JP3072340B2 - Aqueous eye drops and production method thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an aqueous eye drop, and more particularly, to an aqueous eye drop in which a water-insoluble eye drop is dissolved transparently or translucently, and a process for producing the same.

[0002]

2. Description of the Related Art At present, eye drops include hydrocortisone, hydrocortisone acetate, prednisolone, prednisolone acetate, fluormetholone, dexamethasone, indomethacin, erythromycin, chloramphenicol, forskolin, prostaglandin, pendidamine, tinosodine, tiaramid. Various water-insoluble drugs are used.

[0003] Eye drops containing such a water-insoluble drug are currently available in the form of a dispersion-type aqueous solution in which the above-mentioned drug is dispersed in an aqueous solvent, an oil-based ophthalmic solution in which the above-mentioned drug is dissolved in an oil-based solvent such as castor oil, petrolatum, etc. Are marketed in the form of ophthalmic ointments and the like in which the above drugs are mixed with an oily base.

[0004]

However, these dosage forms are not always preferred for patients,
There are the following problems. (1) In order to disperse the drug uniformly, the dispersible eye drops must be shaken each time the eye drops are applied, and when used, the feeling of use is poor, such as a feeling of foreign particles. (2) Oily eye drops are sticky and have a foreign-body sensation, and the feeling of use is not good. (3) In addition to having the same problems as oily eye drops, eye ointments have the problem that it is difficult for a user to instill eye drops on their own.

[0005] For the above reasons, it has been desired to convert a water-insoluble drug to an aqueous solution. However, such a drug is easily used because the drug itself has high crystallinity or has a nonpolar portion in the molecule. It was difficult to solubilize.

[0006] In general, a surfactant used for solubilizing a water-insoluble drug is sometimes added to an eye drop. To solubilize an optimal concentration of a water-insoluble drug (usually 0.05 to 1%), 10 % Surfactant is required and is not used for solubilization purposes at this concentration because it is irritating to the eye.

[0007] The present invention is directed to an aqueous eye drop obtained by dissolving a water-insoluble drug in micelles or vesicles to overcome the drawbacks of the conventional dosage form.
It is an object of the present invention to provide an aqueous eye drop which is non-irritating, enables a user to instill eyes by himself, and has a high drug effect, and a method for producing the same.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that a water-insoluble drug can be solubilized by combining a specific surfactant and a polyhydric alcohol. Heading, the present invention has been completed.

That is, the present invention relates to
0.05-1% by weight of water-insoluble drug, 1-10% by weight
A surfactant comprises from 1 to 20 wt% of a polyhydric alcohol, the water non-soluble drug is an aqueous eye drops and a manufacturing method thereof are micellar dissolved or vesicle lysis.

Hereinafter, the present invention will be described in detail. The aqueous eye drop of the present invention contains a surfactant, a polyhydric alcohol, and a drug for eye drops. Hereinafter, a method for producing these components and an aqueous eye drop will be described.

<1> Ingredients Used in the Aqueous Eye Drop of the Present Invention The surfactant used in the present invention is phospholipid or POE (n) sorbitol tetraoliate (n = 20 to
100) POE (n) sorbitan monooliate (n = 10-4
0) POE (n) Hardened castor oil (n = 5 to 100) POE: One or a mixture of two or more of polyoxyethylene and the like. Examples of the phospholipid include lecithin, phosphatidylserine, phosphatidylglycerol, phosphatidylethanolamine, and phosphatidine.

Further, as a solubilizing aid, a surfactant other than the above may be mixed and used at a ratio of 40% or less based on the total amount of the above essential surfactants. Examples of the polyhydric alcohol used in the present invention include propylene glycol, glycerin, dipropylene glycol, 1,3-butanediol, and polyethylene glycol (average molecular weight of 200 to 200).
1000) and the like, and these can be used alone or in combination of two or more kinds.

The water-insoluble drugs used in the present invention include hydrocortisone, hydrocortisone ester (hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, etc.), prednisolone, prednisolone ester (prednisolone acetate, prednisolone valerate, prednisolone valerate) Corticosteroid anti-inflammatory agents such as prednisolone palmitate), fluormetholone, dexamethasone, dexamethasone ester (dexamethasone valerate, dexamethasone acetate, dexamethasone palmitate, dexamethasone propionate); indomethacin, benzidamine, tinolidine, thiaramid Nonsteroidal anti-inflammatory drugs; erythromycin, chloramphenicol, ofloxacin, erythromycin Antibacterial agents such as Koroishin;
An intraocular pressure lowering agent such as epinephrine and dichlorphenamide can be exemplified.

