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
  • A61K31/435—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
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • 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
• • 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
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • 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
  • A61P27/02—Ophthalmic agents
  • A61P27/14—Decongestants or antiallergics
• • 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
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • 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 novel oral pharmaceutical compositions comprising as pharmaceutically active compounds a combination of an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof, an anticholinergic amount of Belladonna alkaloids (Belladonna) or a pharmaceutically acceptable salt thereof and of a decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof.
• the formulation may comprise methylephedrine (methylephrine) or a pharmaceutically acceptable salt thereof in a decongestant-effective amount.
• the formulation further comprises suitable pharmaceutically acceptable carriers or excipients.
• Another aspect of the present invention relates to methods for the preparation of these compositions and methods of using them in the treatment of allergic diseases and/or disorders.
• the inventive composition is useful in the treatment of Calendaral allergic rhinitis andMonal allergic conjunctivitis.
• SAR is characterised by sneezing, itching, blocked nose (..congested nose”) and runny nose
• SAC is characterised by eye itching, red eye and sensation of foreign body. Both allergic reactions may occur separately of each other or at the same time.
• H1 antihistamine will deal with the histamine driven symptoms such as sneezing or itching. H1 antihistamine may also have an effect on runny noses or red eyes but to a lesser grade. Due to this fact they are not the first choice substances to treat the latter. Additionally, H1 antihistamines are unable treat blocked noses.
• compositions comprising H1 antihistamines and anticholinerics.
• Objective of the present invention It is one objective of the present invention to treat the symptoms of seasonal allergic rhinitis, i.e. sneezing, itching, blocked nose and runny nose.
• Another objective is to develop a suitable pharmaceutical formulation for treating allergic congestion of the Eustachian tubes and / or other diseases from allergic origin deserving the administration of antihistamine and decongestant drugs.
• Another objective of the present invention is the treatment of common cold and in the symptomatic relief associated with cough, cold and flu symptoms.
• Still another objective of the present invention is to overcome the disadvantages of the medications known in the art in the treatment of SAR and/or SAC.
• the present invention solves the problem of insufficient treatment of SAR and/or SAC by providing a pharmaceutical formulation comprising an antihistaminic- effective amount of epinastine or a pharmaceutically acceptable salt thereof, an anticholinergic amount of Belladonna alkaloids or a pharmaceutically acceptable salt thereof and of a decongestant-effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof.
• the formulation may additionally comprise methylephedrine or a pharmaceutically acceptable salt thereof in a decongestant-effective amount.
• Further ingredients of the formulation of the present invention may be pharmaceutically acceptable carriers or excipients.
• Belladonna alkaloids is commonly used in pharmaceutics. The exact method of their winning and the active ingredients of this mixture of alkaloids can be taken from the Deutsches Arzneibuch 9 (DAB 9), Volume 2, pages 932 to 944, Kirliche Verlagsgesellschaft Stuttgart mbH; Govi-Verlag GmbH, Frankfurt. These pages 932 to 944 are herewith incorporated by reference. Belladonna alkaloids are won as an extract of the plant Atropa Belladonna, i.e. an extracts of the leafs and/or the root. The main component of the Belladonna alkaloids is atropin. Atropine itself comprises L-(-)-hyoscyamine and its racemate which develops by drying.
• alkaloids found in Belladonna are L-(-)-hyoscine (L-(-)-scopolamine), N-Oxides of hyoscine and/or hyoscamine, atropamine, belladonnine and optionally nicotine, N-methylpyrroline, N- methylpyrrolidine, pyridin, cuskhygrine and further alkaloids.
• the names of the alkaloids as written above are taken from the German textbook DAB 9, referred to above. In case of ambiguities the names shall be taken directly from the textbook, page 934.
• the mixture of the above named alkaloids are taken.
• the invention is not limited to the use of this exact mixture.
• any mixture or any single alkaloid of the designated alkaloids extracted from Atropa Belladonna can be used.
• the invention comprises atropin or L-(-)-hyoscyamin alone without the other named alkaloids.
• belladonna alkaloids preferably stands mainly for hyoscyamin and scopolamine as major components in extract of belladonna roots and/or leaves.
• These anticholinergic alkaloids have analgesic-antispasmodic action and inhibitory action of secretion. Extract of Datura can also be selected as a substitute for belladonna alkaloids.
