Classifications

• • 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
  • 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
• • 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
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• • 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
  • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to pharmaceutical compositions for topical application.
• the present invention relates to pharmaceutical compositions for topical application in the form of a gel comprising a non-steroidal anti-inflammatory drug and a xanthine derivative.
• the compositions of the present invention are useful as analgesics and anti-inflammatories.
• Xanthine derivatives are known for use in pharmaceutical compositions.
• Caffeine is a particularly well known xanthine derivative.
• Caffeine, or 3,7-dihydro-l ,3,7-trimethyl-lH-purine-2,6- dione, has the structural formula:
• Caffeine has been used alone, intravenously, in the treatment of headaches and has also been used in combination with selected drugs.
• One of the types of topical formulations that caffeine has been used in is a topical gel.
• a commercial aqueous gel product containing caffeine for topical treatment of skin is Percutafeine gel, supplied by Laboratories Pierre Fabre Sante, Paris, France, which contains 4% by weight of caffeine and which is used to treat obesity.
• EP-A-0105635 (Han & Roehrs, published 18 April 1984) relates to ophthalmic aqueous gel compositions for reducing ocular stinging comprising an acidic anti-inflammatory agent and a xanthine derivative.
• Ibuprofen i.e. 2-(4-isobutylphenol) propionic acid
• Ibuprofen is well known non- steroidal anti-inflammatory drug for use in oral compositions as a therapeutic agent having analgesic, anti-inflammatory and anti-pyretic activity. It is often used as an alternative to aspirin (i.e. acetyl salicylic acid) and paracetamol, in the treatment of pain such as headache, toothache and especially when associated with inflammation in, for example, rheumatic diseases.
• Ibuprofen is also known for use in aqueous gel compositions for topical application to the skin.
• GB-A-2134786 discloses oral pharmaceutical compositions comprising a non-steroidal anti-inflammatory drug (NSAID) analgesic, anti-inflammatory drug active such as ibuprofen, together with caffeine.
• NSAID non-steroidal anti-inflammatory drug
• EP-A-0105635 discloses ophthalmic compositions which may be aqueous solutions, suspensions or gels comprising an acidic anti- inflammatory agent, such as ketoprofen, and a xanthine derivative, such as caffeine. There are no examples in this document of aqueous gel compositions containing a xanthine derivative and a non-steroidal anti-inflammatory drug.
• aqueous gel composition for topical application to the skin comprising a combination of a xanthine derivative such as caffeine and non-steroidal analgesic/anti- inflammatory drug such as ibuprofen, which delivers analgesic or anti- inflammatory efficacy.
• a xanthine derivative such as caffeine
• non-steroidal analgesic/anti- inflammatory drug such as ibuprofen
• a topical gel composition comprising:
• a non- steroidal anti-inflammatory drug selected from a propionic acid derivative, acetic acid derivative, fenamic acid derivative, biphenylcarboxylic acid derivative and an oxicam, and salts thereof, and mixtures thereof;
• Rl, R2 and R3 are each independently selected from a hydrogen atom, a methyl or ethyl group, and at least two of Rl , R2 and R3 are methyl or ethyl groups; and mixtures thereof;
• compositions of the present invention exhibit analgesic and anti- inflammatory activity and improved product stability and clarity.
• compositions of the present invention comprise a non- steroidal anti-inflammatory drug, a xanthine derivative, a gelling agent, a cosolvent for the non-steroidal anti-inflammatory agent and the xanthine derivative and water.
• compositions of the present invention are gels which have improved clarity and stability.
• the compositions are formulated as clear gels.
• the term "clear" is intended to have an ordinary dictionary meaning, that is, transparent and free from obscurity.
• Product clarity can be measured using a visible range spectrophotometer. Using this equipment the percent transmittance of the sample at 450 nm is measured by calibration against a reference sample of Ethanol B100 as 100% transmittance.