In the aqueous eye drop of the present invention, these water-insoluble drugs are dissolved in a micelle-dissolved form in which the water-insoluble drug is dissolved in a form in which the water-insoluble drug is incorporated in a closed vesicle consisting of a single layer of a surfactant or a multi-layer of a surfactant. The vesicles are dissolved in the form of vesicles in which the water-insoluble drug is dissolved in the closed vesicles. In the present invention, depending on the type of surfactant used, the eye drops prepared is a micellar solution,
It becomes a vesicle solution. For example, when POE (50) hydrogenated castor oil or POE (20) sorbitan monooliate is used as a surfactant, a micellar solution is formed, and lecithin, phosphatidylserine, phosphatidylethanolamine, and POE (10) hydrogenated castor oil are used. When a solution is used, it becomes a vesicle solution.

[0015] The above components are composed of 0.05 to 1% by weight of a water-insoluble drug and 1 to 10% by weight of an essential surfactant, based on the total amount of eye drops.
% By weight, and a polyhydric alcohol in a range of 1 to 20% by weight. If the amount of the surfactant is less than this range, the eye drops do not become transparent or translucent. On the other hand, if it is too much, it will irritate the eyes, which is not preferable.

If the polyhydric alcohol is less than the above range,
The water-insoluble drug separates as a crystalline or non-crystalline solid. Conversely, if the amount is larger than the above range, the eye will be irritating like the surfactant, which is not preferable.

In addition, in the eye drops of the present invention, timolol maleate, pilocarpine, carteolol hydrochloride,
Neostigmine methyl sulfate, etc., water-soluble drugs used in ordinary eye drops, antioxidants such as α-tocopherol acetate, parabens, preservatives or bactericides such as benzalkonium chloride, sodium hydrogen phosphate, boric acid Components used in ordinary eye drops such as a pH adjuster may be added as appropriate.

<2> Method for producing aqueous eye drop of the present invention Hereinafter, a method for producing an aqueous eye drop of the present invention will be described. Drugs,
Mix and dissolve polyhydric alcohol and surfactant. At this time, heating and melting may be performed as necessary. When water containing water-soluble components is gradually added to this with stirring,
A transparent or translucent aqueous eye drop can be obtained. By this method, both a micelle solution and a vesicle (liposome type) solution can be prepared.

Further, in the case of preparing a vesicle solution, it is preferable to use a dispersing method by a mechanical technique in combination as a post-treatment. For example, a method of high-pressure emulsification using a high-pressure emulsifier, a method of permeating a membrane under pressure, or an ultrasonic treatment may be used.

When a high-pressure emulsifier is used, 500 kg /
Preferably, a pressure of at least cm ² is applied. In membrane pressure transmission, stable vesicles can be formed by using a membrane having a pore size of about 50 to 200 nm.

[0021]

The present invention will be described in more detail with reference to the following examples.

[0022]

Example 1 First, an example of a vesicle-type aqueous eye drop using prednisolone as a water-insoluble drug will be described.

<1> Production Method The components shown in Table 1A were mixed and dissolved in a water bath at 60 ° C., and a phosphate buffer (pH 6.8) was gradually added to make the total volume 100 ml. I got This aqueous eye drop was transferred to a sealed bottle, and autoclaved at 120 ° C. for 2 hours.
Sterilized for 0 minutes and stored.

[0024]

[Table 1]

<2> Evaluation (1) Corneal permeability of the water-insoluble component The corneal permeability of the water-insoluble component of the aqueous eye drops of this example was examined.