• compositions according to the invention may optionally contain one or several compounds selected from the group consisting of mucolitic and analgesic-antipyretic compounds and vitamins.
• mucolitic ingredients are selected from bromhexine and ambroxol.
• Preferred analgesic-antipyretic compounds are selected from paracetamol and ibuprofen.
• Preferred vitamins are selected from vitamin B2. B6 and C.
• a leukotriene antagonist is not present.
• the present invention relates to an oral pharmaceutical composition. Due to the short-lasting effects of pseudoephedrine and Belladonna and - relatively to this - the long-lasting effect of epinastine it is of advantage to have a sustained release of Belladonna and the decongestant effective amount of pseudoephedrine and/or methylephrine and an immediate release of an antihistaminic effective amount of epinastine.
• the preferred dosage forms are tablets or capsules.
• a bilayer tablet is preferred wherein a first layer A provides for the sustained release of Belladonna and pseudoephedrine, which comprises a decongestant effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof and a anticholinergic amount of Belladonna or a pharmaceutically acceptable salt thereof.
• a second layer B provides for the immediate release of epinastine and comprises an antihistaminic effective amount of epinastine or a pharmaceutically acceptable salt thereof.
• the formulation contains additionally methylephedrine or one of its pharmaceutically acceptable salts, the appropriate amount thereof is present in layer A, already comprising pseudoephedrine.
• Both layers A or B may further comprise pharmaceutically acceptable excipients and/or carriers.
• the bilayer tablet according to the invention may additionally contain a tablet coating C consisting of pharmaceutically acceptable excipients, which mask the bitter taste of one of the active compounds.
• inventive bilayer tablet layer A comprises a decongestant effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof and optionally methylephedrine or a pharmaceutical acceptable salt thereof in a matrix of a swellable hydrophilic polymer which provides a sustained release profile in a period of 3 to 24, preferably 6 to 18, most preferably about 12 hours.
• the inventive composition may be formulated as a capsule.
• a capsule can provide the active ingredients either instantly or some of them are provided instantly and others are provided in a sustained manner.
• active ingredients pseudoephedrine (or its salts) and Belladonna alkaloids (or its salts thereof) as well as the optionally used methylephrine (or its salts) as a sustained releases form and epinastine or its salts as immediate release form.
• the capsules are made of materials that at least partially can be digested by humans.
• Such capsules f.e. are disclosed in EP 0143524. The latter discloses a two-part capsule of material which is easily digestible by humans.
• EP 0460921 describes capsules of chitosan and starch, grain powder, oligosaccharides, methacrylic acid-methylacrylate, methacrylic acid-ethylacrylate, hydroxypropylmethylcelluloseacetate, -succinate or -phthaleate.
• GB 938828 discloses capsules comprising water-soluble gelatine, methylcellulose, Polyvinylalkohol or water-soluble non-toxic thermoplasts.
• EP 0 606486 B1 discloses capsules being composed of hydroxypropylmethyl- cellulose, methylcellulose, hydroxypropylcellulose, starch, hydroxypropylstarch, and sodium alginate.
• JP 2002-525412A discloses capsules being composed of pullulan. Principally all theses capsules can be take for the present invention, preferred are gelatine-capsules, in particular hard-gelatine capsules. Other preferred capsules are made of starch or of a cellulose-derivative like hydroxypropylmethylcellulose and pullulan.
• Pullulan is a neutral simple polysaccharide produced from cultured Aureobasidium pullulans. It has a structure of chains of repeated ⁇ -1.6 bondage of maltotriose composed of three glucoses in ⁇ -1.4 bondage. It is listed in Japanese Pharmaceutical Excipients(JPE).
• capsule-size of 1 or 2 are preferred.
• pharmaceutically acceptable salts stands for acid addition salts of the active compounds pseudoephedrine, epinastine, Belladonna alkaloids and/or methylephedrine.
• These acid addition salts can be formed with inorganic acids like hydrochloric acid, hydrobromic acid or sulfuric acid or with organic acids as for instance oxalic acid, fumaric acid or methansulfonic acid.
• Epinastine is preferably used as its hydrochloric acid addition salt.
• Pseudoephedrine and also methylephedrine are preferably used as the hydrochlorides or the sulfates.
• hydrochloride-salts for the latter two compounds are most preferred.
• pseudoephedrine and optionally methylephedrine takes place over 3 to 24, preferably 6 to 24, most preferably about 12 to 24 hours.