• Percent transmittance values for the gel compositions according to the present invention are preferably greater than 70% when first made, preferred compositions herein displaying 80% transmittance values after storage for at least four weeks at 37°C.
• a first essential component of the compositions herein is a non- steroidal anti-inflammatory agent selected from a propionic acid derivative, an acetic acid derivative, a fenamic derivative, a biphenylcarboxylic acid derivative and an oxicam derivative, and salts thereof, and mixtures thereof.
• non-steroidal anti-inflammatory agent as used herein is intended to mean any non- narcotic analgesic non-steroidal anti-inflammatory compound, including the pharmaceutically acceptable non-toxic salts thereof, falling within one of the five structural categories above.
• propionic acid derivative as defined herein means non- narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -CH(CH3)COOH or -CH2CH2COOH group or a combination thereof (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g. -CH(CH3)COCrNa+ or -CH2CH2COO"Na+), typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system.
• a pharmaceutically acceptable salt group e.g. -CH(CH3)COCrNa+ or -CH2CH2COO"Na+
• Suitable propionic acid derivatives for use herein include, but are not limited to, ibuprofen, naproxen, benoxaprofen, flurbiprofen, indoprofen, fenoprofen, ketoprofen, fenbufen and fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid and bucloxic acid.
• Structurally related propionic acid derivatives having similar analgesic and anti- inflammatory properties are also intended to be encompassed by this group.
• any of the foregoing compounds may be utilized in the form of their pharmaceutically-acceptable salt forms, e.g. , sodium salts, potassium salts, and the like, and such salts are intended to be included.
• Particularly preferred propionic derivatives for use herein include ibuprofen, naproxen, naproxen sodium, flurbiprofen, fenoprofen, ketoprofen, suprofen, fenbufen and fluprofen, especially ibuprofen.
• acetic acid derivatives as used herein means non-narcotic analgesics/non-steroidal anti-inflammatory drugs having a free - CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g. -CH2COO ⁇ Na + ), typically attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system.
• a pharmaceutically acceptable salt group e.g. -CH2COO ⁇ Na +
• acetic acid derivatives for use herein include, but are not limited to, indomethacin, sulindac, tolmetin, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac and oxepinac.
• Structurally related acetic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
• fumamic acid derivatives as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure:
• the fenamic acid derivatives suitable for use herein include, but are not limited to, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid. Structurally realted fenamic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
• Representative members of the fenamic group include mefenamic acid, meclofenamate sodium (meclofenamic acid, sodium salt) and flufenamic acid.
• biphenylcarboxylic acid derivatives as used herein means non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure:
• biphenylcarboxylic acid derivatives for use herein include, but are not limited to, diflunisal and flufenisal. Structurally realted biphenylcarboxylic acid derivtiaves having simipar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
• oxicams as defined herein means non-narcotic analgesics/non-steroidal anti-inflammatory drugs which have the general formula:
• R is an aryl or heteroaryl ring system.
• Suitable oxicams for use herein include, but are not limited to, piroxicam, sudoxicam, and isoxicam. Structurally related oxicams having similar analgesic and anti- inflammatory properties are also intended to be encompassed by this group.
• the propionic acid derivatives are most preferred for use in the compositions herein, and especially ibuprofen.
• the non-steroidal anti-inflammatory agent is present in the compositions of the present invention at a level of from about 0.1 % to about 20% , preferably from about 0.1 % to about 15% , especially from about 1 % to about 10% by weight of composition.
• a second essential component of the compositions of the present invention is a xanthine derivative having the general formula:
• Rj , R2 and R3 are each independently selected from a hydrogen atom, a methyl or ethyl group, and at least two of Ri , R2 and R3 are methyl or ethyl groups, and mixtures thereof.
• the xanthine derivative is generally present herein at a level of from about 0.1 % to about 10% , especially from about 1 % to about 5% by weight of composition.
• Particularly preferred for use herein are methyl and ethyl derivatives of xanthine.
