WO2004073680A1 - 液滴分散型軟膏剤 - Google Patents
液滴分散型軟膏剤 Download PDFInfo
- Publication number
- WO2004073680A1 WO2004073680A1 PCT/JP2004/001967 JP2004001967W WO2004073680A1 WO 2004073680 A1 WO2004073680 A1 WO 2004073680A1 JP 2004001967 W JP2004001967 W JP 2004001967W WO 2004073680 A1 WO2004073680 A1 WO 2004073680A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ointment
- dispersed
- droplet
- concentration
- glycolone
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
Definitions
- the present invention relates to topical formulations for treating fibrotic diseases of the skin.
- An oil-based ointment usually called an ointment is a crystal-dispersed ointment in which fine crystals of the active ingredient are uniformly dispersed in an oil-based base, and a dissolution in which the active ingredient is dissolved in an oil-based base
- Ointments are classified into ointments and droplet-dispersed ointments in which the solvent in which the active ingredient is dissolved is dispersed as fine droplets in an oil base.
- Crystal dispersion-type ointments have the advantage that they are easy to prepare, but they have the drawback that the solid component irritates the skin and the drug absorbability and content uniformity are poor.
- Dissolvable ointments have the disadvantage of poor storage stability.
- a droplet-dispersed ointment has better transdermal absorbability of the active ingredient than a crystal-dispersed ointment.
- Solubilizers used in external preparations can generally cause skin irritation. For the treatment of burns and keloids, among other fibrotic diseases of the skin, it is necessary to pay attention to the selection and use of such dissolving agents.
- 5-Methyl-1-phenyl-2- (1H) -pyridone is a drug known as Pirfenidone, which has an anti-fibrotic action (Japanese patent
- Japanese Patent Application Laid-Open No. 2-215719 describes capsules, tablets, creams, ointments and the like as preparations of pirfen-don, and mentions hydrophilic ointments containing 5 to 10% of pirfenidone as ointments. No drop-dispersed ointment is described.
- Antifibrous refers to the repair and normalization of pathological fibrotic tissue in pulmonary fibrosis, arteriosclerosis, and fibrotic diseases of the skin, such as keloids.
- Tokiohei 2002- 5 264 4? (W000 / 16775) describes gels, ointments and creams as external preparations containing pirueudon for treating fibrotic diseases of the skin. Not. It is described that the ointment containing pyrefedone described here has poor storage stability. In addition, Japanese Patent Application Laid-Open No. 8-510251 (W094 / 26249) does not disclose a power droplet dispersion type ointment which suggests a hydrophilic ointment containing 5 to 10% of pirfenidone.
- US 5,310,562 describes capsenoles, tablets, creams, ointments, hydrophilic ointments, etc. as preparations of pirfenidone, but does not describe droplet-dispersed ointments .
- ointments in general, when pharmaceuticals are formulated as external preparations, various dosage forms such as ointments, liquids for external use, creams, lotions, plasters, etc. can be selected. It is an external preparation made in a semi-solid form, and is a useful preparation because it can be applied to diseased skin of various states and can be directly applied to diseased skin of various areas. Therefore, an ointment was selected as an external preparation for pirfenidone, and intensive studies were conducted on pirfenidone ointment, which is superior in skin irritation, drug stability, and transfer to the skin compared to conventionally known external preparations. went.
- the present invention (1) Drops of 5-methyl-1-phenyl-2- (1H) -pyridone or its pharmaceutically acceptable salt dissolved in a dissolving agent as an active ingredient are contained in an ointment base. Ointment dispersed by droplets,
- the dissolving agent is benzyl alcohol, N-methyl-1-pyrrolidone, ethylene glycol salicylate, 1,3-butylene glycol, hexylene glycol, propylene glycol, propylene carbonate, dipropylene glycol, or a mixture thereof.
- the concentration of the dissolving agent is 1 to 1 OT / W with respect to the whole ointment. /. From (1) above
- the concentration of the active ingredient is 0.1 to 5 W / W with respect to the whole ointment.
- Sorbitan sesquistearate in the ointment base is 0.5 to
- the ointment base contains liquid paraffin, white petrolatum, or a mixture thereof; the droplet-dispersed ointment according to any one of (1) to (6) above;
- the concentration of the active ingredient in the whole ointment is 0.1 to 5 W / W
- the concentration of the dissolving agent is 1 to 15 W / W%
- the concentration of sorbitan sesquistearate is 0.5 to 8 W / W%.
