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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• This invention relates to a combination of a histamine H 1 receptor antagonist and a selective histamine H 4 receptor antagonist for the treatment of a range of diseases that may be treated by antagonism of either or both of the H 1 and H 4 receptors including allergic diseases and disorders such as allergic rhinitis and asthma, to the uses of, and to compositions, products and methods of treatment including, such a combination.
• This invention also relates to a selective histamine H 4 receptor antagonist. Allergies are widespread and affect a large proportion of the world population. They may be seasonal in nature and can be caused by a variety of factors present in the environment such as pollen, mites and dust particles.
• Symptoms of allergic rhinitis which may be seasonal or perennial, can include rhinorrhea, nasal congestion and irritation, often accompanied by coughing or sneezing. Irritation and soreness of the throat and eyes is also common. The level of severity of each symptom experienced may vary from representing a minor problem to a person experiencing a severe effect.
• a histamine H 1 receptor antagonist in the treatment of allergic rhinitis is well-documented but when administered alone it does not provide an effective relief for nasal blockage and such agents are therefore often administered concurrently with sympathomimetic amine decongestants such as phenylpropanolamine and pseudoephedrine.
• sympathomimetic amine decongestants such as phenylpropanolamine and pseudoephedrine.
• WO98/06394 discloses the use of a combination of a histamine H 1 receptor antagonist and a histamine H 3 receptor antagonist for the treatment of allergy-induced responses in the mammalian airway, including relief from nasal congestion.
• the present invention is based on the teaching of EP 1096009 A1 (European Patent Application no. 00309364.8) in which, inter alia, a polynucleotide encoding for a polypeptide corresponding to a G-protein coupled receptor (GPCR), newly termed by other researchers the histamine H 4 receptor, are described and claimed.
• GPCR G-protein coupled receptor
• histamine H 4 receptor is defined as a polypeptide comprising:
• homologue in relation to the amino acid sequence for the polypeptide include any substitution of, variation of, modification of, replacement of, deletion of or addition of one (or more) amino acid from or to the sequence providing the resultant polypeptide has GPCR activity, preferably being at least as biologically active as the polypeptide shown in attached SEQ ID NO: 2.
• the term “homologue” covers homology with respect to structure and/or function. With respect to sequence homology, there is at least 70%, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, more preferably at least 95% homology to the sequence shown in SEQ ID NO: 2. Most preferably there is at least 98% homology to the sequence shown in SEQ ID NO: 2.
• This polypeptide corresponds to the orphan G-protein-coupled receptor encoded GPRv53, that has been surmised to be a novel histamine H 4 receptor, as described in The Journal of Biological Chemistry, 275(47), 36781-36786 (November 2000), the teaching of which is incorporated herein by reference.
• histamine-induced chemotaxis we have surprisingly found that histamine-induced chemotaxis
• Eosinophils have been implicated in the pathogenesis of inflammatory and allergic diseases such as asthma and allergic rhinitis and high levels of histamine are released in patients with these conditions.
• Histamine H 4 receptor antagonists may be advantageously used in treating such conditions since (i) they are likely to inhibit eosinophil infiltration into the nose and thus relieve nasal congestion by an additional or independent mechanism to antagonism of the histamine H 3 receptor, or (ii) by inhibiting eosinophil infiltration into the lung they are likely to reduce the inflammation associated with asthma and provide an effective alternative treatment for this disease.
• a combination of a selective histamine H 4 receptor antagonist and a histamine H., receptor antagonist may be advantageously used to treat allergic rhinitis since it would treat all the main symptoms of this disease including nasal congestion.
• a combination of a selective histamine H 4 receptor antagonist and a histamine H 1 receptor antagonist may be advantageously used to treat asthma since it may improve lung function in a synergistic manner.
• the present invention provides a combination of (a) a histamine H 1 receptor antagonist and (b) an antagonist that is at least 10-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor.
• the present invention also provides a combination of (a) a histamine H 1 receptor antagonist and (b) an antagonist that is at least 10-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor, for administration simultaneously, separately or sequentially, for use as a medicament for the treatment of a disease or disorder that may be treated by antagonism of either or both of the histamine H 1 and H 4 receptors such as allergic rhinitis or asthma.
• the present invention further provides the use of a combination of (a) a histamine H., receptor antagonist and (b) an antagonist that is at least 10-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor, for administration simultaneously, separately or sequentially, for the manufacture of a medicament for the treatment of a disease or disorder that may be treated by antagonism of either or both of the histamine H 1 and H 4 receptors such as allergic rhinitis or asthma.