• Examples of xanthine derivatives include theophylline, which has methyl groups at the 1 and 3 positions, caffeine, which has methyl groups at the 1 ,3, and 7 positions, and theobromine which has methyl groups at the 3 and 7 positions.
• Preferred herein in combination with the non-steroidal anti- inflammatory drug from the viewpoint of enhancing analgesic and/or anti-inflammatory activity is caffeine.
• a third essential ingredient herein is a gelling agent for forming a gel in the aqueous base of the compositions of the present invention.
• the gelling agent is generally present in the compositions herein at a level of from about 0.1 % to about 10%, preferably from about 0.5% to about 5% , more preferably from about 0.5% to about 3% by weight.
• Suitable gelling agents for use herein include crosslinked polymeric gelling agents. These can be obtained by the polymerisation or copolymerisation of appropriate monomers together with a suitable crosslinking agent.
• Suitable monomers for use in the crosslinked polymeric gelling agents include unsaturated, polymerizable carboxyl-containing monomers.
• Monomers for use herein can be monoethyleneically or polyethyleneically unsaturated. Suitable monomers of this type include acrylic acid, methacrylic acid, ethacrylic acid, beta-methacrylic acid (crotonic acid), cis-alpha-methylcrotonic acid (angelic acid), trans- alkpha-methyl-crotonic acid (tiplic acid), alpha-butylcrotonic acid, alpha-phenylacrylic acid, alpha-benzylacrylic acid, alpha- cyclohexylacrylic acid, beta-phenylacrylic acid (cinnamic acid), coumaric acid (ortho-hydrocinnamic acid), umbellic acid (p- hydroxycoumaric acid) and the like. Mixtures of these monomers can also be used.
• Preferred monomers for use herein are carboxyl-containing monoethyleneically unsaturated monomers, especially acrylic acid.
• Copolymers prepared from one or more of the above monomers together with one or more other monomers can also be used as long as the resulting copolymers are safe and effective for use as gelling agents in the compositions herein.
• Suitable crosslinking agents for use herein include non-polyalkenyl polyether difuntional crosslinking monomers, polyalkenyl polyether crosslinking agents and diolefinic non-hydrophilic macromeric crosslinking agents.
• Suitable non-polyalkenyl polyether difunctional crosslinking agents include divinyl glycol, 2,3-dihydroxyhexa-l ,5,-diene, 2,5-dimethyl- 1 ,5-hexadiene, divinylbenzene, N,N-diallylacrylamide, N,N- diallylmethacrylamide and the like.
• Suitable diolefinic non-hydrophilic macromeric crosslinking agents include those having molecular weights of from about 400 to about 8,000 such as insoluble di- and polyacrylates and methacrylates of diols and polyols, diisocyanate-hydroxyalkyl acrylate or methacrylate reaction products, and reaction products of isocyanate terminated prepolymers derived from polyester diols, polyether diols or polysiloxane diols with hydroxyalkylmethacrylates, and the like.
• the crosslinking agent is generally present at a level in the range of from about 0.05% to about 5% , preferably from about 0.1 % to about 5% , especially from about 0.75 % to about 2% by weight of the polymer.
• Preferred gelling agents for use herein are polyalkenyl polyether- crosslinked polymers of carboxyl-containing monethyleneically unsaturated monomers. More preferred gelling agents for use herein are polyalkenyl polyether-crosslinked polymers of acrylic acid. Especially preferred gelling agents for use herein are polyallyl sucrose or polyallyl pentaerythritol-crosslinked polymers of acrylic acid.
• Examples of such polymers include those commercially available under the tradename Carbopol, such as Carbopol 934, 934P, 940, 941 , 974P, 980, 981 , manufactured by B.F. Goodrich Chemical Company, U.S.A.
• Carbopol 980 which is a polyallylsucrose-crosslinked polymer of acrylic acid.
