WO1997034607A1 - Formulations d'aciclovir a usage local - Google Patents
Formulations d'aciclovir a usage local Download PDFInfo
- Publication number
- WO1997034607A1 WO1997034607A1 PCT/GB1997/000779 GB9700779W WO9734607A1 WO 1997034607 A1 WO1997034607 A1 WO 1997034607A1 GB 9700779 W GB9700779 W GB 9700779W WO 9734607 A1 WO9734607 A1 WO 9734607A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- aciclovir
- formulation
- diethylene glycol
- water
- monoethyl ether
- Prior art date
Links
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
Definitions
- This invention relates to a topical pharmaceutical formulation suitable for use in treating virus infections of the skin and mucosa, and in particular it relates to topical formulations containing 9-(2-hydroxyethoxymethyl)guanine, otherwise known as aciclovir, and hereinafter referred to as such.
- Aciclovir and pharmaceutically acceptable salts and esters thereof are known to have antiviral activity against various classes of DNA and RNA viruses both in vitro and in vivo, see UK patent No. 1 523 865.
- the compound is active against he ⁇ es simplex virus which causes herpetic keratitis in rabbits, herpetic encephalitis in mice, and cutaneous he ⁇ es in guinea pigs and mice.
- Aciclovir has been found to be effective in the treatment of he ⁇ es simplex virus and he ⁇ es zoster virus in humans.
- Aciclovir suffers from the disadvantage that it has a low solubility in water and is almost totally insoluble in hydrophobic solvent systems. It is accordingly difficult to produce a topical formulation containing a sufficient dissolved concentration of active ingredient for K to exert its full effect and also to optimise the flux of the compound into the skin. In addition to ease of release it is also important that any formulation of a pharmaceutically active compound should be stable for long periods of time, should not lose its potency, should not discolour or form insoluble substances or complexes, and also should not be unduly irritating to the skin or mucosa.
- European Patent No.0044543 describes oil-in-water topical pharmaceutical formulations of aciclovir wherein the aqueous phase contains at least 30% of a water miscible polyhydric alcohol,
- oil-in-water topical pharmaceutical formulations of aciclovir comprising at least 10% by weight of diethylene glycol monoethyl ether have particularly advantageous properties.
- such formulations exhibit enhanced efficacy together with low irritancy and good physical stability.
- the present invention accordingly provides a topical pharmaceutical formulation comprising water, aciclovir and at least 10% w w of diethylene glycol monoethyl ether by weight of the formulation.
- the formulation of the invention contains a maximum of 50% water.
- Such a topical formulation may contain 0.075% to 10% w/w aciclovir or a salt or an ester thereof, from 10% to 50% w/w of diethylene glycol monoethyl ether, from 15% to 50% w/w water and an oil phase.
- aciclovir should be understood to include also its pharmaceutically acceptable salts and esters unless the context clearly indicates otherwise.
- the formulation comprises from 0.5% to 10% w/w aciclovir, from 20% to 40% w/w of diethylene glycol monoethyl ether, from 20% to 40% w/w water together with an oil phase, whilst the most preferred formulation comprises from 1% to 5% w/w aciclovir, from 30% to 40% w/w of diethylene glycol monoethyl ether, from 25% to 40% w w water together with an oil phase.
- Diethylene glycol monoethyl ether is manufactured by Gatttefosse S.A., 36 Chemin de Genas, b.p. 603, 69804 Saint-Priest Cedex, France, under the tradename TRANSCUTOLTM.
- the oil phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it is desirably comprised of a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, as explained in more detail below, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
- the emulsifier(s) with or without stabilisers make up the so-called emulsifying wax
- the wax together with the oil and/or fat make up the so called emulsifying ointment base which forms the oil dispersed phase of the emulsions.
- Emulgents and emulsion stabilisers suitable for use in the formulation of the present invention include cetyl alcohol, sodium lauryl sulphate, stearyl alcohol and polyoxyethylene alkyl ethers, such as brij 721 and brij 72 and polyoxyl stearyl ethers, for example steareth 2 and steareth 21.
- the formulations of the invention may also comprise additional components in the aqueous phase, for example polyhydric alcohols such as propylene glycol.
- polyhydric alcohols such as propylene glycol.
- the formulations of the invention comprise from 0 to 30% by weight of propylene glycol.
- the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of aciclovir in most oils likely to be used in pharmaceutical emulsion formulations is very low.
