WO2004000320A1

WO2004000320A1 - Water-based preparation for eye drop

Info

Publication number: WO2004000320A1
Application number: PCT/JP2003/007903
Authority: WO
Inventors: Hidefumi Yamaguchi
Original assignee: M's Science Corporation
Priority date: 2002-06-24
Filing date: 2003-06-20
Publication date: 2003-12-31
Also published as: AU2003243943A1; JP2004026695A

Abstract

A water-based preparation for eye drops which comprises a boric acid buffer containing 0.01 to 2 wt.% polyvinyl alcohol and dissolved in the buffer 0.01 to 0.4 wt.% either (-)-9-[1'S,2'R-bis(hydroxymethyl)cyclopropan-1'-yl]methylguanine or pharmaceutically acceptable salt thereof. The guanine compound has higher medicinal activity and higher safety than aciclovir and ganciclovir, and its antiviral activity can be advantageously used in treatments for diseases. Due to the use of this compound as an active ingredient, the water-based preparation for eye drops can be an excellent preparation for ophthalmic treatments for viral ophthalmic diseases.

Description

Aqueous ophthalmic formulation

Technical field

The present invention relates to an ophthalmic preparation containing a cyclopropane derivative having excellent antiviral activity and safety. For details, see Ganciclovir

(1) 1 9 1 [1 'S, 2' R-bis (Hita

Droxymethyl) cyclopropane-1'-yl] methyldanine or a pharmaceutically acceptable salt thereof.

Background art

As ophthalmic preparations containing a virus-specific agonist, those containing a guanine-based antiviral agent, for example, Ashikuguchi Building and the like as an active ingredient are known. However, acyclovir has a weak anti-viral effect and is poorly soluble in water, so that it is used as an ointment and has a very poor usability. In addition, gancyclovir has a safety problem due to the appearance of myelosuppression and reproductive toxicity. Therefore, in consideration of its efficacy and safety, there is a problem in using conventionally known guanine-based antiviral agents such as acyclovir and ganshiku-buru as ophthalmic preparations. Necessary, and because acyclovir is an ointment, there is a problem in usability.

(-)-9-[1'S, 2'R-bis (hydroxymethyl) cyclopropane-1'-1yl] Methyldanine is an antiviral agent having a cyclopropane ring on the purine skeleton. Its antiviral activity extends to, for example, simple henless virus (HSV), cytomegalovirus, retrovirus, VZV (varicella-zoster virus), EBV, hepatitis virus, etc. Japanese Patent Application Laid-Open No. 5-78357 describes that in an assay for anti-herpes virus activity using Vero cells infected with HSV-1 and HSV-2, about 20 times less than that of an oral mouth building. A double antiviral activity is shown. In addition, (1) 1-9— [1'S, 2'R-bis (hydroxymethyl) cycloprononone-1'yl] methyldanine is known to exhibit lower toxicity compared to gansirovir. , C ancer Gene T herapy, V o 17, N o. 4, 2 0 0 0: pp 5 5 7—5 6 2 contains (1 'S, 2' R) — 9 {[1 ', 2 It has been reported that 'bis- (hydroxymethyl) cyclopropane-1' [yl] methyl] guanine is more safe than ganciclovir. Thus, in consideration of its efficacy and safety, this compound has superior utility as compared with conventionally known guanine-based antiviral agents.

(-) 1 9 1 [1'S, 2'R-bis (hydroxymethyl) cyclopropane-1'-1 '] methyldanine has been studied mainly for gene therapy. For example, Japanese Unexamined Patent Application Publication No. 2000-1989 and US Pat. No. 6,331,288 disclose the use as an antitumor agent for gene therapy. . The above literature also suggests application to suppression of restenosis after PTCA and suppression of graft-versus-host disease.

However, with respect to the development of eye drops for viral ophthalmic diseases, for example, ophthalmic diseases such as keratitis due to HSV, for example, as disclosed in Japanese Patent Application Laid-Open No. Although the use of a cyclic propane derivative whose hydroxyl group is esterified with a specific amino acid is being studied, this compound needs to be converted to a t-droxymethyl group in the body of patients and animals. However, it is not always suitable, and it is still not enough.