• the preferred dose regimen is a perennial never a day application", regardless of how the formulation is applied.
• the concentration range of pseudoephedrine salt plus methylephedrine salt in the compositions according to the invention is between 5 and 240 mg daily , preferably 10 to 200 mg daily, more preferably 20 to 150 mg daily.
• both compounds pseudoephedrine and methylephedrine are preferably present in the formulation in the same amount, i.e. amount w/w.
• a total amount of pseudoephedrine plus methylephedrine (their salts respectively) of e.g. 78 mg daily each of the two compounds is present in an amount of 39 mg daily, for a total amount of 60 mg daily, each compound is present in an amount of 30 mg daily.
• the concentration range of epinastine salt in the compositions according to the invention is between 2 and 20 mg daily, preferably 5 to 15 mg daily, more preferably 7.5 to 12.5 mg daily.
• the concentration range of Belladonna alkaloids in the compositions according to the invention is between 0.05 and 4.0 mg daily, preferably between 0.05 and 2.0 mg daily, more preferably 0.1 to 1.5 mg daily, most preferably between 0.2 and 0.6 mg daily.
• each layer is in contact with each other in a portion of their surface, but provides independent release profiles for both active substances mentioned before.
• the sustained release layer A comprises beside the active ingredient(s) a swellable hydrophilic polymer.
• Typical swellable hydrophilic polymers include cellulose ethers such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose and carboxyethylcellulose or mixtures thereof.
• HPMC hydroxypropylmethylcellulose
• HPMC USP2910 and USP2208 like for instance Methocel E5. E4M, E15M, K15M, and K100M supplied by the Dow Chemical Company.
• E refers to USP2910
• K refers to USP2208.
• the number designation refers to the viscosity in a 2% aqueous solution (e.g. 5 designates a viscosity of 5 cps; 15M designates a viscosity of 15000 cps).
• excipients that could be optionally used in the sustained release layer A are insoluble polymers, soluble or insoluble fillers, antiadherents, coloring agents, lubricants and additional binders.
• Typical fillers are for example lactose, microcrystalline cellulose, dibasic calcium phosphate and comstarch.
• antiadherents which are used to prevent tablets from sticking to the tablet press, are colloidal silicon dioxide and talc.
• Magnesium stearate, talc and stearic acid are typical lubricants.
• Typical binders are povidone, and cornstarch.
• the immediate release matrix layer B comprises beside the active ingredient different combinations of excipients.
• the excipients that could be optionally used in the immediate release layer B are insoluble polymers, soluble or insoluble fillers, antiadherents, lubricants, coloring agents, disintegrants and additional binders.
• Typical fillers are for example lactose, microcrystalline cellulose, dibasic calcium phosphate and cornstarch.
• antiadherents which are used to prevent tablets from sticking to the tablet press, are colloidal silicon dioxide and talc.
• Typical disintegrants are crospovidone, sodium starch glycolate and crosscarmellose sodium.
• Typical coloring agents are selected from FD&C red 40 HT Aluminum lake, 2-hydroxy-1.V-azonaphthalene-3.6.4'-trisulfonic acid trisodium salt, erythrosine, iron oxides, 1-(4-sulpho-1-naphthylazo)-2-naphthol-6.8-disulphonic acid trisodium salt, 2 , ,4',5 , ,7 , -tetrabromo-4.5.6.7-tetrachloro-fluorescein disodium salt, 2.4.5.7-Tetraiodo- 3.6-dihydroxyxanthene-9-spiro- -(4 , ,5',6 , ,7 , -tetrachloro-3'H-isobenzofuran-3 , one dipotassium salt, trisodium 3-carboxy-5-hydroxy-1-p-sulphophenyl-4-p- sulfophenylazopyr
• Water and ethanol are examples of volatile components which can be used in the manufacture process of both layers to granulate powders. These volatile components are removed during processing and therefore do not appear in the finished product.
• the tablet coating is optional since the presence of it does not modifies significantly the release rates of the active substances present in the core layers.
• the presence of the coating is preferred because it masks the bitter taste of one of the active substances and enhances the properties of dosage form. Because of that a lot different coatings with different polymers, and plasticizers and other excipients could be used with the condition of not modifying significantly the release profile of the active substances present in the core tablet.
• a typical coating comprises a polymer such as hydroxypropylmethylcellulose and a plasticizer such as polyethylene glycol.