• the present invention further provides a method of treatment of a mammal, including a human being, to treat a disease or disorder that may be treated by antagonism of either or both of the histamine H., and H 4 receptors such as allergic rhinitis or asthma including simultaneous, separate or sequential administration to the mammal of a (a) an effective amount of a histamine H 1 receptor antagonist and (b) an effective amount of an antagonist that is at least 10-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor.
• the present invention further provides a pharmaceutical composition including (a) a histamine H 1 receptor antagonist and (b) an antagonist that is at least 10-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor, and a pharmaceutically acceptable excipient, diluent or carrier.
• the present invention further provides a product containing (a) a histamine H 1 receptor antagonist and (b) an antagonist that is at least 10-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or disorder that may be treated by antagonism of either or both of the histamine H 1 and H 4 receptors such as allergic rhinitis or asthma.
• the present invention further provides an antagonist that is at least 10- fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor, the uses of and compositions and methods of treatment including, such an antagonist.
• an antagonist that is at least 10- fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor, the uses of and compositions and methods of treatment including, such an antagonist.
• Such a selective antagonist has not been previously described and thioperamide and clobenpropit, both of which are histamine H 3 receptor antagonists, do not display this degree of selectivity.
• an antagonist that is at least 10-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor means an antagonist that is at least 10-fold selective for the histamine H 4 receptor as defined in EP 1096009 A1 (European Patent Application no. 00309364.8) or as the orphan G-protein-coupled receptor encoded GPRv53 as disclosed in The Journal of Biological Chemistry, 275(47), 36781-36786 (November 2000) as described above, as compared to the known histamine H 3 receptor, by the biological assays described below.
• the antagonist is at least 30-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor.
• the antagonist is at least 50-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor.
• the antagonist is at least 100-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor.
• the antagonist is at least 1000-fold selective for the histamine H 4 receptor as compared to the histamine H 3 receptor.
• the definition "histamine H 1 receptor antagonist" is well-understood in the art and is in accordance therewith.
• the diseases or disorders that may be treated with the present combination or antagonist include those which may be modulated by antagonism of the H 4 receptor such as those which concern aspects of signal transduction.
• Useful therapeutic areas include, but are not limited to, obesity, diabetes and metabolic disease, neurological disease, psychotherapeutics, urogenital disease, reproduction and sexual medicine, inflammation, cancer, tissue repair, dermatology, skin pigmentation, photoageing, frailty, osteoporosis, cardiovascular disease, gastrointestinal disease, anti-infection, allergy and respiratory disease, sensory organ disorders, sleep disorders and hairloss.
• Preferred diseases or disorders that may be treated are allergic disorders such as extrinsic asthma, rhinitis (allergic and chronic), onchocercal dermatitis, atopic dermatitis, drug reactions and NERDS (nodules, eosinophilia, rheumatism, dermatitis and swelling), vasculitic granulomatous diseases such as temporal vasculitis, Churg-Strauss syndrome, polyarteritis, Wegner's granulomatosis and eosinophilic granulomatous prostatitis, immunological disorders such as autoimmune reactions (e.g.
• COPD chronic obstructive pulmonary disease
• eosinophilic pleural effusions transient pulmonary eosinophilic infiltrates (Loffler)
• histiocytosis chronic eosinophilic pneumonia
• hypersensitivity pneumonitis allergic bronchopulmonary aspergillosis, sarcoidosis, idiopathic pulmonary fibrosis and topical eosinophilia
• infectious parasitic diseases such as toxocariasis, filariasis, schistosomiasis, trichinosis, strongyloides, ascariasis and echinococcosis/cysticercosis, other infectious diseases such as acute coccidioidomycosis, cat scratch disease, afebrile tuberculosis and chlamydial pneumonia at infancy, neoplastic and myelop
• asthma both extrinsic and intrinsic
• rhinitis allergic and chronic
• COPD inflammatory bowel diseases
• allergic disorders vasculitic granulomatous diseases
• immunological disorders interstitial and other pulmonary diseases
• infectious diseases infectious diseases
• inflammatory diseases and neoplastic and myeloproliferative diseases.
• said allergic disorder is extrinsic asthma or rhinitis (allergic or chronic)
• said immunological disorder is intrinsic asthma
• said pulmonary disease is COPD
• said inflammatory diseases are inflammatory bowel diseases.
• the selectivity of an antagonist for the histamine H 3 or H 4 receptor can be determined by the following procedures.
