WO2005002561A1 - Antifungal agent composition for external use - Google Patents

Antifungal agent composition for external use Download PDF

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Publication number
WO2005002561A1
WO2005002561A1 PCT/JP2004/009411 JP2004009411W WO2005002561A1 WO 2005002561 A1 WO2005002561 A1 WO 2005002561A1 JP 2004009411 W JP2004009411 W JP 2004009411W WO 2005002561 A1 WO2005002561 A1 WO 2005002561A1
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WO
WIPO (PCT)
Prior art keywords
terbinafine hydrochloride
external use
ph
og
antifungal composition
Prior art date
Application number
PCT/JP2004/009411
Other languages
French (fr)
Japanese (ja)
Inventor
Hideki Kohita
Osamu Kondo
Yoshinori Nishioku
Megumi Ishii
Original Assignee
Taisho Pharmaceutical Co.,Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2003-191271 priority Critical
Priority to JP2003191271 priority
Application filed by Taisho Pharmaceutical Co.,Ltd. filed Critical Taisho Pharmaceutical Co.,Ltd.
Publication of WO2005002561A1 publication Critical patent/WO2005002561A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone

Abstract

For enhancing the migration of terbinafine hydrochloride to the horny layer, it is advantageous to dissolve and incorporate the hydrochloride as the molecular type (nondissociable type). However, it has been difficult to dissolve and incorporate terbinafine hydrochloride as the molecular type because the solubility of terbinafine hydrochloride in neutral to alkaline pharmaceutical preparations is extremely low. The antifungal agent composition for external use comprises terbinafine hydrochloride, a polyol, and a lower alcohol, has a pH in a neutral to alkaline range, and is clear. It is a terbinafine hydrochloride-containing antifungal agent for external use which is excellent in the property of migrating to the horny layer.

Description

 Specification

 External antifungal composition

 Technical field

 The present invention relates to an antifungal composition. More specifically, the present invention relates to an antifungal composition for external use in which the amount of terbinafine hydrochloride transferred to the keratin is improved.

 Background art

 [0002] Since fungi multiply in the stratum corneum of the skin, antifungal activity and the drug concentration in the stratum corneum, which is a site where fungi inhabit only by the antibacterial agent, are important for the antifungal agent to be effective. is there.

 [0003] As an antifungal agent, an antifungal agent that increases the concentration of drug in the stratum corneum immediately after application and maintains the level for a long time is ideal.

[0004] In general, it is known that a drug (non-dissociated type) is superior in percutaneous absorbability and has a larger amount of exfoliated keratin than a dissociated ionic type.

[0005] Terbinafine hydrochloride is a component used as an external antifungal agent because of its excellent pharmacological effect.

 [0006] Terbinafine hydrochloride, like a general drug, is more advantageously dissolved and compounded as a molecular form in order to enhance the exfoliation of keratin.

[0007] In order to dissolve and mix terbinafine hydrochloride as a molecular form, the pH of the antifungal composition for external use should be set to a neutral monoalkaline region exceeding the dissociation constant (pKa) of terbinafine hydrochloride 7.13. desirable.

[0008] However, terbinafine hydrochloride has a very low solubility in a neutral monoalkaline preparation, so that it has been difficult to dissolve and mix it as a molecular form.

Conventionally, a technique has been disclosed in which an antifungal agent is present in a dissolved state in a powder aerosol (Patent Document 1).

Patent Document 1: JP-A-2000-229845

 Disclosure of the invention

Problems the invention is trying to solve [0011] An object of the present invention is to provide an external antifungal agent containing terbinafine hydrochloride having excellent keratin transfer properties.

 Means for solving the problem

 [0012] The present inventors have conducted various studies to provide a liquid preparation in which terbinafine hydrochloride is dissolved, which is a neutral mono-alkali liquid, and as a result, a lower alcohol and a polyol are simultaneously mixed, and the liquid property is specified. By limiting the range, it was found that terbinafine hydrochloride was dissolved in a molecular form and exhibited excellent exfoliation, and the present invention was completed.