In view of the above-mentioned situation, the present invention combines excellent antiviral efficacy and safety. It is an object of the present invention to provide a water-based ophthalmic preparation. Disclosure of the invention

That is, the present invention comprises (1) 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropane-11'-yl] methyldanine or a pharmaceutically acceptable salt thereof. It is an aqueous ophthalmic formulation.

In one embodiment of the present invention, in the buffer, (1) 191 [1'S, 2'R-bis (hydroxymethyl) cyclopro-can- 1 1'yl] methylguanine or a pharmaceutically acceptable salt thereof It is an aqueous ophthalmic preparation containing an acceptable salt dissolved or suspended.

Another embodiment of the present invention relates to a method for preparing (_)-9_ [1'S, 2R-bis (hydroxymethyl) cyclopropane-1'-yl] methylguanine in a borate buffer containing polybutyl alcohol. Or an aqueous ophthalmic preparation in which a pharmaceutically acceptable salt thereof is dissolved.

Polyvinyl alcohol concentrations may be 0.0 1-2 wt ^_0/0.

In another embodiment of the present invention, the concentration of (1) 191 [1'S, 2'R-bis (hydroxymethyl) cyclopropane-11'yl] methyldanine is 0.01 〜0.4% by weight. BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, (1) 1- [1 ′S, 2′R-bis (hydroxymethyl) cyclopropane-1′-yl] methyldanine may be a free form or a hydrate. For example, it may be a dihydrate. (1) one 9 - [1 ¹ S, 2 'R- bis (arsenate Dorokishimechiru) consequent Ropuropan one 1' - I le] Pharmaceutically acceptable salts of Mechirudanin, for example, hydrochloric acid, hydrobromic acid, Salts with acids such as phosphoric acid and sulfonic acid, sodium base, lithium And salts with bases such as calcium base.

In the present invention, (1) -9- [1'S, 2'R-bis (hydroxymethyl) cyclopropane-11-yl] methylguanine or a pharmaceutically acceptable salt thereof is dissolved or suspended. It may be turbid and contained in an aqueous ophthalmic formulation.

(-) Single 9 one [l 'S, 2' R- bis (arsenate Dorokishimechiru) consequent Ropuropa Hmm 1 '- I le] concentration in the Mechirudanin is 0.0 1-0 2.4 wt ^_0/0 approximately Preferably, it is about 0.05 to 0.3% by weight, more preferably about 0.05 to 0.2% by weight.

Aqueous ophthalmic preparations must have a pH that can be used as eye drops. This pH may be, for example, about pH 4 to 8.5, preferably about pH 4.5 to 8, more preferably about pH 6 to 8. Buffer components can be used if necessary. If necessary, a solubilizer, a suspending agent or a suspending agent can be used.

In the aqueous ophthalmic preparation of the present invention, if necessary, an isotonicity agent, a preservative, a thickening agent, a pH adjuster, and other excipients, as long as the object of the present invention is not impaired. Various components commonly used in the technical field of aqueous formulations may be added. Examples of the above-mentioned tonicity agent include sodium chloride, potassium chloride, sodium taenoate, glycerin, d-sorbitol, d-mannitol, xylitol, propylene dalicol and the like. Can be. Preferably, it is glycerin. The tonicity agent is preferably blended so that the osmotic pressure ratio of the aqueous preparation of the present invention is in the range of 0.5 to 3.0, and particularly preferably 0.8 to 1.5. Is good.

As the preservative, for example, parabens such as methylparaben, ethylparaben, and propylparaben, quaternary ammonium salts such as benzalkonium chloride and benzozenium chloride, phenethyl alcohol, and chloroptanol can be used. Preferably, parabens are added. As the above-mentioned thickening agent, for example, polybutylpyrrolidone, alginic acid, sodium chondroitin sulfate, polyethylene dalicol and the like can be used. Examples of the pH adjuster include borax (sodium tetraborate decahydrate), phosphoric acid and carbonic acid and their metal salts, such as hydrochloric acid, sulfuric acid, sodium hydroxide, and hydroxide. Potassium or the like can be used, and borax is preferably added.