• Optional excipients could be added to the coating like antifoaming agents and opacifying agents.
• Example of an antifoaming agent is silicone.
• opacifying agents are Titanium dioxide, talc and aluminum lake dyes.
• inventive formulation also can be applied via a tablet comprising sustained release and non-sustained release granules or a capsule comprising the same.
• non-sustained release granules and sustained release granules, which are coated with a sustained release film are mixed with suitable excipients and then they are compressed as a tablet.
• non-sustained release granules and sustained release granules which are coated with sustained release film are mixed 1 :9 to 9:1 , preferably 3:7 to 7:3 are filled into a capsule or are compressed into tablet.
• a non-sustained release granule comprises an amount of epinastine or a pharmaceutically acceptable salt thereof.
• it may comprises a portion of the total amount of belladonna alkaloids or a pharmaceutically acceptable salt thereof and a portion of the total amount of pseudoephedrine or a pharmaceutically acceptable salt thereof and optionally a portion of the total amount of methylephedrine or a pharmaceutically acceptable salt thereof, if necessary.
• a sustained release granule comprises either a portion or the total amount of belladonna alkaloids or a pharmaceutically acceptable salt thereof, pseudoephedrine or a pharmaceutically acceptable salt thereof and optionally methylephedrine or a pharmaceutically acceptable salt thereof.
• non-sustained release granules contain only epinastine or a pharmaceutically acceptable salt thereof as active ingredient while the sustained release granules comprise the remaining active ingedients.
• any compounds conventionally used as a sustained-release coat can be used for the purpose of this invention.
• Specific examples which can be given include water insoluble polymers such as ethylcellulose, aminoalkyl methacrylate copolymer polyvinyl acetate, polyvinyl chloride, polyethylene, and the like; intestinally soluble polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, styrene acrylic acid copolymer, methacrylic acid copolymer, maleic anhydrous acid copolymer, shellac, and the like; paraffin waxes such as paraffin, microcrystalline wax, and the like; higher alcohols, preferably saturated and unsaturated C 6 - C 26 -alcohols, preferred unbranched and unsubstituted, such as stearyl alcohol, cetyl alcohol, and the like; esters of higher fatty acids, preferably
• the excipients that could be optionally used in sustained release film are water soluble polymers, sugar alcohols, plasticizers, titanium oxide, talc, coloring agents and so on.
• Typical water soluble polymers and sugar alcohols are hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol.
• Typical plasticizers are glycerine fatty acid ester, triethyl citrate, propylene glycol, triacetin.
• bilayer tablet, tablet or capsule any of the aformentioned ingredients can be taken, if appropriate.
• capsules and tablets comprising sustained release and non-sustained release granules are preferred.
• PR means Premium grade and CR means Controlled Released grade.
• A1 Dissolve povidone in a hydroalcoholic mixture
• A2. Blend pseudoephedrine hydrochloride, methylephedrine hydrochloride, Belladonna alkaloids, a portion of the microcrystalline cellulose, lactose and
• Methocel K15M for 5-30 minutes in a suitable mixer.
• A3. Use alcoholic or hydroalcoholic solution prepared previously in step A1 to granulate the powder mix of step A2.
• A4. Dry and mill the granulation from step A3, using suitable size screen.
• A5. Blend the screened granulation with a portion of the microcrystalline cellulose and colloidal silicon dioxide for 3-15 minutes.
• A6. Add magnesium stearate and blend for 3-15 minutes.
• B Second layer B1. Pass through a suitable screen Epinastine HCI, Allura red AC (FD & C red 40 HT) aluminum lake and microcrystalline cellulose. Blend for 5-30 minutes in a suitable mixer. B2. Add lactose and povidone. Blend for 60 minutes 15-120 minutes in a suitable mixer. B3. Add magnesium stearate. Blend for 3-20 minutes in a suitable mixer. 0
• Compress A and B into a suitable bilayer tableting machine in suitable size tablets Compress A and B into a suitable bilayer tableting machine in suitable size tablets.
• PR means Premium grade and CR means Controlled Released grade.
• A. First layer A1. Blend pseudoephedrine hydrochloride, methylephedrine hydrochloride, Belladonna alkaloids, microcrystalline cellulose, lactose, colloidal silicon dioxide and HPMC K15M for 5-30 minutes in a suitable mixer.