- the drug absorbability is better because pyrueudon is dissolved in the dissolving agent and dispersed in the ointment. It also has excellent drug stability and content uniformity. Furthermore, since there is no solid matter, there is no rough feeling and the feeling of use is excellent, and it does not cause skin irritation.
- Figure 1 Graph showing the change in concentration of pirfenidone in rat plasma.
- the droplet-dispersed ointment of the present invention means a preparation in which a dissolving agent for an active ingredient is uniformly dispersed as droplets in a small ointment base having compatibility with the active ingredient. Drops of 5-methyl-1-phenyl-1- (1H) -pyridone or its pharmaceutically acceptable salt dissolved as an active ingredient in a dissolving agent dispersed in an ointment base It is an ointment.
- the droplet-dispersed ointment of the present invention is generally composed of droplets containing an active ingredient and an ointment base, and this ointment base can also contain an active ingredient.
- a droplet-dispersed ointment is a droplet-dispersed ointment by observing that the droplets are dispersed in the ointment base using an optical microscope or the like. It can be distinguished from crystal-dispersed ointments and dissolved ointments.
- the size of the droplet is preferably 50 ⁇ m or less, more preferably 20 ⁇ m or less.
- the droplet-dispersed ointment of the present invention containing pirfenidone as an active ingredient is useful for treating fibrotic diseases of the skin, such as keloids, hypertrophic scars, fibrotic lesion tissues, contact warts, contact dermatitis, and the like. ⁇ Useful for treating postoperative burns.
- “5-Methyl-1-phenyl-2- (1H) -pyridone (pyruvedone) J as an active ingredient contained in the ointment of the present invention is described in JP-A-49-187677.
- the pharmaceutically acceptable salts of pirfenidone include salts with amino acids, inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.), and organic acids (acetic acid, quinone). Acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.)
- the concentration of the active ingredient is preferably 0.1 to 5% based on the whole ointment. And more preferably 0.1 to 3%.
- the solubilizing agent constituting the droplets contained in the ointment of the present invention is a solvent that has excellent solubility of py-40idone, can stably retain pyblaidone in a solution state, and can maintain a stable droplet dispersed state. is there.
- the dissolving agent is preferably one having low compatibility with an ointment base such as white petrolatum or liquid paraffin and forming droplets in the ointment base with a dispersant. Further, a solvent that promotes transdermal absorption or a solvent that causes little skin irritation is desirable.
- Preferred dissolving agents are benzyl alcohol, N-methyl-2-pyrrolidone, ethylene glycol salicylate, 1,3-butylene glycol, hexylene glycol, propylene glycolone, propylene carbonate, dipropylene glycolone, or a mixture thereof. It is a mixed solution. More preferred are benzyl alcohol, N-methyl-2-pyrrolidone, ethylene glycol salicylate, hexylene glycol, propylene glycol, propylene carbonate, or a mixture thereof. Preferable combination in case of liquid mixture and its preference!
- the amount of solubilizer used should be as low as possible. Preferably, it is 1 to 15%, more preferably 2 to 12%, most preferably 4 to 8% based on the whole ointment.
- liquid paraffin for example, liquid paraffin, white serine, beeswax, caster wax, or a mixture thereof is preferably used.
- the ointment base of the ointment of the present invention contains a dispersant for the purpose of stably dispersing the droplets of the dissolving agent.
- a dispersant for the purpose of stably dispersing the droplets of the dissolving agent.
- the dispersant one or more sorbitan fatty acid esters or polyoxysorbitan fatty acid esters are used.
- Preferred dispersants are sorbitan fatty acid esters, and more preferred are sorbitan sesquistearate.
- the amount used is preferably 0.5 to 8 W /%, more preferably 2 to 6 WZW%, based on the whole ointment.
- Typical formulations and typical ratios (W / W% based on the whole ointment) of the ointment of the present invention are as follows. Pizolefenidone 0.:! ⁇ 5 W / W%
- Liquid paraffin 2 ⁇ 10 W / W ° / o
- White petrolatum 62-96.4 W / W ° / o The preferred formulation of the present invention was obtained from the results of drug stability at 40 ° C for 2 months or 60 ° C for 1 week shown in Table 4 below. Even when stored at room temperature for more than a month, it is presumed that it contains pyruyudon stably, does not synerise, does not precipitate crystals, and maintains a homogeneous droplet dispersion state.
- the droplet-dispersed ointment of the present invention can be easily prepared by heating and mixing an ointment base and a dispersant, cooling, adding a dissolving agent in which pycliidone is dissolved, and mixing with a stirrer. Be prepared. The dispersion state of the prepared ointment is visually observed with an optical microscope.
