JPH03271291A - Eye drop - Google Patents

Abstract

PURPOSE:To obtain eye drop consisting essentially of a specific hydantoin derivative capable of exhibiting excellent aldose reduction inhibiting action, useful in prevention or treatment for cataract and having good long term stability, cornea permeability and transition to crystalline lens. CONSTITUTION:The aimed medicine consisting essentially of d or 1-hydantoin derivative expressed by the formula (W is halogenomethyl, 1H-tetrazol-5-yl, etc. ; X is O or S; Y and Z are H, halogen, etc.). d-6-Fluoro-2,3-dihydro-2',5'- dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxamide is preferably used as the compound expressed by the formula. Furthermore, the above mentioned medicine is prepared e.g. by adding the compound expressed by the formula to sterilized and purified water and as necessary adding an isoelectric agent, pH adjusting agent, etc., thereto.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to eye drops containing an aldose reductase inhibitor as a main ingredient, and particularly to eye drops for preventing or treating cataracts.

(Prior Art) Various studies have been conducted on effective oral anti-diabetic drugs, particularly for complications related to diabetes (e.g. diabetic cataracts, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, etc.). ) is known to be effective against aldose reductase inhibitors (Jap, J, Opth
almol, Vol. 20, p. 399 (1976)
Int, Congr, Ser, Excelpt
a Med.

Volume 403, page 594, etc.).

On the other hand, it has been described in JP-A-61200991 and JP-A-63-57588 that certain hydantoin derivatives are excellent aldose reductase inhibitors, and their high activity and low toxicity as well as their ability to be used by oral administration. It has been demonstrated that galactitol has an inhibitory effect on the accumulation of galactitol in the sciatic nerve.

(Problems to be Solved by the Invention) However, in this publication, the effectiveness of the above-mentioned compound for treating cataracts has not been demonstrated, and furthermore, the method of administration focuses on oral administration.

For local diseases such as eye diseases, it is efficient to administer drugs locally, and for this reason, it was necessary to research the application of orally administered drugs to eye drops.

Important factors for anti-cataract eye drops include not only excellent medicinal efficacy, but also long-term stability given that they will be administered over a long period of time.

Furthermore, in order for the medicinal ingredient in the eye drop to make a sufficient contribution, it is required that the medicinal ingredient has good corneal permeability and transfer to the crystalline lens when prepared as an eye drop.

Therefore, an object of the present invention is to provide an anti-cataract eye drop that has not only medicinal efficacy but also long-term stability, corneal permeability, and migration into the crystalline lens.

(Means for Solving the Problems) As a result of various studies, the present inventors found that -Form (1) (Formula (1)
Among them, W is halogenomethyl, IH-tetrazol-5-yl group, -COOR group [R is hydrogen atom, alkyl group, -(
CHICH! 0), lCH, group (n is an integer of 1 to 113) or substituted phenyl group are the same or different, respectively hydrogen atom, alkyl group, (CHz CHz O) -CH3
group (n is an integer from 1 to 113) or a substituted phenyl group, or R8 and R2 together form a 5- to 6-membered heterocycle with a nitrogen atom or further with other nitrogen or oxygen atoms ), CH20R3 group (R3
means a hydrogen atom or an alkyl group) or different, meaning a hydrogen atom or an alkyl group, respectively;
X means oxygen or sulfur atom, Y and Z are the same or different, and each represents a hydrogen atom, a halogen atom, an alkyl group,
It has been found that the above-mentioned problem can be solved by an eye drop characterized by containing as a main component 6 or 61 hydantoin derivatives represented by (meaning an alkoxy group or an alkylmercapto group). That is, it has been found that compound (1) can be applied to a useful eye drop that is stable over a long period of time and exhibits excellent anti-cataract effects on the eyes.

As mentioned above, it is already known that compound (1) has an excellent aldose reductase inhibitory effect, but its application to eye drops and its effect on cataracts have not been known.

As a result of intensive research, the present inventors found that the compound (■) has high efficacy against white naijin, as well as long-term stability, good corneal permeability, and migration into the crystalline lens. This cannot be inferred from the properties of oral preparations, but can only be discovered through applied research to eye drops.

