JPH1171282A - Aqueous preparation for eye drop - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an aqueous preparation for dye drop, capable of significantly increasing the concentration of penciclovir as an active metabolite of famciclovir in instillation of drop, by including famciclovir and a water-soluble polymer. SOLUTION: This preparation comprises (A) preferably about 0.01-3 (w/v) % of famciclovir or its pharmacological permissible salt as a main component and (B) about 0.01-10 (w/v) % of a water-soluble polymer such as a mucopolysaccharide such as hyaluronic acid having about 5,000-2,000,000 average molecular weight. Preferably the objective preparation has pH about 5-7, several drops are applied once and the preparation is applied about several times daily.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an aqueous ophthalmic preparation containing famciclovir as a main component, and more particularly, to the concentration and persistence of penciclovir, an active metabolite of famciclovir, in ocular tissues when instilled. The present invention relates to an aqueous ophthalmic preparation which can increase the amount of ophthalmic solution.

[0002]

2. Description of the Related Art Famciclovir is a compound represented by the following formula: 2-amino-9- (4
-Acetoxy-3-acetoxymethylbut-1-yl)
It is a pudding.

[0003]

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[0004] Famciclovir itself has no antiviral action, but when administered orally, it undergoes deacetylation and oxidation in the intestinal lining and liver to be converted to the active metabolite penciclovir. It is known that it exerts an effective antiviral action, particularly an antiviral action against herpes virus. That is, famciclovir is useful as a prodrug of penciclovir, which is a therapeutic drug for diseases caused by herpes virus, for example, varicella, herpetic encephalitis, herpes simplex and the like.

A Japanese patent application relating to the production method, intermediates, uses and compositions of famciclovir is disclosed in
No. 59583, JP-A-2-73087, JP-A-2-121992, JP-T5-503428, JP-T-6-5049995, JP-T-7-50
No. 3246, Japanese Patent Application Laid-Open No. 7-300480, Japanese Patent Application Laid-Open No. 8-502505, Japanese Patent Application Laid-Open No. 2-275821, Japanese Patent Application Laid-Open No. 4-275229, Japanese Patent Application Laid-Open No. 4-27.
No. 5230, Japanese Unexamined Patent Publication No. 5-507719, Japanese Unexamined Patent Application Publication No. 6-25131, Japanese Unexamined Patent Application Publication No. 6-41189, Japanese Unexamined Patent Application Publication No. 6-502865, Japanese Unexamined Patent Application Publication No. 8-507.
No. 760 and Japanese Patent Publication No. Hei 8-509476.
In addition to these, there are two Japanese patent applications cited below which relate to famciclovir and mention eye drops.

Japanese Unexamined Patent Publication No. 61-85388 (JP-B-5-88388)
-86792, Japanese Patent No. 1881451) include:
There is disclosure of famciclovir, its preparation and pharmaceutical compositions containing it, stating that famciclovir is effective against herpesvirus infections. In this publication, the main aim is to orally administer famciclovir, but it can be formulated for topical use in the eye, and the composition to be applied to the eye is a conventionally used ophthalmic composition known to those skilled in the art. There is a mention that it is a thing.

[0007] JP-A-63-145279 (Patent No. 2513519) discloses a pharmaceutical product containing interferon and a compound represented by the following formula or a prodrug thereof or an acyl derivative thereof (prodrug). And when two OH groups are acetyl derivatives, the compound of the above-mentioned formula 1 is obtained. The publication states that the composition can be formulated for topical application to the eye, and that the composition for application to the eye will be a conventional ophthalmic composition or an additional ointment composition well known to those skilled in the art. References have been made.

[0008]

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[0009]

As described above, famciclovir is useful as a prodrug of penciclovir and has favorable water solubility, so that it can be prepared as an aqueous preparation. If an aqueous preparation for ophthalmic preparation is prepared using this famciclovir, it is considered that it may be converted into penciclovir in ocular tissues.

However, according to the study of the present inventors, it was found that simply using an ophthalmic solution prepared from famciclovir in an aqueous preparation according to a conventional method is not sufficient in terms of the concentration and persistence of penciclovir in ocular tissues. It was found that there was a problem in that an inexpensive result was not obtained (see a comparative example described later) and frequent instillation was required. In this case, even if the concentration of famciclovir in the ophthalmic solution is increased to increase the concentration in the anterior segment of the eye, famciclovir itself has no activity, so that it is not easy to obtain a sufficient effect. Is expected.

[0011] Under such a background, the present invention significantly reduces the concentration of penciclovir, an active metabolite of famciclovir, in ocular tissues when administered in an aqueous ophthalmic solution containing famciclovir as a main component. It is an object of the present invention to provide an aqueous ophthalmic preparation which can be increased and maintained.

[0012]

The aqueous ophthalmic preparation of the present invention comprises famciclovir or a pharmaceutically acceptable salt thereof as a main component and contains a water-soluble polymer. is there.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

As described above, famciclovir is a compound represented by the following formula: 2-amino-9
-(4-acetoxy-3-acetoxymethylbut-1-)
Ill) It's pudding.