• hydrophobically-modified carboxylate monomers such as C1-C30 alkyl substituted carboxylate-containing monomers, such as C1-C30 acrylic acid (acrylate) monomers.
• C1-C30 alkyl substituted carboxylate-containing monomers such as C1-C30 acrylic acid (acrylate) monomers.
• These can be used to form hydrophobically modified, cross-linked copolymers wherein the modified polymeres have amphipathic properties.
• examples include copolymers of acrylic acid and C1-C30 alkyl substituted acrylic acid, such as those available under the Trade Name Carbopol 1342 and Pemulen TR-1 (CTFA Designation: Acrylates/ 10-30 Alkyl Acrylate Crosspolymer).
• CTFA Designation Acrylates/ 10-30 Alkyl Acrylate Crosspolymer.
• Combinations of the polyalkenyl polyether cross-linked acrylic acid polymer and the hydrophobically modified cross-linked acrylic acid polymer are also suitable for use herein.
• Neutralizing agents suitable for use herein include sodium hydroxide, potassium hydroxide, ammonium hydroxide, monoethanolamine, diethylamine, diisopropanolamine, diethanolamine and triethanolamine.
• a preferred neutralizing agent for use herein is diethylamine.
• the neutralizing agent is preferably present in a level from about 0.1 % to about 5% , preferably from about 2% to about 5% by weight.
• Suitable gelling agents for use herein are lower alkyl ethers of cellulose.
• the lower alkyl ether of cellulose suitable for use herein I I results fom at least partial substitution of the same or different lower alkyl ether groups for a plurality of hydroxyl groups of cellulose.
• the lower alkyl ether groups may be substituted by substituents. Preferred examples of such substituents are a hydroxyl group, and alkali metal carboxylate groups such as sodium carboxylate group.
• Examples of the optionally substitued lower alkyl groups are a methyl group, hydroxy lower alkyl groups having 2 or 3 carbon atoms, and carboxylate groups resulting from substitution of an alkali metal for the hydrogen atom of the carboxyl group of a carboxy lower alkyl group having 2 or 3 carbon atoms.
• Specific examples of the hydroxy lower alkyl groups are B-hydroxyethyl and B-hydroxypropyl groups
• specific examples of the carboxylate groups are carboxylate groups resulting from substitution of an alkali metal for a carboxymethyl, a- carboxyethyl or B-carboxyethyl group.
• lower alkyl ethers of cellulose include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylhydroxyethyl cellulose, and sodium carboxymethyl cellulose.
• Preferred cellulose ethers for use herein are methyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose.
• the lower alkyl ethers of cellulose can be used either singly or in combination with each other, or with other gelling agents.
• the gelling agent used herein has a viscosity (Brookfield RVT, Spindle No. 7, 20 rpm, 20°C, undiluted) of at least about 4,000 mPa.s, preferably at least about 10,000 mPa.s.
• Preferred gelling agents for use herein have an average molecular weight in the range from about 1 ,000,000 to about 4,500,000.
• a fourth essential component of the compositions herein is a cosolvent for the xanthine derivative and the non-steroidal anti-inflammatory drug.
• Suitable cosolvents for use herein include any solvent which is miscible with water and which is suitable for topical application which aids in the solubilisation of the xanthine derivative and the non- steroidal anti-inflammatory drug.
• Suitable cosol vents include straight chain and branched chain alcohols having from 1 to 6 carbon ⁇ toms, and mixtures thereof.
• the preferred cosolvent for use hereii is a straight chain alcohol having from 1 to 4 carbon atoms, espe ially ethanol.
• the solvent is generally present herein in a level of from about 5 % to about 60% by weight.
• compositions herein also comprise water, generally from abou. 10% to about 90% , preferably from about 30% to about 80%, more preferably from about 30% to about 60% by weight of water.