• the cDNA for the human histamine H 3 and H 4 receptor can be expressed in a suitable cell line such as HEK293 or CHO.
• membranes can be prepared from tissues or cells which naturally express either the histamine H 3 and/or H 4 receptor. Affinity can be assessed at either receptor by assessing the ability of ligands to inhibit the binding of a suitable radioactively labelled ligand to membranes containing either the histamine H 3 or H 4 receptor. The potency of compounds is compared by calculating their pK, values.
• the functional activity of ligands to determine agonist or antagonist activity is determined in whole cells expressing either the H 3 or H 4 receptor.
• Agonists full or partial are identified as agents which inhibit forskolin stimulated cyclic AMP production which can be measured directly (as cyclic AMP) or indirectly as changes in beta-lactamase activity in cells co-expressing the CRE-beta-lactamase reporter system and the appropriate histamine receptor. Agonist activities may be expressed as IC 50 values.
• Inverse agonists can also be identified by the inhibition of the basal cAMP activity (i.e. in the absence of forskolin).
• Agents which have no effect on forskolin stimulated cAMP or inhibit basal cAMP may be antagonists and such activity can be measured in an assay where cells are pre-incubated with the ligand of interest and their ability to inhibit H 3 or H 4 agonist-induced reduction of forskolin stimulated cyclic AMP is measured as described above.
• the experiments can be performed in one of two ways. Firstly, by increasing the concentration of antagonist versus fixed concentration of agonist and calculating the IC 50 for each antagonist. Secondly, by increasing the concentration of antagonist versus increasing the concentration of agonist and expressing the antagonist potency as a pk b or pA 2 value, as appropriate.
• a further functional assay for the histamine H 4 receptor determines the ability of histamine to induce chemotaxis in eosinophils isolated from human blood.
• cells are primed with interleukin 5 and the ability of histaminergic ligands to promote migration of eosinophils across a permeable membrane is studied. The number of cells migrating in a defined period is then counted. Agonist potencies are expressed as EC 50 values.
• Antagonists can also be studied by pre-incubating eosinophils with the compound and then assessing the inhibitory effects on histamine (or other suitable ligand) on eosinophil chemotaxis. The experiments can be performed in one of two ways.
• the present combination (or each active element thereof) or antagonist can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
• the present combination or antagonist can be administered orally, buccally or sublingually in the form of tablets, capsules, multi- particulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
• the present combination or antagonist may also be administered as fast-dispersing or fast-dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations of the present combination or antagonist may be in coated or uncoated form, as desired.
• Such solid pharmaceutical compositions may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
• excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and
• a formulation of a tablet could typically contain from 0.01 mg to 500mg of each active element of the combination or of the antagonist whilst tablet fill weights may range from 50mg to 1000mg.
• An example of a formulation for a 10mg tablet is illustrated below:
• the tablets are manufactured by a standard process, for example, direct compression or a wet or dry granulation process.
• the tablet cores may be coated with appropriate overcoats.
• Solid compositions of a similar type may also be employed as fillers in gelatin or HPMC capsules.
• Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
• the present combination or antagonist may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
• the present combination or antagonist can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrastemally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion or needleless injection techniques.
• parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
• the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
• the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
• each active element of the present combination or of the present antagonist will usually be from 0.01 to 50mg/kg body weight of the subject to be treated, preferably from 0.1 to 20mg/kg (in single or divided doses), or they may be administered by intravenous infusion at a dose of from 0.001 to 10mg/kg/hour.
• the daily dosage level of each active element of the combination or of the antagonist may typically be from 10 to 500mg (in single or divided doses).
• tablets or capsules of the present combination or antagonist may contain from 5 to 100mg of each active element of the combination or of the antagonist for administration singly or two or more at a time, as appropriate.
• the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
• the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
• the present combination or antagonist can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, with or without the use of a suitable propellant, e.g.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• the pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound(s), e.g.
• a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
• a lubricant e.g. sorbitan trioleate.
• Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the present combination or antagonist and a suitable powder base such as lactose or starch. Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff contains from 10 ⁇ g to 1 mg of each active element of the present combination or antagonist for delivery to the patient.
• the overall daily dose with an aerosol will be in the range of from 10 ⁇ g to 10mg of each active element of the present combination or antagonist which may be administered in a single dose or, more usually, in divided doses throughout the day.
• the present combination or antagonist can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
• the present combination or antagonist may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary or rectal routes.
• the compounds may also be administered by the ocular route, particularly for treating allergic conditions of the eye.