Other excipients include sulfite compounds, sodium edetate, sodium glutamate, sodium thiosulfate, epsilon aminocaproic acid, creatine, glucose, monoethanolanolamine. And pendinoleanol, various nonionic or amphoteric surfactants and the like can be used.

Aqueous ophthalmic preparations in which (-)-1-1 [1'S, 2'R-bis (hydroxymethyl) cyclopropane-1-yl] methylguanine or a pharmaceutically acceptable salt thereof are dissolved include, for example, In a boric acid buffer solution containing polyvinyl alcohol, (1) 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropane-1'-yl] methylguanine or a pharmaceutically acceptable salt thereof The salt used as (1) -9- [1'S, 2'R-bis (hydroxymethyl) cyclopropane-1'-yl] methylguanine is, for example, 0.01 to 0.4. About 0.5% by weight, preferably about 0.05 to 0.3% by weight, and more preferably about 0.05 to 0.2% by weight.

The concentration of boric acid varies depending on the amount of the active ingredient contained and the set pH, but is, for example, about 0.01 to 0.5 M, preferably about 0.05 to 0.5 M, Particularly preferably, it is about 0.05 to 0.4 M.

The amount of polybutyl alcohol used cannot be unconditionally limited by the concentration of the active ingredient and boric acid in the aqueous solution, but is used in an amount sufficient to ensure the solubility as a stable aqueous solution. Just do it. For example, it may be about 0.01 to 1% by weight. For polyvinyl alcohol, it is preferable to use a partially saponified product, preferably a completely saponified product and a partially saponified product. Re, o Example

Hereinafter, the present invention will be described in more detail with reference to Production Examples and Examples, but the present invention is not limited thereto. Hereinafter, "parts" indicates parts by weight.

Preparation A

(1) 1 9 1 [1 'S, 2' R-bis (hydroxymethyl) cyclopropane 1 '1'yl] methyldanan dihydrate (hereinafter referred to as cyclopropane derivative) 4 7.97 mg ( 42.08 nig) as an anhydride was added to 0.32M borate buffer solution (20 ml), and the mixture was sonicated and dissolved by stirring at 55 ° C while heating. After heating to 55 ° C, stirring was continued until the temperature fell to the temperature of 0.3 ° C, and the total volume was adjusted to 21 ml with the addition of 0.32 M borate buffer.

Preparation B

To cyclopropane derivative 47.88 mg (4.209 mg as an anhydride), 0.5 M phosphate buffer 2.1 ml and water 1 filtered with Millipore pure water production equipment 9 HI 1 was added thereto, and the mixture was subjected to ultrasonic treatment, followed by stirring to dissolve while heating to 55 ° C. After heating to 55 ° C, stirring was continued until the temperature was lowered to room temperature, and water filtered with a pure water production device manufactured by Millipore Co., Ltd. was added to adjust the total amount to 21 m1. Formulation that ensures dissolution stability when storing aqueous solution at room temperature (1 to 30 ° C) and its performance>

The dissolution stability of the aqueous solution of a cyclopropane derivative-containing aqueous solution at room temperature, especially in the low temperature range, which is a problem when stored in winter or cold regions, was investigated as follows. Preparation Example 1 Preparation of 0.35%? ¥ and 0.2% glycerin in 0.23M borate buffer

Approximately 50 ml of water filtered with a pure water production device manufactured by Millipore Co. was added to 1.41 g of boric acid and 0.80 g of borax, followed by stirring to dissolve. After adding 35 ml of 1% PVA and 0.8 ml of 25% glycerin and stirring, the total amount was adjusted to 100 ml with water filtered with a pure water production device manufactured by Millipore. % Represents% by weight. same as below.

Formulation Example 1

0.5% Polyvinyl alcohol (PVA) -1.8% glycerin solution (5 ml) was added to the cyclopropane derivative-containing borate buffer solution (5πι1) of Preparation Example A, and the total amount was adjusted to 10 in 1.

Formulation Example 2

The cyclopropane derivative was weighed in an amount of 3 2. Ol mg, added with 25 ml of the borate buffer solution of Preparation Example 1, sonicated, and then stirred and dissolved while heating to 55 ° C. After heating to 55 ° C, stirring was continued until the temperature was lowered to room temperature, and the borate buffer of Preparation Example 1 was added to adjust the total volume to 28 m 1.