In the definition of each substituent in the compound of the above formula CI) according to the present invention, the alkyl group means a linear, branched or cyclic alkyl group, and the linear alkyl group is one having 1 to 6 carbon atoms. , such as methyl, ethyl, n-propyl,
Examples of branched alkyl groups include isopropyl, isobutyl, S-butyl, t-butyl, etc., and examples of cyclic alkyl groups include carbon Number 3 or more, such as cyclopropyl, cyclobutyl, cyclopentyl,
Examples include cyclohexyl. Examples of the halogenomethyl group include fluoromethyl, chloromethyl, bromomethyl, and iodomethyl. n relates to the average degree of polymerization of the polyethylene glycol methyl ether moiety, and there are various average degrees of polymerization, but representative examples include those where n = 4.7.12.16.42 and 113. can. Examples of the substituents of the substituted phenyl group include chlorine, bromine, methyl, methoxy and hydroxyl at the o, m or 9-positions, and when R2 together and with the nitrogen or oxygen atom form a heterocycle, examples include pyrrolidine, Morpholine, piperidine, piperazine and the like can be mentioned. Examples of alkoxy groups and alkylmercapto groups include those having a linear alkyl group, such as methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, and methylmercapto, ethylmercapto, n-propylmercapto. , n-butylmercapto, n-pentylmercapto, n-hexylmercapto, etc.
or those having a branched alkyl group, such as isopropoxy, isobutoxy, S-butoxy, t-butoxy, and isopropylmercapto, isobutylmercapto, 3
Examples include butyl mercapto, t-butyl mercapto, and the like. Halogen atoms include fluorine, chlorine, bromine and iodine, with fluorine being particularly preferred.

The salt of the compound according to the present invention refers to a pharmaceutically acceptable salt, and specifically refers to a salt formed by combining with a cation such as sodium, potassium, calcium, or magnesium ion.

Compound (I) of the present invention has two stereoisomers (diastereomers) derived from the asymmetric carbon atoms at the 2- and 4-positions of the spiro (4H-1-benzobilane-4,4'-imidazolidine) ring. ) is expected to be produced.Although both racemic and optically active compounds are effective in the present invention, 4-compound or racemic (61-compound) compounds are particularly preferably used.

The synthesis method of the compound of formula (1) of the present invention and the optical resolution method of the obtained compound can be carried out according to the method described in JP-A-63-57588.

As a result of further study by the present inventors, the above-format [■
Among the compounds represented by the formula [11], Yo represents a halogen atom, and Z is as defined above. ) 4 or 61 hydantoin derivatives were found to be effective.

Further, in the above formula (II), Wo is preferably chloromethyl, bromomethyl or -CONH, Yo is preferably a fluorine atom, and Z is preferably a hydrogen atom, particularly d-6-fluoro-2,3-dihydro- 2', 5'-
Dioxo-spiro[4H-1-benzopyran-4,4'
-Imidazolidine]-2-carboxamide (hereinafter referred to as compound A) was found to be excellent as an anti-cataract agent.

The present invention is not simply limited to eye drops, but includes all forms of ophthalmic preparations that are administered locally, such as suspensions and eye ointments. can be adjusted. The solvent usually used for eye drops is sterile purified water, and the pH adjusting agents are boric acid solution (borax, boric acid), citric acid, acetic acid, tartaric acid, phosphoric acid solution (phosphoric acid-hydrogen). sodium, sodium dihydrogen phosphate), but tonicity agents include sodium chloride, potassium chloride, calcium chloride, propylene glycol,
Glycerin, mannitol, glucose, lactose, etc. are used as preservatives, benzalkonium chloride, benzethonium chloride, paraoxybenzoic acid esters, etc., stabilizers are sodium sulfite, sodium edetate, etc., and thickeners are water-soluble. Polymers (polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), glycerin, etc. Surfactants include polysorbate 80, polyoxyethylene hydrogenated castor oil, etc.
1 from eye ointment bases such as petrolatum and liquid paraffin
More than one type is selected.

The pH of the eye drops of the present invention may be within an acceptable range for ophthalmic preparations, but it is preferable to adjust the pH of the eye drops of the present invention from the viewpoint of long-term stability. A pH range of 5 to 6 is preferred.

The concentration of the present compound (1) in the eye drops of the present invention may be any concentration that can exhibit a therapeutic effect, and is preferably 0.01 to 1%.

Typical manufacturing methods for the eye drops of the present invention include the following. Wt bacteria purified water is a compound (
1) and adjust by adding isotonic agents, buffering agents, stabilizers, preservatives, surfactants, pH adjusters, etc. as necessary.