- the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
- Straight or branched chain, mono- or dialkyl esters such as diisopropyl adipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixed ester of 2-ethyl hexanoic acid with a blend of cetyl or stearyl alcohols known as Crodamol CAP may be used, the last three being the preferred esters. These may be used singly or incombination depending on the properties' required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
- a preferred formulation according to the invention comprises diethylene glycol monoethyl ether, 30-40% w/w; aciclovir, approximately 5% w/w; cetyl alcohol 3-10% w/w; stearyl alcohol, 4-10% w/w; propylene glycol, 0-10% w/w; light mineral oil, 8-15% w/w; steareth 21 or brij 721, 2-5% w/w; steareth 2 or brij 72, 1-3% w/w; and purified water to 100% w/w.
- the formulations of the invention may, if desired, include one or more pharmaceutically acceptable preservatives.
- preservatives is not essential in the formulations of the invention, which finding represents an advantage of the said formulations.
- the present invention further provides a method for the preparation of a topical pharmaceutical formulation, as hereinbefore defined, which comprises mixing the combination of aciclovir, diethylene glycol monoethyl ether and water with the oil phase.
- the manner of formulating the emulsion will of course vary according to the amount and nature of the constituents, but nevertheless follows known techniques in emulsion technology (see the Pharmaceutical Codex, London, the Pharmaceutical Press, 1979).
- the aciclovir may be initially inco ⁇ orated wholely in the aqueous portion where it may form a solution alone, or a mixed solution/suspension, and then emulsified with the ointment base.
- a part of the aqueous portion may be formulated as an emulsion, and the balance of the water, diethylene glycol monoethyl ether and aciclovir added to and dispersed into the emulsion
- the aciclovir may be included in the emulsifying ointment prior to emulsification with the aqueous portion.
- a topical formulation of the present invention may be used in the treatment or prevention of viral infections caused for example by He ⁇ es zoster, He ⁇ es varicella and He ⁇ es simplex types I and 2, which cause diseases such as shingles, chicken pox, cold sores and genital he ⁇ es.
- the formulation should desirably be applied to the affected area of skin from 1 to 6 times daily, preferably from 3 to 5 times.
- the oil phase comprising stearyl alcohol, cetyl alcohol, light mineral oil, brij 72 and brij 721 is heated to 70-75 °C with mixing.
- Purified water is heated to 65- 70 °C and added to the oil phase, maintaining the temperature at 70-75 °C, with mixing to form an emulsion.
- the mixture is maintained at a temperature of 70-75 °C for approximately 5 minutes.
- TRANSCUTOLTM is weighed into an appropriate container and aciclovir added with mixing to form a suspension.
- the aciclovir suspension is added to the emulsion, rinsing in with a small amount of purified water.
- the emulsion is homogenized for approximately 5 minutes, then made up to final batch weight with purified water.
- the resulting cream is cooled to ambient temperature (approximately 30 °C) with continuous mixing and filled into suitable tubes which are then sealed.
- Example 2 ingredient % w/w
- TRANSCUTOLTM 30.0 aciclovir 5.0 stearyl alcohol 5.0 cetyl alcohol 4.0 light mineral oil 10.2
- Purified water to 100 The oil phase comprising stearyl alcohol, cetyl alcohol, light mineral oil, brij 72 and brij 721 is heated to 70-75°C with mixing.
- Purified water is heated to 70- 75 °C and added to the oil phase, maintaining the temperature at 70-75° C, with mixing to form an emulsion.
- the mixture is maintained at a temperature of 70-75°C for approximately 5 minutes.
- TRANSCUTOLTM is weighed into an appropriate container and propylene glycol and aciclovir added with mixing to fo ⁇ n a suspension which is homogenized at 65-70 °C for approximately 5 minutes.
- the propylene aciclovir suspension is added to the emulsion at 50- 70°C, suitably 50-55°C, rinsing in with a small amount of purified water.
- the emulsion is homogenized for approximately 5 minutes, then made up to final batch weight with purified water.
- the resulting cream is cooled to ambient temperature (approximately 30°C) with continuous mixing and filled into suitable tubes which are then sealed.
- the oil phase is weighed and heated to 70-75 °C with continuous slow mixing; Purified water is heated to 65-70 °C. The purified water is added with propeller agitation to the suspension of aciclovir in TRANSCUTOLTM. The resulting aqueous mixture is heated to 65-70 °C. Whilst maintaining the temperature of the oil phase at 70-75 °C, the aqueous phase is slowly added with sweep agitation for at least 5 minutes. The aqueous phase container is rinsed with purified water and the rinsings added to the main batch. The temperature of the batch is maintained at 70-75 °C and the batch is homogenized for at least 5 minutes. The batch is cooled to 30-35 °C with continuous sweep agitation and purified water added to adjust to final batch weight. The batch is mixed until uniform and cooled to 30 °C.