The cornea was excised from the rabbit and mounted on the glass diffusion cell shown in FIG. On the outside of the cornea, 0.5 ml of the aqueous eye drop and artificial tear (0.72% sodium chloride)
g, potassium chloride 0.14 g, sodium bicarbonate 0.1 g.
22 g, calcium chloride 0.017 g, glucose 0.
003 g, 0.39 g of albumin, and 0.06 g of D-glucosamine were adjusted to 100 ml with a 10 mM phosphate buffer solution (pH 7.3).
0 ml of artificial aqueous humor (0.784 g of sodium chloride, 0.165 g of sodium bicarbonate, 0.035 g of potassium chloride)
8 g, glucose 0.077 g, lactic acid 0.039 g, ascorbic acid 0.019 g, citric acid 0.0021 g,
0.024 g of hyaluronic acid, 0.0169 g of albumin
100 ml with 10 mM phosphate buffer (pH 7.3)
Was put).

Thereafter, every 100 hours of artificial aqueous humor
Was collected, and the concentration of prednisolone contained therein was quantified by high performance liquid chromatography. For comparison, a commercially available dispersion eye drop containing prednisolone acetate (prednisolone acetate 0.11 w /
v%, other polysorbate 80, benzalkonium chloride and the like. ) Was performed in the same manner.

FIG. 2 shows the results. The number of samples is n = 4 in both the present example and the commercially available product. As is clear from these results, in the aqueous eye drops of this example, prednisolone penetrates well into the cornea, but hardly permeates in the dispersion eye drops. From the above, it was clarified that the aqueous eye drops of the present example are superior to the dispersion eye drops in the corneal permeability of the water-insoluble drug.

(2) Therapeutic Effect of the Aqueous Eye Drop of the Example The rabbit eye caused sensitizing inflammation due to the foreign protein in the eyes of the rabbit, and the therapeutic effect on this inflammation was compared with that of a conventional dispersed eye drop.

The body of rabbit eyes sensitized by intravenous injection of 12.5 mg of bovine serum albumin (BSA) per kg of body weight was treated with BSA physiological saline (5 mg / kg).
ml) was injected, causing irritation of the iris.

Thereafter, the aqueous eye drops of this example were instilled five times a day at intervals of 2 hours, and the degree of inflammation was evaluated at regular intervals. This evaluation was performed by measuring the iris stimulation score based on the following criteria.

0: No reaction is observed 1: Mild hyperemia is observed in the iris 2: Mild hyperemia is observed in the iris 3: Moderate hyperemia and weak edema are observed in the iris 4: Irido Severe hyperemia and moderate edema. Also, for comparison, 0.11 instead of the aqueous eye drop was used.
The same operation was performed using the above comparative product containing w / v% prednisolone acetate.

FIG. 3 shows the results. The number of samples is n = 4 in both the present example and the comparative product. As is evident from these results, the aqueous eye drops of the present example have a higher rate of reduction of the iris irritation score and a higher therapeutic effect than the conventional dispersion eye drops. To cure inflammation inside the vitreous body, drugs need to penetrate through the cornea. Therefore, it is estimated that the aqueous eye drops have better corneal permeability of the water-insoluble component than the dispersed eye drops.

From the results of the above two experiments, it was found that the water-insoluble drug of the present invention permeated the water into the cornea better than the conventional dispersion eye drops, and exhibited a high effect.

[0035]

Example 2 Next, an example of a micelle-type aqueous eye drop using hydrocortisone as a water-insoluble drug will be described.

After the components shown in Table 2A were mixed and dissolved in a water bath at 60 ° C., a borate buffer (pH 4.2) was gradually added to make the total amount 100 ml, thereby obtaining a solubilized solution. This aqueous eye drop was sterilized using a 0.22 μm membrane filter, and then stored in a sealed bottle.

[0037]

[Table 2]

A corneal permeability test was performed on this aqueous eye drop in the same manner as in Example 1, and the same results as in Example 1 were obtained.

[0039]

Example 3 Next, an example of a vesicle type translucent eye drop using indomethacin as a water-insoluble drug will be described.

<1> Production Method The components shown in Table 3A were mixed and dissolved in a water bath at 50 ° C., and a phosphate buffer (pH 6.8) was gradually added to bring the total amount to 100 ml.

This solution was passed through a high-pressure emulsifier (microfluidizer) seven times at 1000 kg / cm ² to obtain a vesicle-type translucent eye drop. This vesicle type translucent eye drop was sterilized using a 0.45 μm membrane filter, and then stored in a sealed bottle.