The dosage of compound (1) depends on the type, dosage form, degree of disease, etc., but when it is administered to the ocular mucosa as a therapeutic agent for cataracts or when used as eye drops, the amount of the active ingredient is about 0.01 to
As an eye drop or suspension containing 0.5%, the same amount of 1 to 1
Preferably, several drops are administered 3 to 5 times a day.

(Example) The present invention will be explained in more detail by giving examples of stability experiment, rabbit isolated corneal permeability experiment, and drug efficacy pharmacology experiment below, but the present invention is limited to the following example. isn't it.

Example 1 Formulation A (pH 7,4) Compound A O0IQg Sodium hydrogen phosphate 0.76g Sodium dihydrogen phosphate 0.16g Sodium chloride in 100 mji
0.42g benzalkonium chloride
0.01g sterile purified water Appropriate amount sterile purified water 80mj! After adding and dissolving sodium dihydrogen phosphate, sodium hydrogen phosphate, and benzalkonium chloride, compound A is added.

After dissolving Compound A, add sterile purified water to bring the total amount to 1.
00m4.

Eye drops of formulations BG were obtained in the same manner as formulation A.

Prescription B (pH 7,4) 100mj! Medium Compound A 0.10g Sodium hydrogen phosphate 0.76g Sodium dihydrogen phosphate 0.16g Sodium chloride
0.40g benzalkonium chloride
0.01g = I'llll
O.05g Sterile purified water Appropriate amount Prescription C (pH 7,4) 100mj! Medium Compound A 0.10 g Sodium hydrogen phosphate 0.76 g Sodium dihydrogen phosphate Sodium chloride Benzalkonium chloride PVA (completely saponified) Sterile purified water Formula D (pH 7) 100 mffi Medium Compound A Sodium hydrogen phosphate phosphate Sodium dihydrogen chloride Sodium benzalkonium chloride Sterile purified water Formulation E (pH 6) Compound A in 100rrl Sodium borate carbonate 0.16g 0.42g 0.01g 1.0g Appropriate amount 0.05g 0.57g 0.32g 0.43g 0.01g Appropriate amount 0.05g 1.238g 0.004g Sodium chloride Benzalkonium chloride sterile purified water formulation F (pH 5) 100mj! Medium Compound A Borate Potassium Benzalkonium Chloride Sterile Purified Water Formulation G (pH 7,4) In 100rrl Compound A Sodium Hydrogen Phosphate Sodium Trihydrogen Phosphate Sodium Chloride Benzalkonium Chloride Sterile Purified Water 0.43g 0.01g Appropriate amount 0.05g 1.24g 0.74g 0.01g Appropriate amount 0.05g 0.76g 0.16g 0.42g 0.01g Appropriate amount Stability Jikugakudo (Storage test) a) Sample Sample The above formulation was used as the sample. DG was used.

b) Experimental conditions: Storage temperature: 40°C, Storage period: 30 days, Storage container: 10ml vial Test items: Appearance, quantitative determination, pH C) Experimental results: (Comparison between day 0 and day 30) Appearance, pH
No changes were observed for all regimens.

Quantitatively, a decrease in content was observed in formulations D-G. Also, p
Stability differed depending on H.

From the results of the above storage test at 40℃ for 1 month, especially at pH 5~
No particular abnormality was observed with eye drops No. 6, indicating that it exhibits excellent stability.

Experimental Example 2 (Rabbit excised corneal permeability experiment) a) Experimental equipment The diagram of the corneal permeability experimental apparatus shown in FIG. 1 was used.

The corneal permeability experimental device 1 shown in FIG. 1 is based on Ussing's device and has been improved for corneal permeability experiments.
It is made of acrylic resin, and a sclerocorneal piece 2 extracted from a rabbit weighing 2 to 3 kg is fixed between two chambers 4 and 6.

b) Experimental conditions Membrane: Extracted cornea from a domestic rabbit (2.8-3.3 kg male, 8-9 years old) Temperature: 35°C (temperature in constant temperature bath 14) Donor phase: Compound A/culture solution 4.0 m4 drug Concentration 1.
OXIO-3M.

■9. OXIO-3M The experiment was carried out using two types.

Receptor phase: culture solution (199 medium "Nissui"), receptor phase collection time: 1, 2, 3.4, 5 hr.

Receptor phase sampling amount: 0.20mA.