- the ointment of the present invention may further contain an antioxidant and the like.
- Test example 1 The present invention will be described in more detail with reference to the following Examples and Experimental Examples, but the present invention is not limited thereto.
- Test example 1 The present invention will be described in more detail with reference to the following Examples and Experimental Examples, but the present invention is not limited thereto.
- droplet-dispersed ointments were prepared with the compositions (W / W) shown in the table below.
- a crystalline dispersion type ointment was prepared.
- Example 4 The ointments prepared in Example 1 and Control Example 1 were stored at 40 ° C for 2 months or 60 ° C for 1 week, and the content of pirfenidone was measured by an HPLC method (internal standard method). Table 4
- Pirfenidone 3W / W 0 A crystal dispersion-type ointment comprising 5W / W% liquid paraffin and 92W / W% white petrolatum was prepared. Control 3
- Pirfenidone 5W / W 0 Carboxybule polymer (CVP) 1.7W / W%, isopropanol 15WWfo Propylene glycol 25W / W.
- Polyethylene glycol 400 12.5 W / W%, triisoprononolamine 1.
- a gel preparation consisting of OW / W ° / o, deionized water 39.8 W / W% was prepared.
- Example 1-1, Example 1-4, Example 1-8, Example 2-1, Example 2-2, and the ointment of Control Example 3 and the ointment of Control Example 3 and 300 mg of the gesle preparation of Control Example 3 were respectively administered to the abdomen of rats. 6 hours after administration, the amount of transdermal administration into the skin was measured. The administration was performed by attaching a glass cell to the abdomen of the rat from which the hair had been removed with a razor, placing the preparation in the cell, and keeping the administration area constant. The administration method was a closed administration in which the upper part of the glass cell was covered with a rubbing lid, and an open administration in which the lid was removed.
- the preparation remaining at the administration site was removed with a black mouth form.
- the skin at the administration site was collected, cut into small pieces, and pyrueudon in the skin was extracted with ethyl acetate and quantified by HPLC.
- Example 2-1 1.0 Mixed solvent 16.9 ⁇ 4.3
- Example 2-2 3.0 Mixed dissolution agent 31.3 ⁇ 7.4 13.5 ⁇ 4.8 Control 23.0 None (crystal dispersion ointment) 9.2 ⁇ 2.4
- Table 6 shows that the present invention In the ointment of the droplet dispersion type, even if the drug content is smaller than that of the crystal dispersion type ointment, the intradermal distribution is high, and pirfenidone is easily transferred into the skin. Indicates that it can be done. Test example 4
- FIG. 1 shows that despite the low content of pirfenidone in the preparation of Example 1-8, the drug is rapidly transferred into the skin.
- N -methyl-2-pyrrolidone has an absorption-promoting effect as a solubilizer for an external preparation of pyrphenidone and is suitable.
- the preparation of Example 2-2 also showed that the drug was rapidly transferred into the skin despite the lower content of pirfenidone as compared with the preparation of Control Example 4. All of these preparations are expected to have a lower solubilizer content and less skin irritation than the gel preparation of Control 3 (isopropanol, propylene glycol, and polyethylene glycol 400).
- Test example 5 is expected to have a lower solubilizer content and less skin irritation than the gel preparation of Control 3 (isopropanol, propylene glycol, and polyethylene glycol 400).
- Example 6 0.5 g of the ointment of Example 1-8 or Example 2-2 was repeatedly applied once a day for 14 days to the back skin of a egret, and a skin irritation test was performed. Almost no skin irritation was observed with any of the preparations. Test example 6
- Example 1-1 Example 1-8, and Example 2-2 was stored at -20, 5, 40, and 60 ° C for 3 months, but no crystal precipitation was observed after storage over time.
- Example 1-8 Example 1-8, and Example 2-2 was stored at -20, 5, 40, and 60 ° C for 3 months, but no crystal precipitation was observed after storage over time.
- Example 2-2 was stored at -20, 5, 40, and 60 ° C for 3 months, but no crystal precipitation was observed after storage over time.
