Classifications

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  • 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
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  • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
  • A61K31/4965—Non-condensed pyrazines
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  • 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
  • A61K31/549—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 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
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  • A61P13/00—Drugs for disorders of the urinary system
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P5/00—Drugs for disorders of the endocrine system
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  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P9/12—Antihypertensives

Definitions

• the invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising
• AT r receptor antagonists also called angiotensin II receptor antagonists or ARBs
• ARBs angiotensin II receptor antagonists
• these antagonists can, for example, be employed as anti- hypertensives or for treating congestive heart failure.
• the class of A ⁇ receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones.
• Preferred ATrreceptor antagonist are those agents that have been marketed, most preferred is valsartan or a pharmaceutically acceptable salt thereof.
• a preferred pharmaceutically acceptable salt of amiloride is the hydrochloride.
• Amiloiride hydrochloride is the most preferred component (ii).
• a thiazide diuretic is, for example, selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon. Most preferred is hydrochlorothiazide.
• an ATrreceptor antagonist or a pharmaceutically accepted salt thereof (i) an ATrreceptor antagonist or a pharmaceutically accepted salt thereof and (ii) amiloride or a pharmaceutically acceptable salt thereof and (iii) hydrochlorothiazide or a pharmaceutically acceptable salt thereof.
• the structure of the active agents identified by generic or tradenames may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g. Life Cycle Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
• the corresponding active ingredients or a pharmaceutically acceptable salts thereof may also be used in form of a solvate, such as a hydrate or including other solvents, used for crystallization.
• the compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
• the compounds having an acid group for example COOH can also form salts with bases.
• the diuretics amiloride or triameterine or, in each case, a pharmaceutically acceptable salt thereof block the Na+ channels in the late distal tubules and collecting ducts by increasing the loss of sodium and chloride ions while reducing the excretion of potassium. It is known that the thiazide diuretics reduce the re-absorption of electrolytes from renal tubules, thereby increasing the excretion of sodium and chloride ions and consequently of water. The excretion of potassium is also increased by administering e.g. hydrochlorothiazide.
• amiloride especially the hydrochloride thereof, or triameterine, respectively
• a thiazide diuretic for example, hydrochlorothiazide
• a further diuretic or a pharmaceutically acceptable salt results not only in a beneficial, especially potentiation, preferably a synergistic, therapeutic effect, but also in additional benefits resulting from the combined treatment and further surprising beneficial effects compared to a monotherapy applying only one of the pharmaceutically active compounds used in the combinations disclosed herein.
• a surprising effect of the combination of the present invention is the fact that a higher blood pressure lowering with lower dose of every component of the three therapy. - Better potassium handling and homeostasis. etter protection of the myocardium because of the haemodynamic effects of the three components and the protective effect of valsartan and amiloride.
• valsartan by blocking the detrimental actions of AT II on myocardial perfusion and remodeling post myocardial ischemia and necrosis and amiloride by blocking Na+/H+ exchanger that play a role in ischemia-reperfusion injury can protect the myocardium to a high extent in repetitive ischemia and acute myocardial infarction.
• both active ingredients are administered as a fixed combination, i.e. as a single tablet, in all cases desribed herein. Taking a single tablet is even easier to handle than taking two tablets at the same time. Furthermore, the packaging can be accomplished with less effort.
• the beneficial effects on blood pressure can, for example, be demonstrated in the test model as disclosed in R.L. Webb et al., in J. Hypertension, 16:843-852, 1998.
• treatment groups consisting of at least 6 animals per group. Each study is best performed in which the effects of the combination treatment group are determined at the same time as the individual components are evaluated.
• the combination therapy can be compared to that of the monotherapy groups by determining the maximum change in blood pressure or the area under the curve (AUC) for change in blood pressure over time in each of the treatment groups. All values are represented as the group mean + SEM. Statistical significance is obtained when p ⁇ 0.05.
• the AUC values for each of the treatment groups can be compared statistically using a oneway ANOVA followed by the appropriate post-hoc analysis, for example by performing a Tukey's test.