 [0013] That is, the present invention provides

 (1) An external antifungal composition comprising terbinafine hydrochloride, a polyol, and a lower alcohol, wherein the liquidity of the preparation is in a neutral monoalkaline region.

 (2) The antifungal composition for external use according to (1), wherein the polyol is one or more selected from the group consisting of polyethylene glycol, propylene glycol, 1,3-butylene glycol and glycerin.

 (3) The antifungal composition for external use according to (1), wherein the blending amount of the polyol is 10 to 30 W / V% of the whole preparation.

 (4) The antifungal composition for external use according to (1), wherein the lower alcohol is ethanol.

 (5) The antifungal composition for external use according to (4), wherein the compounding power of ethanol is S47-56 W / V%.

(6) The content of terbinafine hydrochloride is 0.22 W / V in the whole preparation. 2. The antifungal composition for external use according to (1), wherein the composition is / o.

 (7) The antifungal composition for external use according to (1), wherein the pH of the preparation is 7.5-9.0.

 It is.

 [0014] In the present invention, the compounding amount of terbinafine hydrochloride is preferably 0.22 W / V% of the whole preparation (in the case of an aerosol, in a stock solution), more preferably 0.5-1.5 W / V%. is there. 0.

If the content is less than 2 W / V%, the efficacy will be insufficient, and if the content is more than 2 W / V%, it will be difficult to provide a product with a high solubility.

[0015] In the present invention, a lower alcohol is a straight-chain or branched-chain alcohol having 2 to 4 carbon atoms, which can be safely applied as an external preparation. Preferred lower alcohols Examples include ethanol and isopropanol, with ethanol being particularly preferred.

 [0016] The amount of the lower alcohol is preferably as large as possible in view of the solubility of terbinafine hydrochloride. However, if the lower alcohol is added in a large amount, irritation may occur at the time of application to the skin. Therefore, the blending amount of the lower alcohol is preferably 40-60 W / V%, more preferably 47 W / V% (60% by volume) and 56 W / V% (70% by volume).

 [0017] Preferable examples of the polyol to be blended in the present invention include polyethylene glycol (Macguchi Gal), propylene glycol, 1,3-butylene glycol, glycerin and the like.

 In the present invention, the amount of the polyol varies depending on the type and amount of the lower alcohol, and the amount of the polyol can be experimentally determined while confirming the dissolution of terbinafine hydrochloride. Also, if the polyol is added in a large amount, the stickiness at the time of application to the skin and the feeling of use will be very poor, so the usual compounding amount is 10-30 W / V of the whole preparation (in the case of aerosol, in the stock solution). %, Preferably 15-25 W / V%. Further, two or more kinds of polyols can be used in combination. Here, as an example, ethanol is used as a lower alcohol, and when the compounding amount is 47.7 \ //% (60% by volume) of the whole preparation, the compounding amount of the polyol is 25-30 W / V%, When the amount of ethanol is 55.7 W / V% (70% by volume), the amount of polyol is 10-30 W / V%.

 [0019] The pH of the drug product is in the region where terbinafine hydrochloride exists in a molecular form. The dissociation constant (pKa) is a neutral monoalkaline region exceeding 7.13. Force S. If the alkalinity is too strong, it will damage the skin. Therefore, the range of ρΗ7.5 · 9 · 0 is preferable.

 [0020] The composition of the present invention may be mixed with ordinary additives as necessary and prepared in an external manner such as a liquid, lotion, emulsion, tincture, cream, aqueous gel, aerosol, etc. Agent.

 The invention's effect

 According to the present invention, it has become possible to further enhance the keratin transfer of terbinafine hydrochloride, and to provide an antifungal agent which is extremely effective against dermatophytes.

 Brief Description of Drawings

FIG. 1 is a diagram showing the results of a keratin transfer test of terbinafine hydrochloride, with the vertical axis showing keratin transfer. The application time was shown on the horizontal axis of the row ratio (%).

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples.