• Second layer B1. Pass through a suitable screen Epinastine HCI, and microcrystalline cellulose.
• Compress A and B into a suitable bilayer tableting machine in suitable size tablets Compress A and B into a suitable bilayer tableting machine in suitable size tablets.
• Second layer and coating are identical to example 2; the manufacture method was conducted analogously to the method outlined in example 2;
• PR means Premium grade and CR means Controlled Released grade.
• Second layer and coating are identical to example 1 ; the manufacture method was conducted analogously to the method outlined in example 1 ;
• Second layer and coating are identical to example 1 ; the manufacture method was conducted analogously to the method outlined in example 1 ;
• Second layer and coating are identical to example 1 ; the manufacture method was conducted analogously to the method outlined in example 1; Example N° 7
• Second layer and coating are identical to example 1 ; the manufacture method was conducted analogously to the method outlined in example 1 ;
• Second layer and coating are identical to example 1 ; the manufacture method was conducted analogously to the method outlined in example 1 ;
• Second layer and coating are identical to example 1 ; the manufacture method was conducted analogously to the method outlined in example 1 ;
• Second layer and coating are identical to example 1 ; the manufacture method was conducted analogously to the method outlined in example 1 ; Example N° 11
• CR means Controlled Released grade.
• Second layer and coating are identical to example 1 ; the manufacture method was conducted analogously to the method outlined in example 1 ;
• Second layer and coating are identical to example 1 ; the manufacture method was conducted analogously to the method outlined in example 1 ;
• Second layer and coating are identical to example 1 ; the manufacture method was conducted analogously to the method outlined in example 1 ;
• step A1 over sucrose introducing the powder mix obtained from step A2.
• step A4 Dry and pass through granules from step A3 with suitable size screen to produce non-sustained release granules.
• step B3 Produce spherical granules by spraying the solution prepared previously in step B1 over sucrose introducing the powder mix obtained from step B2.
• step B4 Dry and pass through granules from step B3 with suitable size screen
• step B6 Coat the granules obtained from step B4 with the solution prepared previously in step B5 to produce sustained release granules.
• step A3 Dry and pass through granules obtained from step A2 with suitable size screen to produce non-sustained release granules
• B2 Blend pseudoephedrine hyrochloride .methylephedrine hydrochloride and belladonna in a suitable mixer.
• B3. Produce spherical granules by spraying the solution prepared previously in step B1 over sucrose introducing the powder mix obtained from step B2.
• B4. Dry and pass through granules from step B3 with suitable size screen B5.
• B6 Coat the granules obtained from step B4 with the solution prepared previously in step B5 to produce sustained release granules.
• C1. Mix non-sustained release granules and sustained release granules with microcrystalline cellulose, croscarmellose sodium, talc and magnesium stearate. C2. Compress the mixture into a suitable tableting machine in suitable size tablets.
• Examples No° 20 to 40 The same as examples No° 1 to 20 but the methylephrine is displaced by the same amount of pseudoephedrine, i.e. the amount of pseudoephedrine is doubled.

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Citations (2)

• 2002
  • 2002-04-03 EP EP02007568A patent/EP1350512A1/en not_active Withdrawn
• 2003
  • 2003-03-25 US US10/396,234 patent/US20030228359A1/en not_active Abandoned
  • 2003-03-28 EP EP03717248A patent/EP1492532A1/en not_active Withdrawn
  • 2003-03-28 WO PCT/EP2003/003263 patent/WO2003082285A1/en not_active Ceased
  • 2003-03-28 PL PL03371382A patent/PL371382A1/xx unknown
  • 2003-03-28 AU AU2003221532A patent/AU2003221532A1/en not_active Abandoned
  • 2003-03-28 CA CA002477751A patent/CA2477751A1/en not_active Abandoned
  • 2003-03-28 JP JP2003579822A patent/JP2005522467A/ja active Pending
  • 2003-03-28 BR BR0308982-7A patent/BR0308982A/pt not_active Application Discontinuation
  • 2003-03-28 RU RU2004132205/15A patent/RU2004132205A/ru not_active Application Discontinuation
  • 2003-03-28 MX MXPA04009582A patent/MXPA04009582A/es unknown
  • 2003-04-01 PE PE2003000332A patent/PE20040080A1/es not_active Application Discontinuation
  • 2003-04-02 AR ARP030101144A patent/AR039221A1/es unknown

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