- Example 4 Experimental Data
- mice Female HRS/J mice were infected cutaneously with wild-type HSV-1. After the mice were anaesthetised with ketamine and xylazine, the skin of the snout region was lightly abraded with a Dremel® roto-tool. Groups of ten mice were then innoculated on the skin of the snout from an SC-16 HSV stock solution diluted to a final concentration of 1 E6 PFU/ml. The abrasion area was then swabbed for ten seconds with a sterile cotton swab soaked with the viral stock.
- Formulation A 5% w w aciclovir
- Formulation B 5% w/w aciclovir
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU20362/97A AU2036297A (en) | 1996-03-20 | 1997-03-20 | Topical formulations of aciclovir |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9605859.9 | 1996-03-20 | ||
GBGB9605859.9A GB9605859D0 (en) | 1996-03-20 | 1996-03-20 | Medicaments |
GBGB9618975.8A GB9618975D0 (en) | 1996-09-11 | 1996-09-11 | Medicaments |
GB9618975.8 | 1996-09-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997034607A1 true WO1997034607A1 (fr) | 1997-09-25 |
Family
ID=26308961
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1997/000779 WO1997034607A1 (fr) | 1996-03-20 | 1997-03-20 | Formulations d'aciclovir a usage local |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU2036297A (fr) |
WO (1) | WO1997034607A1 (fr) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998010768A1 (fr) * | 1996-09-11 | 1998-03-19 | Glaxo Group Limited | Compositions antivirales |
WO1999012545A2 (fr) * | 1997-09-05 | 1999-03-18 | Glaxo Group Limited | Medicaments contenant acyclovir |
WO2000001390A1 (fr) * | 1998-07-03 | 2000-01-13 | Recordati S.A. Chemical And Pharmaceutical Company | Formulations topiques d'aciclovir |
FR2837102A1 (fr) * | 2002-03-18 | 2003-09-19 | Palbian Snc | Composition a l'etat de gel aqueux, procede de fabrication et utilisation pour la fabrication d'un medicament, notamment antiherpetique |
AU2004202929B2 (en) * | 1999-09-22 | 2006-11-23 | B. Ron Johnson | Systems for agitated delivery of anti-infective compositions to treat disordered tissue such as cold sores |
US7198801B2 (en) | 2000-08-03 | 2007-04-03 | Antares Pharma Ipl Ag | Formulations for transdermal or transmucosal application |
US8268346B2 (en) | 2006-04-21 | 2012-09-18 | Antares Pharma Ipl Ag | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
US8338400B2 (en) | 2005-05-27 | 2012-12-25 | Antares Pharma Ipl Ag | Methods and apparatus for transdermal or transmucosal application of testosterone |
US8652491B2 (en) | 2000-08-03 | 2014-02-18 | Antares Pharma Ipl Ag | Transdermal compositions for anticholinergic agents |
US8980309B2 (en) | 2003-10-10 | 2015-03-17 | Antares Pharma Ipl Ag | Transdermal testosterone formulation for minimizing skin residues |
US9125911B2 (en) | 2013-03-14 | 2015-09-08 | Quadex Pharmaceuticals, Llc | Combined systemic and topical treatment of disordered tissues |
US9463180B2 (en) | 2013-03-14 | 2016-10-11 | Quadex Pharmaceuticals, Llc | Treatment of molluscum contagiosum |
US9549930B2 (en) | 2013-03-14 | 2017-01-24 | Quadex Pharmaceuticals, Llc | Combined systemic and topical treatment of disordered and/or prodromal stage tissue |
GB201819418D0 (en) | 2018-11-29 | 2019-01-16 | Daniel Calladine Ltd | Anti-viral compositions |
CN115025119A (zh) * | 2022-06-15 | 2022-09-09 | 任嘉斌 | 一种治疗带状疱疹、疱疹的软膏及其制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0044543A1 (fr) * | 1980-07-18 | 1982-01-27 | The Wellcome Foundation Limited | Formulations topiques à base de 9(2-hydroxyéthoxyméthyl) guanine |
WO1990011064A1 (fr) * | 1989-03-22 | 1990-10-04 | Cygnus Research Corporation | Compositions ameliorant la penetration a travers la peau |
JPH0372426A (ja) * | 1989-05-18 | 1991-03-27 | Teikoku Seiyaku Kk | 神経痛治療用アスピリン含有軟膏組成物 |
WO1994015614A1 (fr) * | 1992-12-30 | 1994-07-21 | Agis Industries (1983) Limited | Compositions pharmaceutiques antivirales a usage local |