• the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
• they may be formulated in an ointment such as petrolatum.
• the present combination or antagonist can be formulated as a suitable ointment containing the active compound(s) suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
• they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
• Each element of the present combination or the present antagonist may also be used in combination with a cyclodextrin.
• Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes.
• the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
• Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A- 98/55148.
• the present invention embraces any other suitable formulations and administration routes described in EP 1096009 A1 (European Patent Application no. 00309364.8).
• the present combination or antagonist can also be administered together with a steroid, a beta-adrenoceptor agonist, a muscarinic antagonist or a mucolytic.
• the present combination, antagonist or composition can be used to treat the above-mentioned conditions in humans or in other animals.
• WO98/06394 discloses histamine H 3 receptor antagonists including thioperamide and clobenpropit without mention of any antagonist activity for the histamine H 4 receptor.
• Thioperamide, clobenpropit and iodophenpropit were tested for (i) binding affinity for the histamine H 4 receptor using the method described on page 7 using the HEK293 cell line, and (ii) binding affinity for the histamine H 3 receptor using the method described on page 7 using human brain tissue which naturally expresses the histamine H 3 receptor. The results are shown below.
• histamine promoted chemotaxis of human isolated eosinophils over a concentration range of 10 "8 to 10 "5 M.
• agonists individually selective for the Hi (HTMT), H 2 (dimaprit) and H 3 (imetit) receptors each did not promote chemotaxis of human eosinophils at concentrations of from 10 "8 to 10 "5 M.
• histamine H receptor antagonists may be advantageously used in treating asthma and allergic rhinitis since (i) they are likely to inhibit eosinophil infiltration into the nose and thus relieve nasal congestion by an additional or independent mechanism to antagonism of the histamine H 3 receptor, or (ii) by inhibiting eosinophil infiltration into the lung they are likely to reduce the inflammation associated with asthma and provide an effective alternative treatment for this disease.
• a combination of a selective histamine H 4 receptor antagonist and a histamine Hi receptor antagonist may therefore be advantageously used to treat allergic rhinitis since it would treat all the main symptoms of this disease including nasal congestion.
• a combination of a selective histamine H 4 receptor antagonist and a histamine Hi receptor antagonist may also be advantageously used to treat asthma since it may improve lung function in a synergistic manner.

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Cited By (6)

• 2001
  • 2001-01-17 GB GBGB0101223.6A patent/GB0101223D0/en not_active Ceased
• 2002
  • 2002-01-10 JP JP2002557379A patent/JP2004517883A/ja not_active Withdrawn
  • 2002-01-10 CA CA002435121A patent/CA2435121A1/en not_active Abandoned
  • 2002-01-10 HU HU0302767A patent/HUP0302767A2/hu unknown
  • 2002-01-10 KR KR10-2003-7009493A patent/KR20030069216A/ko not_active Application Discontinuation
  • 2002-01-10 MX MXPA03006408A patent/MXPA03006408A/es unknown
  • 2002-01-10 EE EEP200300335A patent/EE200300335A/xx unknown
  • 2002-01-10 BR BR0206502-9A patent/BR0206502A/pt not_active IP Right Cessation
  • 2002-01-10 PL PL02362793A patent/PL362793A1/xx not_active Application Discontinuation
  • 2002-01-10 CZ CZ20031853A patent/CZ20031853A3/cs unknown
  • 2002-01-10 IL IL15608702A patent/IL156087A0/xx unknown
  • 2002-01-10 EP EP02732099A patent/EP1353657A1/en not_active Withdrawn
  • 2002-01-10 EA EA200300537A patent/EA200300537A1/ru unknown
  • 2002-01-10 SK SK857-2003A patent/SK8572003A3/sk unknown
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  • 2002-01-10 WO PCT/IB2002/000042 patent/WO2002056871A2/en not_active Application Discontinuation
  • 2002-01-10 CN CNA028036840A patent/CN1486178A/zh active Pending
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  • 2002-01-14 PA PA20028537101A patent/PA8537101A1/es unknown
  • 2002-01-16 AR ARP020100145A patent/AR032101A1/es not_active Application Discontinuation
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  • 2002-01-16 TN TNTNSN02003A patent/TNSN02003A1/fr unknown
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• 2003
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  • 2003-05-21 BG BG107834A patent/BG107834A/bg unknown
  • 2003-05-22 CR CR6983A patent/CR6983A/es not_active Application Discontinuation
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  • 2003-07-16 NO NO20033223A patent/NO20033223D0/no not_active Application Discontinuation
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