 Example 1

[0024] (Lotion)

 Terbinafine hydrochloride 1. Og

 Benzalkonium chloride 0 ・ 05g

 Dipotassium glycyrrhizinate 0.5g

 1 menthol 1. Og

 Posiethylene glycolone 400 20.Og

 ヱ ノ 50 50. Og

 BHT 0.05 g

 Diisopropanolamine qs

 Purified water total lOOmL

 With the above formulation, a lotion was prepared by a conventional method (the pH of Synthetic IJ was adjusted to about 8 with diisopropanolamine).

 Example 2

[0025] (Lotion)

 Terbinafine hydrochloride 1 · Og

 Lidocaine 2. Og

 Decalinium chloride 0.1 lg

 0.5 g of dipotassium glycyrrhizinate

 Tomentonore 1.0g

 Polyethylene glycolone 400 20.0 g

 Petano 1 50 g

 BHT 0.05 g

 Sodium hydroxide

Purified water total lOOmL A lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 8 with sodium hydroxide).

Example 3

(Gel)

Terbinafine hydrochloride 1. Og

Lidocaine 2. Og

Propylene glycolone 15.Og

Canoleboxivini / Repolymer 1. Og

EDTA-2Na 0.lg

Ethanore 50. Og

Diisopropanolamine qs

Purified water total lOOg

 The carboxyvinyl polymer was dissolved in water and propylene glycol, and allowed to stand at room temperature to swell the propyloxyvinyl polymer. Ethanol, terbinafine hydrochloride, lidocaine and EDTA-2Na were added thereto. Further, diisopropanolamine was added to adjust the pH of the preparation to about 8, thereby producing a gel.

Example 4

(Aerosol)

Stock solution:

Terbinafine hydrochloride 1. Og

Shio-Dani Benzanore Nicum 0.05g

0.5 g of dipotassium glycyrrhizinate

1,3 butylene glycol 20.0 g

Ethanore 50.0 g

Diisopropanolamine qs

Purified water total lOOmL

Propellant:

DME 50mL After dissolving the other stock solutions in ethanol and purified water base, the pH of the formulation was adjusted to about 8 with diisopropanolamine to prepare stock solutions. After filling the container, a valve was attached and the propellant was filled to produce an aerosol.

 Example 5

[0028] (Lotion)

 Terbinafine hydrochloride 1. Og

 Polyethylene glycol 400 25.Og

 Ethanorne 47g

 Sodium hydroxide

 Purified water total lOOmL

 A lotion was prepared using the above formulation in a conventional manner (the pH of the formulation was adjusted to about 8 with sodium hydroxide).

[0029] Comparative Example 1

 (Lotion)

 Terbinafine hydrochloride 1. Og

 Polyethylene glycolone 400 25.Og

 Ethanore 47.7 g

 Sodium hydroxide

 Purified water total lOOmL

 A lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 5 with sodium hydroxide).

 Example 6

[0030] (Lotion)

 Terbinafine hydrochloride 1. Og

 2. Og

 Benzalkonium chloride 0.05 g

 0.5 g of dipotassium dalitinoleritinate

1 menthol 1. Og 1,3 butylene glycol 10.0 g

 Ethanore 55.0 g

 Diisopropanolamine qs

 100m of purified water

 A lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).

 Example 7

[0031] (Lotion)

 Terbinafine hydrochloride 1.0 g

 Jib force in 0.5g

 Benzetonium chloride 0.5 g

 0.5 g of dipotassium glycyrrhizinate

 1—mentoring 1.0 g

 1,3 butylene glycol 20.0 g

 Ethanore 50.0 g

 Sodium hydroxide

 Purified water total lOOmL

 A lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 8 with sodium hydroxide).

 Example 8

[0032] (Lotion)

 Terbinafine hydrochloride 1.0 g

 Lidocaine hydrochloride 2.0 g

 Benzetonium chloride 0.5 g

 0.5 g of dipotassium glycyrrhizinate

 1—mentoring 1.0 g

 Propylene glycolonole 20.0 g

Petano 1 50 g Diisopropanolamine qs

 Purified water total lOOmL

 A lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).