• Blood pressure can be reduced to a similar degree using lower dosages of each of the components when given in combination than when the individual monotherapies are administered.
• An additional unexpected finding is that the blood pressure can be lowered to a greater extent with the combination than when the individual compound of formulat (I) or a pharmaceutically acceptable salt thereof is given alone at a higher dosage.
• CAO coronary artery occlusion
• cardiomyocytes cross-sectional area and length in sections of LV myocardium
• Infarct size Six ⁇ m-thick transverse histological sections of the left ventricle are stained with nitroblue tetrazolium and acquired by a B/W XC-77CE CCD video camera (Sony). The resulting image is processed on a KS 300 image analysis system (Carl Zeiss Vision) using a software specifically developed (Porzio et al., 1995). A single operator blinded to treatment interactively defines the boundaries of the interventricular septum, and the infarcted area on each section is semiautomatically identified as the area of unstained ventricular tissue. The software automatically calculates for each component of the ventricular section defined as the chamber, septum, infarcted area, infarcted LV wall and viable LV wall, a set of geometric parameters (Porzio et al., 1995).
• Hearts are fixed in situ, by retrograde perfusion with buffered 4% formaldehyde after arrest in diastole by i.v. injection of 0.5 M KCI. After fixation, the left ventricle (LV) and the free wall of the right ventricle are separately weighed; LV longer diameter is measured with a caliper.
• LV histological sections are stained with hematoxylin & eosin for qualitative examination and to quantify cardiomyocytes cross-sectional area with a semi-automated image analysis routine. Interstitial collagen deposition in LV is evaluated on Sirius red stained sections with a semi-automated image analysis routine (Masson et al., 1998).
• Collagen content in LV spared myocardium LV tissue in the spared myocardium is homogenized, subjected to PAGE-SDS electrophoresis and electroblotted onto nitrocellulose membrane. The blots are exposed to primary antibodies, i.e. rabbit anti-rat collagen type I or type III antiserum (Chemicon). The primary antibodies are recognized by secondary antibodies conjugated to alkaline phosphatase (for colagen type I) or peroxidase (collagen type III).
• LV chamber volume is determined in hearts arrested in diastole (KCI) and fixed in formalin under a hydrostatic pressure equivalent to the measured LV end-diastolic pressure.
• a metric rod is inserted into the LV to measure LV inner length.
• the transverse diameters of the LV chamber are measured in two 1-mm thick transverse sections near to the base and the apex of the ventricle (Jeremic et al., 1996).
• the chamber volume is computed from an equation integrating transverse diameters and inner length.
• a microtip pressure transducer (Millar SPC-320) connected to a recorder (Windograf, Gould Electronics) is inserted into the right carotid artery to record systolic and diastolic blood pressures.
• the pressure transducer is advanced into the LV to measure LV systolic (LVSP) and end-diastolic (LVEDP) pressures, the first derivative of LV pressure over time (+dP/dt) and heart rate.
• LVSP LV systolic
• LVEDP end-diastolic
• Non-invasive blood pressure Systolic blood pressure and heart rate are measured by the tail-cuff method (Letica LE 5002) in conscious rats.
• Urine electrolytes, hormones Rats are individually housed in metabolic cages and 24-h urine collected on 1 ml HCI 6N. Water intake is measured.
• Urine catecholamines are extracted on Bondelut C18 columns (Varian), separated by HPLC (Apex-ll C18, 3 ⁇ m,
• Plasma and urine aldosterone, and plasma angiotensin II are determined with specific radioimmunoassays (Aldoctk-2, DiaSorin and Angiotensin II, Nichols Diagnostics). Urine sodium and potassium are measured by flame photometry.
• Endothelial dysfunction is being acknowledged as a critical factor in vascular diseases.
• the endothelium plays a bimodal role as the source of various hormones or by-products with opposing effects: vasodilation and vasoconstriction, inhibition or promotion of growth, fibrinolysis or thrombogenesis, production of anti-oxidants or oxidising agents.
• Genetically predisposed hypertensive animals with endothelial dysfunction constitute a valid model for assessing the efficacy of a cardiovascular therapy.