[0015]

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The pharmacologically acceptable salts of famciclovir include, for example, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid And salts of organic acids such as succinic acid, methanesulfonic acid and ethanesulfonic acid.

The concentration of famciclovir in the aqueous ophthalmic solution of the present invention is about 0.01 to 3 (w / v)%, preferably
It is appropriate to set it to about 0.1 to 2.6 (w / v)%. When the concentration is too low, the efficacy is insufficient.

The aqueous ophthalmic preparation of the present invention contains a water-soluble polymer in order to increase the concentration and persistence of penciclovir, an active metabolite of famciclovir, in ocular tissues.

As the water-soluble polymer, mucopolysaccharides (polysaccharides containing hexosamine) such as hyaluronic acid, chondroitin sulfate, sodium alginate, collagen and xanthan gum are preferably used, and methylcellulose, ethylcellulose and carboxymethylcellulose are preferably used. Cellulose-based polymers such as sodium salt, hydroxyethylcellulose, hydroxypropylcellulose, and methylhydroxypropylcellulose, and water-soluble synthetic polymers such as polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, and sodium polyacrylate can also be used. These water-soluble polymers are also advantageous in that they have low eye irritation.

The molecular weight of the water-soluble polymer is not particularly limited. However, in the case of hyaluronic acid, the average molecular weight is often about 5,000 to 2,000,000.

The concentration of the water-soluble polymer in the aqueous ophthalmic preparation is 0.01 to 10 (w / v)%, preferably 0.02 to 5 (w / v).
%, More preferably 0.05 to 2 (w / v)%. When the concentration is too low, the intended effect is not obtained, while when the concentration is too high, the viscosity becomes excessive and the usability as an aqueous preparation becomes poor.

In preparing the aqueous ophthalmic preparation, in addition to the above-mentioned famciclovir or a salt thereof and the above-mentioned water-soluble polymer, a solubilizing agent (nonionic, cationic,
Anionic surfactants (polysorbate 80, polyoxyethylene hydrogenated castor oil, benzalkonium chloride, benzethonium chloride, sodium dodecyl sulfate, etc.), polyvalent metal salts, cyclodextrins, barbituric acid, nicotinic acid, etc., buffers Agents (phosphate buffer, borate buffer,
Acetate buffer, tartrate buffer, etc.), preservatives (benzalkonium chloride, benzethonium chloride, paraoxybenzoate, benzyl alcohol, parachloromethoxyphenol, chlorcresol, phenethyl alcohol,
Sorbic acid or a salt thereof, dehydroacetic acid or a salt thereof,
Thimerosal, chlorobutanol, etc.), tonicity agents (glycerin, polyethylene glycol, sorbitol, glucose, mannitol, sodium chloride, boric acid, borax, etc.), stabilizers (amino acids or their salts (glutamic acid, alginic acid, etc.), A polyhydric alcohol (such as propylene glycol), a pH adjuster and the like can be contained as necessary.

The pH of the ophthalmic aqueous preparation is suitably about 4 to 8, especially about 5 to 7. Aqueous preparations can be administered in 1 drop, 1 drop
It should be instilled about several times a day.

<Action> In the present invention, an aqueous ophthalmic preparation containing famciclovir or a pharmaceutically acceptable salt thereof as a main component contains a water-soluble polymer (particularly mucopolysaccharide, especially hyaluronic acid). A special twist is taken.

The water-soluble polymer may be a solubilizer and a dispersant for famciclovir or a salt thereof in an aqueous preparation,
In addition to acting as a thickener, it also facilitates the transfer of famciclovir or its salts into ocular tissues, and furthermore, penclovir, an active metabolite of famciclovir, which is an active metabolite of famciclovir when instilled in aqueous formulations. It has been found that the compound has an effect of significantly increasing and maintaining the tissue concentration.

[0026]

The present invention will be further described with reference to the following examples.

Example 1, Comparative Example 1 <Preparation of an aqueous preparation for eye drops> Famciclovir 1000 mg
Was dissolved in purified water, and sodium acetate (buffer) 100 mg, concentrated glycerin (isotonicity agent) 260
0 mg and 200 mg of sodium hyaluronate (water-soluble polymer) having an average molecular weight of 1.5 million were added and dissolved, and purified water and a small amount of hydrochloric acid were added to adjust the total volume to 100 ml. pH was 5.5.

For comparison, an aqueous ophthalmic solution was prepared in the same manner as described above except that only the addition of sodium hyaluronate was omitted.

<Concentration of Penciclovir in Eye Tissue> The effect of a water-soluble polymer on the concentration of penciclovir in eye tissue after instillation of an aqueous formulation of famciclovir was examined as follows.