 Example 9

[0033] (Lotion)

 Terbinafine hydrochloride 1. Og

 Lidocaine 2 Og

 Shio-Dani Benzanore Nicum 0.05g

 0.5 g of dipotassium glycyrrhizinate

 1—Mention 1.Og

 1,3 butylene glycol 10.Og

 Ethanore 45.0g

 Isopropyl alcohol 10.0 g

 Diisopropanolamine qs

 Purified water total lOOmL

 A lotion was prepared according to the above formulation by a conventional method (the pH of the preparation was adjusted to about 8 with diisopropanolamine).

 Example 10

[0034] (Lotion)

 Terbinafine hydrochloride 1. Og

 Lidocaine 2 Og

 Decalinium chloride 0.1 lg

 0.5 g of dipotassium glycyrrhizinate

 1—Mention 1.Og

 1,3 butylene glycol 10.Og

 Polyethylene glycol 400 10.0 g

Petano 1 50 g Diisopropanolamine qs

 100m of purified water

 With the above formulation, a mouthwash was prepared by a conventional method (the pH of the formulation was adjusted to about 8 with diisopropanolamine).

Test Example 1

 Solubility test of terbinafine hydrochloride

 (Test method)

 The solubility of terbinafine hydrochloride (1 W / V%) in solutions having different “water: ethanol: PEG400” ratios was visually confirmed. The pH was adjusted with sodium hydroxide.

[0036] Table 1 Etanonore 39.8 wt% (50 vol 0/0) solubility of hydrochloric Terubinafuin against the PEG400 amount in formulation, ethanol 47.7 wt% in Table 2 (60 vol%) Blend Formulation Table 3 shows the solubility of terbinafine hydrochloride with respect to the amount of PEG400 in Table 3, and Table 3 shows the solubility of terbinafine hydrochloride with respect to the amount of PEG400 in a formulation containing 55.7% by weight (70% by volume) of ethanol. In the table, 〇 indicates that it was dissolved, and X indicates that it was not dissolved.

 [Table 1]

10, 0 X X X X

 9.5 X X X X

 9.0 X X X X

 8.5 X X X X

 8.0 X X X X

 7.5 X X X X

 7.0 X X X X

 8. B X X X X

 8, 0 X X o o

 B, 5 X o o O

 5, 0 o O O O

 4.5 O O O O

 0 1 0 2 0

 P E G 400 K combined weight (location%)

[Table 2]

 400 Ε G 400 compounding amount (mane stalk%)

 [Table 3]

 P E G 400 compounding (weight%)

 [0040] As is clear from the table, terbinafine hydrochloride usually has extremely poor solubility at a pH of more than pKa 7.13, but the formulation of the present invention has a terbinafine hydrochloride even at a pH of 7.5 or more. It was possible to dissolve naphine (1% by weight).

 Test Example 2 (Test of terbinafine hydrochloride transfer to keratin rats)

 (experimental method)

A hairless rat (Claire Nippon, male, 11-15 weeks old) was fixed in the dorsal position, and the abdomen was electrically sheathed. After removing the hair, the dirt was wiped off. 20 Ai L of each sample (Example 5 and Comparative Example 1) was weighed with a micropipette and uniformly applied to the abdomen (1.8 × 2.5 cm). Six hours after application or 24 hours after application, the sample remaining on the skin surface was sufficiently wiped off using absorbent cotton impregnated with 70% ethanol. Thereafter, a commercially available pressure-sensitive adhesive tape was stuck to the application site, and pressure-bonded to peel off the stratum corneum. This stratum corneum peeling operation was repeated 10 times. Terbinafine hydrochloride was extracted from 10 adhesive tapes used for peeling the stratum corneum with methanol, and the amount of exfoliated keratin was measured by high performance liquid chromatography.

 FIG. 1 shows the results. The results are the average of three tests for each sample.