Formulation Example 3

1.2 ml of the borate buffer of Preparation Example 1 was added to 9 ml of the solution of the cyclopropane derivative obtained by the formulation of Formulation Example 2.

Formulation Example 4

2.5 ml of the borate buffer of Preparation Example 1 was added to 7.5 ml of the solution of the cyclopropane derivative obtained by the formulation of Formulation Example 2.

Formulation Example 5

Preparation Example 25 25% glycerin 0.36 m1 and water filtered with a pure water production device manufactured by Millipore Co. were added to 5 ml of a phosphate buffer containing a cyclopropane derivative of Preparation A, and the total amount was 10 ml. And Formulation Example 6

Preparation Example 0.4 5% hydroxypropylmethylcellulose (HPMC)-1.8% glycerin solution 5 ml in 5 ml of borate buffer solution containing the propane derivative in the mouth of Example A, and add a total volume of 1 ml And

Formulation Example 7

To 5 ml of the borate buffer containing the propane derivative in Preparation Example A, 5 ml of 0.5% polyvinylpyrrolidone (PVP) -1.8% glycerin solution was added to make the total amount 10 ml.

Formulation Example 8

To 5 ml of the phosphate buffer solution containing the cyclopropane derivative of Preparation Example B, 0.36 ml of 25% dariserin and water filtered with a pure water production device manufactured by Millipore were added to make a total volume of 1 Oml. .

Formulation Example 9

To 5 ml of the phosphate buffer solution containing the cyclopropane derivative of Preparation Example B, 5 ml of 0.4% hydroxypropylmethylcellulose-1.8% glycerin solution was added to bring the total amount to 1 Oml.

Formulation Example 10

To 5 ml of the phosphate buffer containing the cyclopropane derivative of Preparation Example B, 5 ml of 0.5% polyvinyl alcohol-1.8% glycerin solution was added to make the total amount 10 ml.

Formulation Example 1 1

To 5 ml of the phosphate buffer solution containing the propane derivative of Preparation Example B, 5 ml of 0.5% polyvinylpyrrolidone-1.8% glycerin solution was added to adjust the total amount to 10 ml.

Formulation Example 1 2

Preparation Example 5 0.5% hydrate in 5 ml of phosphate buffer containing cyclopropane derivative of B Droxityl cellulose (HEC) — 1.8 ml of 5% glycerin solution was added to bring the total volume to 1 O ml.

Formulation Example 1 3

To 5 ml of the phosphate buffer solution containing the cyclopropane derivative of Preparation Example B, 5 ml of 0.5% methylcellulose (MC) -1.8% glycerin solution was added to bring the total volume to 10 ml.

Evaluation

The pH of the cyclopropane derivative solution obtained in Formulation Example 13 was measured and stored in a refrigerator kept at about 4 ° C. Every day after the start of storage, the presence of crystals was observed with the naked eye and a stereomicroscope. The evaluation criteria were as follows. Crystal precipitation on the day after storage: I

No crystal precipitation for 8 days: I I

No crystal precipitation for 18 days: I I I

No crystal precipitation more than 30: I V

The results are shown in Tables 1 and 2.

table 1

Replacement paper (fine! 126) Table 2

From the results in Tables 1 and 2, it was confirmed that the permanent solution for ophthalmic preparations of the present invention of Formulation Examples 1 to 4 suppressed crystal precipitation during refrigerated storage and significantly improved dissolution stability.

<4 ° C storage test and severe storage test (60 ° C)>

Preparation Example 2 Preparation of 0.24 M borate buffer containing 1.0% PVA and 0.5% glycerin

0.5M boric acid 12. Oml, 25% glycerin 0.5ml, 2.5% polyvinyl alcohol (PVA) 10.0m1 were added, stirred and dissolved.

0.1 M borax or 1 M sodium hydroxide with desired pH (6.5 to 8.

After adjusting to 0), purified water was added to make the total volume 25 m 1.