[0042]

[Table 3]

<2> Evaluation A test was conducted in the same manner as in Example 1 to examine the corneal permeability of the vesicle type translucent eye drops. As a comparative product, a dispersed eye drop containing indomethacin (indomethacin 0.5
g, 0.5 g of polysorbate (80) and 5 g of propylene glycol in 100 ml of a phosphate buffer (pH 6.3).
The same operation was carried out using

FIG. 4 shows the results. As is clear from these results, the vesicle-type translucent eye drops have higher corneal permeability of indomethacin than the dispersed eye drops.

[0045]

Example 4 An example using erythromycin as a water-insoluble drug as a vesicle-type aqueous eye drop will be described.

In the components of Table 4A, erythromycin, PO
E (10) Hardened castor oil, polyethylene glycol
After mixing and dissolving in a 60 ° C. water bath, glycerin and a phosphate buffer (pH 6.8) are added with stirring, and finally a total amount of 100 ml is added with a phosphate buffer (pH 6.8).
And

After the solution was cooled to room temperature, it was passed four times at 1000 kg / cm ² using a high-pressure emulsifier (Microfluidizer, manufactured by Microfluidic) to obtain a vesicle-type translucent eye drop having a particle diameter of 90 nm. was gotten. The solution was sterilized using a 0.45 μm membrane filter and stored in a sealed bottle.

[0048]

[Table 4]

A corneal permeability test was performed on this vesicle-type translucent eye drop in the same manner as in Example 1.
The vesicle-type translucent eye drops of the present invention had better erythromycin permeability than the dispersion eye drops.

[0050]

Example 5 An example of a micelle-type aqueous eye drop using dichlorphenamide as a water-insoluble drug will be described.

The ingredients of Table 5A were mixed in a hot water bath at 60 ° C.
After dissolution, a borate buffer (pH 4.
2) was added gradually to make the total amount 100 ml. After cooling this solution to room temperature, it was sterilized using a 0.22 μm membrane filter and stored in a sealed container.

[0052]

[Table 5]

Example 1 of this micelle-type aqueous eye drop
A corneal permeability test was performed in the same manner as described above. As a result, the aqueous eye drops of the present invention were superior in the corneal permeability of dichlorphenamide to the eye drops of the dispersion system.

[0054]

According to the present invention, a water-insoluble drug can be dissolved in micelles or vesicles by combining a specific surfactant with a polyhydric alcohol.

As a result, the water-insoluble drug can be solubilized in the eye drops and can be blended. The water-based eye drops have no foreign body sensation during use, have low irritation, and are easy for the user to apply by themselves. Can be provided.

Further, the aqueous eye drops of the present invention have better corneal permeability of water-insoluble drugs than conventional dispersion eye drops, and can provide eye drops having a high therapeutic effect.

[Brief description of the drawings]

FIG. 1 is a diagram schematically showing a glass diffusion cell.

FIG. 2 shows corneal permeability of aqueous and dispersed eye drops containing prednisolone.

FIG. 3 shows the therapeutic effect of aqueous and dispersed eye drops containing prednisolone.

FIG. 4 shows corneal permeability of aqueous and dispersed eye drops containing indomethacin.

[Explanation of symbols]

 10. Glass diffusion cell 11. Rabbit cornea 12. Artificial aqueous humor 13. Mixture of artificial tears and eye drops 14. 15, Stirrer 16. Thermostat

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/7048 A61K 31/7048

Claims (2)

(57) [Claims] 1. A water-insoluble drug in an amount of 0.05 to 1% by weight and a non-ionic compound represented by the following group A in an amount of 1 to 10% by weight, based on the total amount.
One or two or more selected from surfactants ;
0 comprises a weight percent of a polyhydric alcohol, aqueous eye drops wherein the water non-soluble drug is micellar dissolved or vesicle lysis. A) Phospholipids, polyoxyethylene (n) sorbitate
Laoriate (n = 2-100), polyoxyethylene
(N) Sorbit mono-oliate (n = 10 to 40) 2. The method according to claim 1, wherein the water-insoluble drug is any one of hydrocortisone, hydrocortisone ester, blednisolone, blednisolone ester, dexamethasone, dexamethasone ester, indomethacin, erythromycin, and dichlorfenamide. The aqueous eye drop according to claim 1, wherein