• Endothelial disfunction is characterized by, for example, increased oxidative stress, causing decreased nitric oxide, increased factors involved in coagulation or fibrinolysis such as plasminogen activating inhibitor-1 (PAI-1 ), tissue factor (TF), tissue plasminogen activator (tPA), increased adhesion molecules such as ICAM and VCAM, increased growth factors such as bFGF, TGFb, PDGF, VEGF, all factors causing cell growth inflammation and fibrosis.
• PAI-1 plasminogen activating inhibitor-1
• TF tissue factor
• tPA tissue plasminogen activator
• ICAM interleukinogen activator
• VCAM increased adhesion molecules
• growth factors such as bFGF, TGFb, PDGF, VEGF, all factors causing cell growth inflammation and fibrosis.
• the treatment e.g. of endothelial dysfunction can be demonstrated in the following pharmacological test:
• the drugs are administered in drinking fluid.
• the doses to be used are selected from the work of Sweet et al. (1987) indicating significantly increased survival in rats with healed myocardial infarction.
• the pressor effect of Ang II at 1 mg/kg obtained in controls normotensive rats can be reducted after treatment with the compound of formula (I) in form of the hemi-fumarate (Gervais et al. 1999).
• Body weight is measured every week.
• Systolic blood pressure and heart rate are recorded by tail cuff plethysmography 3 and 2 weeks before starting the study and at 2 weeks after drug administration.
• Urine is collected over a 24 hour period from rats kept in individual (metabolic) cages the week before starting treatment and at weeks 4 and 12 for volume measurement and protein, creatinine, sodium and potassium determination using standard laboratory methods.
• blood samples are withdrawn from the retro- orbital plexus (maximum 1 ml) for creatinine, Na + and K + assays.
• mice Ten rats from each group are sacrificed at 4 weeks for collection of kidney and heart for morphological analysis. The remaining rats are sacrificed at 12 weeks. Cardiac and kidney weight is recorded. Terminal blood sampling is performed in 5 % EDTA at 4 (morphometry study) and 12 (end of the study) weeks for aldosterone, determination by radioimmunoassay using a DPC coat-a-count aldosterone-RIA kit (B ⁇ hlmann, Switzerland).
• compositions of the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
• a factorial design study in naive or previously treated hypertensive patients is initated in order to select the more appropriate dose(s) for subsequent use will be.
• the positive outcome of the selected dosage is based on synergy in blood pressure lowering, low incidence of side effects and better potassium handling of the combination.
• This study includes up to 120 patients in every cells of the explored doses of monotherapy and/or marketed combination of two of the three components of the triple combination.
• the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, separately or in a fixed combination.
• composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.
• the invention furthermore relates to a method for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of
• Atherosclerosis atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
• (g) diabetic retinopathy, and (h) peripheral vascular disease comprising administering to a warm-blooded animal, including man, in need thereof a jointly effective amount of a combination of the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof with at least one therapeutic agent comprising
• Atherosclerosis atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
• the invention furthermore relates to a pharmaceutical composition for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of
• Atherosclerosis atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
• compositions of the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
• the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, separately or in a fixed combination.
• composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.
• a further aspect of the present invention is a kit for the prevention of, delay of progression of, treatment of a disease or condition according to the present invention comprising
• the present invention likewise relates to a "kit-of-parts", for example, in the sense that the components to be combined according to the present invention can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. simultaneously or at different time points.
• the parts of the kit of parts can then e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
• the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components.
• the invention furthermore relates to a commercial package comprising the combination according to the present invention together with instructions for simultaneous, separate or sequential use.
• These pharmaceutical preparations are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances.
• the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compound.
• Pharmaceutical preparations for enteral or parenteral, and also for ocular, administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner that is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilizing processes.
• compositions for oral use can be obtained by combining the active compound with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.
• the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
• Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commerically available. Normally, in the case of oral administration, an approximate daily dose of from about 1 mg to about 360 mg is to be estimated e.g. for a patient of approximately 75 kg in weight.
• the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
• the pharmaceutical preparation will be supplied in the form of suitable dosage unit form, for example, a capsule or tablet for oral treatment.