Formulation Example 1 4

Add 10 ml of the borate buffer of Preparation Example 2 (pH 6.5) to 11.4 mg of the cyclopropane derivative, sonicate, and dissolve with stirring while heating to 55 ° C. To prepare a 0.1% solution. Replacement paper (m 26) Formulation Example 15

Add the borate buffer (pH 6.7) 10 in 1 of Preparation Example 2 to 1.1.4 mg 'of the mouth-opening propane derivative, sonicate, and dissolve with stirring while heating to 55 ° C. Thus, a 0.1% solution was prepared.

Formulation Example 16

Add 10 ml of the borate buffer of Preparation Example 2 (pH 7.0) to 11.4 mg of the cyclopropane derivative, sonicate, and dissolve with stirring while heating to 55 ° C. A 0.1% solution was prepared.

Formulation Example 1 7

Add 10 ml of the borate buffer (pH 7.3) of Preparation Example 2 to 11.4 mg of the cyclopropane derivative, sonicate, and dissolve with stirring while heating to 55 ° C. A 0.1% solution was prepared.

Formulation Example 1 8

Add 10 ml of the borate buffer of Preparation Example 2 (pH 7.6) to 1.1.4 mg of the spiked mouth propane derivative, sonicate, and dissolve with stirring while heating to 55 ° C. To prepare a 0.1% solution.

Formulation Example 1 9

Add 10 ml of the borate buffer of Preparation Example 2 (pH 8.0) to 11.4 mg of the cyclopropane derivative, sonicate, and dissolve with stirring while heating to 55 ° C. A 0.1% solution was prepared. Evaluation

After measuring the pH of the 0.1% solution prepared in Formulation Examples 14 to 19 and the concentration of the propane derivative in the mouth, each 5 ml was dispensed into two tubes. One was stored in a refrigerator kept at 4 ° C, and the presence or absence of crystals was observed visually over time. The other was stored in a thermostat kept at 60 ° C. After 7 days, the cyclopro The bread derivative concentration was measured and compared with the concentration of the propane derivative in the mouth at the time of preparation. The evaluation criteria were as follows.

I: No crystal precipitation, no change in content

Π: No change in content

Table 3 shows the results. Table 3

From the results of Formulation Examples 14 and 19, it was confirmed that the aqueous ophthalmic solution preparation of the present invention was stable not only at 4 ° C but also at 60 ° C, which is a severe condition. Industrial applicability

According to the present invention, an aqueous ophthalmic preparation containing (1) 1-9- [1'S, 2'R-bis (hydroxymethinole) cyclopropane-1'-yl] methyldananine having both excellent antiviral efficacy and safety is provided. realizable.

The siccula propane derivative, which is an active ingredient in the present invention, is a compound that has higher antiviral activity and safety than acicl mouth building and ganshik mouth building, and can make use of its medicinal properties for therapeutic effects. The present invention has made it possible to overcome the problem of low water solubility that was a weak point in realizing ophthalmic use of this compound, A long-awaited aqueous ophthalmic preparation for ophthalmic treatment can be realized for a lupus ophthalmic disease, for example, ophthalmic diseases such as keratitis due to HSV.

Claims

The scope of the claims

1. (1) one 9 one ^[1 'S, 2 λ R- bis (arsenate Dorokishimechiru) consequent b propane one 1' single I le] Mechirudanin or for aqueous ophthalmic comprising a pharmaceutically acceptable salt thereof Formulation.

2. Dissolve or dissolve (1) 1- [1'S, 2'R-bis (hydroxymethyl) cyclopropane- 1'-yl] methyldane or a pharmaceutically acceptable salt thereof in a buffer solution. 2. The aqueous ophthalmic preparation according to claim 1, which is contained in suspension.

3. Contains polybutyl alcohol. In a borate buffer, (1) 1-9 [1'S, 2 'R-bis (hydroxymethinole) cycloprono II. -1

3. The aqueous ophthalmic preparation according to claim 2, wherein methyldanine or a pharmaceutically acceptable salt thereof is dissolved.

4. (I)-9-[1'S, 2'R—bis (hydroxymethyl) cyclopropane-1'-yl] Methyldanine, 0.1 to 0.4 weight ⁰ /. The aqueous ophthalmic preparation according to any one of claims 1 to 3, which is contained therein.

5. The aqueous ophthalmic preparation according to claim 3 or 4, which contains 0.01 to 2% by weight of polybutyl alcohol.