To the eyes of six male white rabbits weighing 2 kg, 20 parts each of the aqueous ophthalmic preparation of Example 1 (with water-soluble polymer) and the aqueous ophthalmic preparation of Comparative Example 1 (without addition of water-soluble polymer).
Each μl was instilled. Rabbits were euthanized 1 hour and 6 hours after instillation, and the extraocular part was washed with a sufficient amount of physiological saline. The anterior aqueous humor was collected with a syringe, and the eyeball was excised, and the cornea was cut off. Penciclovir was extracted from the obtained cornea and aqueous humor, and the penciclovir concentration was measured by HPLC.
Table 1 shows the composition of the aqueous ophthalmic solution, and Table 2 shows the results of measuring the concentration of penciclovir.

[0031]

[Table 1] Comparative Example 1 Example 1 famciclovir 1000 mg 1000 mg sodium acetate 100 mg 100 mg concentrated glycerin 2600 mg 2600 mg sodium hyaluronate-200 mg hydrochloric acid qsqs sterile purified water qsqs (total) 100 ml 100 ml (pH) 5.5 5.5

[0032]

[Table 2] Elapsed penciclovir concentrations (ng / ml, g) tissue Time Comparative Example 1 Example 1 Aqueous humor 1 hr 284.7 ± 67.4 515.8 ± 150.5 6 hr 145.2 ± 63.0 326.9 ± 316.0 cornea 1 hr 3403.1 ± 338.8 6523.7 ± 1898.9 6 hr 215.4 ± 184.6 1981.2 ± 1504.4 (Note) The numerical values in the table indicate the mean ± standard deviation of six eyes.

<Analysis> From Table 2, when comparing the aqueous ophthalmic preparation of Example 1 containing a water-soluble polymer with the aqueous ophthalmic preparation of Comparative Example 1 containing no water-soluble polymer, the following is obtained. You can see that.

(1) Penciclovir concentration in aqueous humor 1 hour after instillation: When water-soluble polymer is contained, it is nearly twice (515.8 / 284.7 = 1.8) compared to the case where water-soluble polymer is not contained, and it is significantly increased ( p <0.01). (2) Pencyclovir concentration in cornea 1 hour after instillation: When water-soluble polymer is included, it is about twice as high as when it is not contained
(6523.7 / 3403.1 = 1.9), a significant increase (p <0.01)
Is recognized. (3) Pencyclovir concentration in aqueous humor 6 hours after instillation: about 2 times (32
6.9 / 145.2 = 2.25), showing a significant increase (p <0.01). (4) Pencyclovir concentration in cornea 6 hours after instillation: about 9 times (198
1.2 / 215.4 = 9.2), and the effect due to the inclusion of the water-soluble polymer becomes more prominent as time passes. (5) Changes in the concentration of penciclovir in the aqueous humor 1 hour and 6 hours after instillation: about 50% (14
5.2 / 284.7 = 0.51), whereas when the water-soluble polymer is contained, it is only about 65% (326.9 / 515.8 = 0.65). (6) Changes in the concentration of penciclovir in the cornea 1 hour and 6 hours after instillation: about 6% (215.
4 / 3403.1 = 0.063), whereas when a water-soluble polymer is contained, it is only about 30% (1981.2 / 6523.7 = 0.304).

Examples 2 to 4 Other formulation examples of the aqueous ophthalmic preparation are shown in Table 3 below.

[0036]

[Table 3] Example 2 Example 3 Example 4 Famciclovir 1000 mg 1000 mg 1000 mg Sodium acetate 1000 mg Sodium glutamate 1000 mg Sodium citrate 1000 mg Sodium chloride 800 mg 800 mg Concentrated glycerin 2600 mg Sodium hyaluronate 200 mg Sodium chondroitin sulfate 1000 mg hydroxypropyl methylcellulose 500 mg benzalkonium chloride 5 mg 5 mg methyl p-oxybenzoate 26 mg propyl p-oxybenzoate 14 mg chlorobutanol 300 mg hydrochloric acid qsqsqs sterile purified water qsqsqs (total) 100 ml 100 ml 100 ml ( pH 5.5 5.5 5.5

[0037]

According to the present invention, when the aqueous ophthalmic preparation of the present invention is instilled,
The concentration of penciclovir, the active metabolite of famciclovir, in ocular tissues is significantly increased and sustained. The frequency of eye drops can be reduced.

In addition, since the aqueous ophthalmic preparation of the present invention has a low viscosity, there is almost no discomfort at the time of instillation, and since the instillation can be easily performed by the patient himself, compliance with the patient is very good.

Claims (4)

[Claims] 1. An aqueous ophthalmic preparation characterized by comprising famciclovir or a pharmaceutically acceptable salt thereof as a main component and a water-soluble polymer. 2. The water-soluble polymer is a mucopolysaccharide.
The ophthalmic aqueous preparation according to the above. 3. The mucopolysaccharide is hyaluronic acid.
The ophthalmic aqueous preparation according to the above. (4) The concentration of the water-soluble polymer in the aqueous preparation is 0.1%.
The aqueous ophthalmic preparation according to claim 1, wherein the amount is from 01 to 10 (w / v)%.