- pirfenidone which is effective for repairing and normalizing pathological fibrotic tissue in pulmonary fibrosis, arteriosclerosis, and other skin fibrotic diseases such as keloids, A preparation having excellent stability and transferability to the skin is provided.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003-045108 | 2003-02-21 | ||
JP2003045108 | 2003-02-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004073680A1 true WO2004073680A1 (ja) | 2004-09-02 |
Family
ID=32905480
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2004/001967 WO2004073680A1 (ja) | 2003-02-21 | 2004-02-20 | 液滴分散型軟膏剤 |
Country Status (2)
Country | Link |
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TW (1) | TW200418516A (ja) |
WO (1) | WO2004073680A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008290984A (ja) * | 2007-05-25 | 2008-12-04 | Lead Chemical Co Ltd | 5−メチル−1−フェニル−2−(1h)−ピリドン含有貼付剤 |
WO2010058844A1 (ja) * | 2008-11-21 | 2010-05-27 | リードケミカル株式会社 | 5-メチル-1-フェニル-2-(1h)-ピリドン含有貼付剤 |
KR20180097672A (ko) * | 2015-12-28 | 2018-08-31 | 오츠카 세이야쿠 가부시키가이샤 | 연고 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990009176A1 (en) * | 1989-02-15 | 1990-08-23 | Margolin Solomon B | Composition for reparation and prevention of fibrotic lesions |
WO1994026249A1 (en) * | 1993-05-07 | 1994-11-24 | Margolin Solomon B | Compositions and methods for reparation and prevention of fibrotic lesions |
WO1997041830A1 (en) * | 1996-05-09 | 1997-11-13 | Margolin Solomon B | Reparation and prevention of fibrotic lesions |
WO2000016775A1 (en) * | 1998-09-18 | 2000-03-30 | Mepha Ag | Topical formulation of alkyl-, phenyl-pyridone |
-
2004
- 2004-02-20 TW TW093104276A patent/TW200418516A/zh unknown
- 2004-02-20 WO PCT/JP2004/001967 patent/WO2004073680A1/ja not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990009176A1 (en) * | 1989-02-15 | 1990-08-23 | Margolin Solomon B | Composition for reparation and prevention of fibrotic lesions |
WO1994026249A1 (en) * | 1993-05-07 | 1994-11-24 | Margolin Solomon B | Compositions and methods for reparation and prevention of fibrotic lesions |
WO1997041830A1 (en) * | 1996-05-09 | 1997-11-13 | Margolin Solomon B | Reparation and prevention of fibrotic lesions |
WO2000016775A1 (en) * | 1998-09-18 | 2000-03-30 | Mepha Ag | Topical formulation of alkyl-, phenyl-pyridone |
Non-Patent Citations (3)
Title |
---|
SAITO IZUMI ET AL., JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, vol. 50, no. 3, 1990, JAPAN, pages 279 - 285, XP002904049 * |
SAITO IZUMI ET AL., JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, vol. 50, no. 3, 1990, JAPAN, pages 286 - 291, XP002904050 * |
SAITO IZUMI ET AL., JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, vol. 54, no. 1, 1994, JAPAN, pages 35 - 41, XP002904051 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008290984A (ja) * | 2007-05-25 | 2008-12-04 | Lead Chemical Co Ltd | 5−メチル−1−フェニル−2−(1h)−ピリドン含有貼付剤 |
WO2008146796A1 (ja) * | 2007-05-25 | 2008-12-04 | Lead Chemical Co., Ltd. | 5-メチル-1-フェニル-2-(1h)-ピリドン含有貼付剤 |
US8287900B2 (en) | 2007-05-25 | 2012-10-16 | Lead Chemical Co., Ltd. | Medicated patch comprising 5-methyl-1-phenyl-2-(1H)-pyridone |
WO2010058844A1 (ja) * | 2008-11-21 | 2010-05-27 | リードケミカル株式会社 | 5-メチル-1-フェニル-2-(1h)-ピリドン含有貼付剤 |
JP2010120912A (ja) * | 2008-11-21 | 2010-06-03 | Lead Chemical Co Ltd | 5−メチル−1−フェニル−2−(1h)−ピリドン含有貼付剤 |
US8568770B2 (en) | 2008-11-21 | 2013-10-29 | Lead Chemical Co., Ltd. | Adhesive material containing 5-methyl-1-phenyl-2-(1H)-pyridone |
KR20180097672A (ko) * | 2015-12-28 | 2018-08-31 | 오츠카 세이야쿠 가부시키가이샤 | 연고 |
JP2019503989A (ja) * | 2015-12-28 | 2019-02-14 | 大塚製薬株式会社 | 軟膏剤 |
JP2021107437A (ja) * | 2015-12-28 | 2021-07-29 | 大塚製薬株式会社 | 軟膏剤 |
KR102643824B1 (ko) * | 2015-12-28 | 2024-03-07 | 오츠카 세이야쿠 가부시키가이샤 | 연고 |
Also Published As
Publication number | Publication date |
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TW200418516A (en) | 2004-10-01 |
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