deviation (5 or 6 cases). * 2 and * 3 are each p <0.01
And p <0.001 (vs. solvent group), which were analyzed by Student's t test or Aspin-Welch's t test. Compound (1) at 3 mg / kg showed a significant intraocular pressure lowering effect 1 to 4 hours after intravenous administration as compared to the vehicle group.

Formulation Example 1 Injection

[Table 1]

About 1.5 L of distilled water for injection was heated to about 60 ° C., and 5.2 g of concentrated glycerin and polyethylene glycol 4 were added.
After 20 g of 000 and 2.0 g of 10% lactic acid were added and sufficiently dissolved, finally 3.0 g of compound (1) was stirred and dissolved, and it was confirmed that the pH was 3.5. Finally, add distilled water for injection to make up the total volume to 2L, filter with a sterilizing filter, fill 2ml into glass ampules and seal.
The solution was sterilized at 115 ° C. for 30 minutes, and then quickly cooled to room temperature with water to prepare an injection.

Formulation Example 2 Tablet

[Table 2]

After mixing 257.5 g of compound (1) with 357.5 g of lactose, the mixture was pulverized with a bantam mill (manufactured by Tokyo Atomizer). 100 g of corn starch is uniformly mixed with the pulverized product in a fluidized granulation coating apparatus (manufactured by Okawara Seisakusho), and then a 10% aqueous solution of hydroxypropyl cellulose 1
50 g was sprayed and granulated. After drying, the mixture was passed through a 24-mesh sieve, and then 2.5 g of magnesium stearate was added, and 6.5 mmφ was obtained using a rotary tableting machine (manufactured by Kikusui Seisakusho).
A tablet of 100 mg per tablet was prepared using a × 5R mortar. The tablets were treated with hydroxypropyl methylcellulose 29 using a coating device (manufactured by Freund Corporation).
10 20 g, polyethylene glycol 6000 2.5
g and 2.5 g of titanium oxide were sprayed with 300 g of an aqueous coating solution, and each tablet was coated with 5 mg to give a film-coated tablet.

Formulation Example 3 Capsules

[Table 3]

Compound (1) was made into a powder, and 390 g of crystalline cellulose, 116 g of lactose, 50 g of low-substituted hydroxypropylcellulose and 30 g of polyvinylpyrrolidone were added to 10 g of the powder, and 120 mL of ethanol was added to uniformly mix and granulate. The mixture was dried at 50 ° C. for 12 to 16 hours, passed through a 25-mesh sieve, 4 g of magnesium stearate was added thereto, and the mixture was mixed uniformly. Hard capsules containing 5 mg per capsule.

Formulation Example 4 Eye drops

[Table 4]

0.04 g of benzalkonium chloride is 0.5%
Compound (1) 3 was added to a solution dissolved in about 800 mL of HCO60.
g, dissolve with stirring, and adjust the pH with sodium hydroxide and hydrochloric acid.
After adjusting to 4, the total amount was adjusted to 1000 mL, and the mixture was aseptically filtered through a membrane filter (pore size: 0.22 μm). 5mL
To prepare eye drops.

[0032]

[Effect of the Invention] Compound (1) has a reliable and excellent intraocular pressure lowering effect upon instillation and intravenous administration, and is expected as a therapeutic agent for glaucoma and ocular hypertension.

[Brief description of the drawings]

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a graph showing a temporal change of an intraocular pressure difference (a difference from an intraocular pressure value before administration) by applying a 0.3% compound (1) or a solvent ophthalmic solution to normal intraocular pressure in a white rabbit.

FIG. 2 Compound (1) 3 mg / k for normal intraocular pressure in white rabbits
FIG. 7 is a diagram showing a temporal change of an intraocular pressure difference (a difference from an intraocular pressure value before administration) due to intravenous application of g or a solvent.

Continued on front page F term (reference) 4C050 AA01 AA07 BB05 CC10 EE03 FF02 GG01 HH01 4C076 AA12 AA37 AA54 BB01 BB13 BB24 BB31 CC10 DD09F DD23Z DD29U DD30Z DD38D DD41C DD43Z DD49R EE16A32 EE23A32 EE23A32 EE23A32 MAE NA05 NA06 ZA33

Claims (6)

[Claims] (1) Formula (1) A therapeutic agent for glaucoma, comprising the compound represented by the formula: (2) Formula (1) A therapeutic agent for ocular hypertension containing a compound represented by the formula: 3. An intravenous agent according to claim 1 or claim 2. 4. A topical administration agent according to claim 1 or claim 2. 5. An ophthalmic solution according to claim 4, wherein 6. An oral preparation according to claim 1 or 2.