Quantification was performed using an ultraviolet absorption photometer (measurement wavelength: 282 nm).

C) Experimental Results The average value of the corneal permeation amount in two experiments increases over time, indicating that the corneal permeability is good.

Further, when the initial concentration of Compound A and the apparent corneal permeation constant were determined using the calculation formula Dm' =/ImXDm, the amount of corneal permeation was proportional to the initial concentration of Compound A.

Experimental circuit (lens migration experiment) a) Experimental conditions Lens: Extracted lens from domestic rabbit (2.8-3.3 kg male, 8-9 years old), Temperature: 35°C, Donor phase: Compound A/culture solution 40ml Drug concentration 1.
0XIO-"M Culture solution: 199 medium "Nissui" Lens collection time: Q, 5.1.2.3.4 hours Quantification was performed using an ultraviolet absorption photometer (measurement wavelength: 282 nm).

b) Experimental method After washing the excised crystalline lens with culture solution, 5%
40mf of drug-added culture solution heated to 35°C under COt gas
Put it in. Stirring, 5% CO! kept at 35°C under gas;
Remove the crystalline lens after a certain period of time.

The removed crystalline lens is phornated and then centrifuged to obtain an upper layer liquid. The upper layer liquid was quantified to measure the amount transferred to the crystalline lens.

C) Experimental Results The transfer of Compound A from the culture medium to the lens reached equilibrium by 2 hours.

Test swelling test (medicinal efficacy pharmacology experiment) a) Sample As a test sample, 0.25.0°05.0.
Eye drops with a concentration of 0.01% were used.

b) Test method Sprauge-Daw Iey rats (body weight approx.
g) on a diet containing 25% galactose for 14 days.
After breeding, 0.25.0.05°0.01 of compound A
% concentration of eye drops was instilled into both eyes twice a day, and the degree of progression of rat galactose cataract was observed on days 7 and 14 after the instillation in comparison with a drug-free group.

C) Experimental results Looking at the preventive effect of administering eye drops with different concentrations to both eyes twice a day, cataract formation was suppressed depending on the eye drop concentration for rat galactose cataracts induced by a diet containing 25% galactose. It turned out that. Furthermore, under the above conditions, the required eye drop concentration to prevent cataract formation is 0.0.
It was thought to be over 5%.

(Effects of the Invention) According to the present invention, it is possible to obtain eye drops that are stable for a long period of time and exhibit excellent anti-cataract effects on the eyes.

[Brief explanation of drawings]

FIG. 1 is a sectional view of the corneal permeability experimental device used in Experimental Example 2. 1... Corneal permeability experimental device 2... Sclerocorneal piece 4... Aqueous humor side chamber 6... Lachrymal fluid side chamber 8... Silicone backing 10... Fixing screw 12... Chip 14... Constant temperature bath 16... Stirrer No. (3 others)

Claims (4)

[Claims] (1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] (In formula [I], W is halogenomethyl, 1H-tetrazol-5-yl group, -COOR group [R is a hydrogen atom, an alkyl group, -(CH_2CH_2O)_nCH_3 group (n
means an integer of 1 to 113) or a substituted phenyl group]
, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Groups [R_1 and R
_2 are the same or different, and each is a hydrogen atom, an alkyl group, -(CH_2CH_2O)_nCH_3 group (n is 1 to
113) or a substituted phenyl group, or R_
1 and R_2 can form a 5- to 6-membered heterocycle together with a nitrogen atom or with another nitrogen or oxygen atom], -CH_2OR_3 group (R_3 means a hydrogen atom or an alkyl group) ) or ▲ Numerical formulas, chemical formulas, tables, etc. ▼ means a group (R_4 and R_5 are the same or different and each means a hydrogen atom or an alkyl group), X means an oxygen or sulfur atom, and Y and Z Eye drops characterized by containing as a main component a d- or dl-form hydantoin derivative represented by the same or different hydrogen atom, halogen atom, alkyl group, alkoxy group, or alkylmercapto group, respectively. (2) The hydantoin derivative is d-6-fluoro-2,3
-dihydro-2',5'-dioxo-spiro [4H-1
-Benzopyran-4,4'-imidazolidine]-2-carboxamide, the eye drops according to claim (1). (3) The eye drop according to claim (1), which is characterized by pH adjustment. (4) The eye drops according to any one of claims (1) to (3), which are used as a preventive or therapeutic agent for cataracts.