WO1995035095A1 (fr) * | 1994-06-22 | 1995-12-28 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions destinees a l'application de substances actives sur la peau |
-
1997
- 1997-03-20 AU AU20362/97A patent/AU2036297A/en not_active Abandoned
- 1997-03-20 WO PCT/GB1997/000779 patent/WO1997034607A1/fr active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0044543A1 (fr) * | 1980-07-18 | 1982-01-27 | The Wellcome Foundation Limited | Formulations topiques à base de 9(2-hydroxyéthoxyméthyl) guanine |
WO1990011064A1 (fr) * | 1989-03-22 | 1990-10-04 | Cygnus Research Corporation | Compositions ameliorant la penetration a travers la peau |
JPH0372426A (ja) * | 1989-05-18 | 1991-03-27 | Teikoku Seiyaku Kk | 神経痛治療用アスピリン含有軟膏組成物 |
WO1994015614A1 (fr) * | 1992-12-30 | 1994-07-21 | Agis Industries (1983) Limited | Compositions pharmaceutiques antivirales a usage local |
WO1995035095A1 (fr) * | 1994-06-22 | 1995-12-28 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions destinees a l'application de substances actives sur la peau |
Non-Patent Citations (1)
Title |
---|
PATENT ABSTRACTS OF JAPAN vol. 015, no. 231 (C - 0840) 12 June 1991 (1991-06-12) * |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998010768A1 (fr) * | 1996-09-11 | 1998-03-19 | Glaxo Group Limited | Compositions antivirales |
WO1999012545A2 (fr) * | 1997-09-05 | 1999-03-18 | Glaxo Group Limited | Medicaments contenant acyclovir |
WO1999012545A3 (fr) * | 1997-09-05 | 1999-06-10 | Glaxo Group Ltd | Medicaments contenant acyclovir |
WO2000001390A1 (fr) * | 1998-07-03 | 2000-01-13 | Recordati S.A. Chemical And Pharmaceutical Company | Formulations topiques d'aciclovir |
AU2004202929B2 (en) * | 1999-09-22 | 2006-11-23 | B. Ron Johnson | Systems for agitated delivery of anti-infective compositions to treat disordered tissue such as cold sores |
US7198801B2 (en) | 2000-08-03 | 2007-04-03 | Antares Pharma Ipl Ag | Formulations for transdermal or transmucosal application |
US8980290B2 (en) | 2000-08-03 | 2015-03-17 | Antares Pharma Ipl Ag | Transdermal compositions for anticholinergic agents |
US8652491B2 (en) | 2000-08-03 | 2014-02-18 | Antares Pharma Ipl Ag | Transdermal compositions for anticholinergic agents |
FR2837102A1 (fr) * | 2002-03-18 | 2003-09-19 | Palbian Snc | Composition a l'etat de gel aqueux, procede de fabrication et utilisation pour la fabrication d'un medicament, notamment antiherpetique |
WO2003077922A1 (fr) * | 2002-03-18 | 2003-09-25 | Palbian Societe En Nom Collectif | Composition a l'etat de gel aqueux, procede de fabrication et utilisation pour la fabrication d'un medicament, notament antiherpetique |
US8980309B2 (en) | 2003-10-10 | 2015-03-17 | Antares Pharma Ipl Ag | Transdermal testosterone formulation for minimizing skin residues |
US8338400B2 (en) | 2005-05-27 | 2012-12-25 | Antares Pharma Ipl Ag | Methods and apparatus for transdermal or transmucosal application of testosterone |
US8647665B2 (en) | 2006-04-21 | 2014-02-11 | Antares Pharma Ipl Ag | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
US8268346B2 (en) | 2006-04-21 | 2012-09-18 | Antares Pharma Ipl Ag | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
US9125911B2 (en) | 2013-03-14 | 2015-09-08 | Quadex Pharmaceuticals, Llc | Combined systemic and topical treatment of disordered tissues |
US9463180B2 (en) | 2013-03-14 | 2016-10-11 | Quadex Pharmaceuticals, Llc | Treatment of molluscum contagiosum |
US9545408B2 (en) | 2013-03-14 | 2017-01-17 | Quadex Pharmaceuticals, Inc. | Combined systemic and topical treatment of disordered tissues |
US9549930B2 (en) | 2013-03-14 | 2017-01-24 | Quadex Pharmaceuticals, Llc | Combined systemic and topical treatment of disordered and/or prodromal stage tissue |
GB201819418D0 (en) | 2018-11-29 | 2019-01-16 | Daniel Calladine Ltd | Anti-viral compositions |
WO2020109442A1 (fr) | 2018-11-29 | 2020-06-04 | Daniel Calladine Limited | Compositions antivirales |
CN115025119A (zh) * | 2022-06-15 | 2022-09-09 | 任嘉斌 | 一种治疗带状疱疹、疱疹的软膏及其制备方法 |
Also Published As
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