As is clear from FIG. 1, it was confirmed that the preparation of Example 5 in which the pH was adjusted to 8 exhibited higher exfoliating properties than the preparation of Comparative Example 1 in which the pH was adjusted to 5.

 Industrial applicability

[0044] The present invention can be used as a therapeutic agent for athlete's foot, cotton beetle, common bug or tinea unguium.

Claims

The scope of the claims
 [1] An external antifungal composition comprising terbinafine hydrochloride, a polyol and a lower alcohol, wherein the pH of the preparation is in a neutral and monoalkaline range.
[2] The antifungal composition for external use according to claim 1, wherein the polyol is one or more selected from the group consisting of polyethylene glycol, propylene glycol, 1,3-butylene glycol and glycerin.
[3] The external antifungal composition according to claim 1, wherein the blending amount of the polyol is 10 to 30 W / V% of the whole preparation.
 [4] The external antifungal composition according to claim 1, wherein the lower alcohol is ethanol.
5. The antifungal composition for external use according to claim 4, wherein the compounding power of ethanol is 7 to 56 W / V%.
 [6] The antifungal composition for external use according to claim 1, wherein the amount of terbinafine hydrochloride is 0.2 to 2 W / V% of the whole preparation.
[7] The topical antifungal composition according to claim 1, wherein the pH of the preparation is 7.5-9.0.
PCT/JP2004/009411 2003-07-03 2004-07-02 Antifungal agent composition for external use WO2005002561A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2003-191271 2003-07-03
JP2003191271 2003-07-03

Applications Claiming Priority (1)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006131597A (en) * 2004-11-09 2006-05-25 Hisamitsu Pharmaceut Co Inc Aerosol composition
WO2010086727A1 (en) * 2009-01-30 2010-08-05 Galderma Pharma Sa Stable compositions for nail onychomycosis treatment

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016144121A2 (en) * 2015-03-12 2016-09-15 동아제약 주식회사 Pharmaceutical composition for treating fungal infectious diseases of ketratin tissue
KR101690765B1 (en) * 2015-04-17 2016-12-28 동아제약 주식회사 Transdermal formulation comprising antifungal agent

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0585929A (en) * 1991-03-08 1993-04-06 L'oreal Sa Use of hydrophilic penetrant into dermatological composition for treating onychomycosis and corresponding composition
JPH05132419A (en) * 1991-05-20 1993-05-28 Sandoz Ag Pharmaceutical composition
WO2000038731A1 (en) * 1998-12-28 2000-07-06 Taisho Pharmaceutical Co.,Ltd. External preparation
JP2001518879A (en) * 1997-03-31 2001-10-16 ジョンソン・アンド・ジョンソン・コンシューマー・カンパニーズ・インコーポレイテッド The solvent system for improved penetration of the drug compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0585929A (en) * 1991-03-08 1993-04-06 L'oreal Sa Use of hydrophilic penetrant into dermatological composition for treating onychomycosis and corresponding composition
JPH05132419A (en) * 1991-05-20 1993-05-28 Sandoz Ag Pharmaceutical composition
JP2001518879A (en) * 1997-03-31 2001-10-16 ジョンソン・アンド・ジョンソン・コンシューマー・カンパニーズ・インコーポレイテッド The solvent system for improved penetration of the drug compound
WO2000038731A1 (en) * 1998-12-28 2000-07-06 Taisho Pharmaceutical Co.,Ltd. External preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PETRANYI G. ET AL.: "Antifungal activity of the allylamine derivative terbinafine in vitro", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 31, no. 9, September 1987 (1987-09-01), pages 1365 - 1368, XP002980982 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006131597A (en) * 2004-11-09 2006-05-25 Hisamitsu Pharmaceut Co Inc Aerosol composition
WO2010086727A1 (en) * 2009-01-30 2010-08-05 Galderma Pharma Sa Stable compositions for nail onychomycosis treatment

Also Published As

Publication number Publication date
JP5435836B2 (en) 2014-03-05
JPWO2005002561A1 (en) 2006-10-19

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