• the gel compositions preferably have a pH of from about 3 to about 8, more preferably from about 4 to about 7, more preferably about 7, and a viscosity of from about 10,000 to about 50,000, preferably from about 20,000 to about 40,000 cps (Brookfield RVT, 20°C, Spindle 7, 20 rpm, undiluted)
• compositions herein can comprise a wide range of optional ingredients.
• a surfactant can be present in the compositions herein.
• Suitable surfactants for use herein include anionic, nonionic, cationic, amphoteric and zwitterionic surfactants and mixtures thereof. When present the surfactant is preferably at a level of up to about 1 % by weight of composition.
• compositions herein can contain cooling agents such as menthol.
• menthol is present in the compositions herein, when used, at a level of from about 0.1 % to about 5 % , preferably from about 1 % to about 5 % by weight.
• compositions herein can additionally include preservatives.
• preservatives can be water-soluble or solubilizable preservatives such as DMDM Hydantoin (RTM), Germall (RTM) 115, methyl, ethyl, propyl and butyl esters of hydrobenzoic acid, benzoic acid, Euxyl (RTM) K400, Bronopol (RTM) (2-bromo-2-nitropropane-l ,3-dioI), sodium benzoate, chlorhexadine, benzalkonium chlorides and 2-phenoxyethanol, Cetrimide, potassium sorbate and thiomersal.
• Preferred preservatives for inclusion in the present invention are methyl and propyl parabens. In general, amounts of from about 0.005% to about 0.5 % are suitable herein with amounts of from about 0.01 % to about 0.1 % being preferred.
• compositions of the invention may comprise additional therapeutic agents including steroids, antibiotics, antiinfectives and antiallergics such as antihistamines, and other ingredients for modifying the appearance or aesthetic propertise of the composition, such as fragrances, colouring agents, and the like.
• Carbopol 980 1 2 3 2 3 2
• Methyl Salicylate 0 0 3 0 0
• compositions can be prepared as follows.
• the Carbopol is dissolved in water with stirring and then the caffeine is added, followed by addition of propylene glycol.
• the ibuprofen is dissolved in the ethanol and the resulting premix is added to the main batch.
• the diethylamine is finally added quickly to produce the required gel.
• methyl salicylate When methyl salicylate is part of the final composition it is added to the ethanol before the ibuprofen.
• menthol When menthol is part of the final composition, menthol is dissolved in a small amount of ethanol before being added to the main batch.
• the caffeine is added to the main batch just before the diethylamine.
• compositions of the examples exhibit excellent product stability and clarity and excellent analgesic and anti-inflammatory activity when applied to the skin.

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Citations (2)

• 1996
  • 1996-06-27 GB GBGB9613457.2A patent/GB9613457D0/en active Pending
• 1997
  • 1997-06-24 CA CA002258199A patent/CA2258199A1/en not_active Abandoned
  • 1997-06-24 JP JP10503550A patent/JPH11513037A/ja active Pending
  • 1997-06-24 HU HU9903835A patent/HUP9903835A3/hu unknown
  • 1997-06-24 KR KR1019980710665A patent/KR20000022245A/ko not_active Application Discontinuation
  • 1997-06-24 CZ CZ984091A patent/CZ409198A3/cs unknown
  • 1997-06-24 NZ NZ333180A patent/NZ333180A/xx unknown
  • 1997-06-24 TR TR1998/02701T patent/TR199802701T2/xx unknown
  • 1997-06-24 WO PCT/US1997/011205 patent/WO1997049405A1/en not_active Application Discontinuation
  • 1997-06-24 EP EP97933190A patent/EP0973522A1/en not_active Withdrawn
  • 1997-06-24 BR BR9709997A patent/BR9709997A/pt not_active Application Discontinuation
  • 1997-06-24 IL IL12742697A patent/IL127426A0/xx unknown
  • 1997-06-24 AU AU36438/97A patent/AU3643897A/en not_active Abandoned
• 1998
  • 1998-12-22 NO NO986042A patent/NO986042L/no not_active Application Discontinuation

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