• Valsartan as a representative of the class of ATrreceptor antagonists, will be supplied in the form of suitable dosage unit form, for example, a capsule or tablet, and comprising a therapeutically effective amount, e.g. from about 20 to about 320 mg, of valsartan which may be applied to patients.
• a suitable dosage unit form may comprise 40 mg, 80 mg, 160 mg or 320 mg per dosaqe unit form.
• the application of the active ingredient may occur up to three times a day, starting e.g. with a daily dose of 20 mg or 40 mg of valsartan, increasing via 80 mg daily and further to 160 mg daily up to 320 mg daily.
• valsartan is applied twice a day with a dose of 80 mg or 160 mg, respectively, each. Corresponding doses may be taken, for example, in the morning, at mid-day or in the evening. Preferred is b.i.d. administration.
• Hydrochlorothiazide will be supplied in of suitable dosage unit form, for example, a capsule or tablet, and comprising a therapeutically effective amount, e.g. from about 5 mg to about 50 mg which may be applied to patients.
• Preferred doses per unit dosage form is 6,25 mg, 12,5 mg or 25 mg.
• the application of the active ingredient may occur up to three times a day.
• the dosage of amiloride or triameterine, respectively, are those that are normally being used for mono-therapy, most preferably, the lower range of the prescribed doses.
• the application of the active ingredient may occur up to three times a day.
• a preferred dose per unit dosage form is 5 mg of amiloride hydrochloride.
• compositions comprising (i) a dose of valsartan selected from 40 mg, 80 mg, 160 mg and 320 mg of valsartan, (ii) 5 mg of amiloride hydrochloride, and (iii) a dose of hydrochlorothiazide selected from 1275 and 25 mg of hydrochlorothiazide.
• Preferred are dosage unit forms or a single dosage unit form comprising (i) a dose of valsartan selected from 40 mg, 80 mg, 160 mg and 320 mg of valsartan, (ii) 5 mg of amiloride hydrochloride, and (iii) a dose of hydrochlorothiazide selected from 12.5 and 25 mg of hydrochlorothiazide.
• the film-coated tablet is manufactured e.g. as follows:
• a mixture of valsartan, microcrystalline cellulose, crospovidone, part of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200, silicon dioxide and magnesium stearate is premixed in a diffusion mixer and then sieve through a screnning mill.
• the resulting mixture is again pre-mixed in a diffusion mixer, compacted in a roller compacter and then sieve through a screening mill.
• the rest of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200 are added and the final blend is made in a diffusion mixer.
• the whole mixture is compressed in a rotary tabletting machine and the tabletts are coated with a film by using Diolack pale red in a perforated pan.
• the film-coated tablet is manufactured e.g. as described in Formulation Example 1.
• the film-coated tablet is manufactured e.g. as described in Formulation Example 1.
• the tablet is manufactured e.g. as follows: Granulation/Drying Valsartan and microcrystallin cellulose are spray-granulated in a fluidised bed granulator with a granulating solution consisting of povidone and sodium lauryl sulphate dissolved in purified water. The granulate obtained is dried in a fluidiesd bed dryer. Milling/Blending The dried granulate is milled together with crospovidone and magnesium stearate. The mass is then blended in a conical srew type mixer for approximately 10 minutes. Encapsulation Teh empty hard gelatin capsules are filled with the blended bulk granules under controlled temperature and humidity conditions. The filed capsules are dedustee, visually inspected, weightchecked and guarantied until by Quality assurance department.
• the formulation is manufactured e.g. as described in Formulation Example 4.

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• Emergency Medicine (AREA)
• Hospice & Palliative Care (AREA)
• Vascular Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Steroid Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 2003
  • 2003-11-03 GB GBGB0325605.4A patent/GB0325605D0/en not_active Ceased
• 2004
  • 2004-02-11 US US10/577,370 patent/US20070072848A1/en not_active Abandoned
  • 2004-11-02 DE DE602004012593T patent/DE602004012593T2/de not_active Revoked
  • 2004-11-02 CA CA002544230A patent/CA2544230A1/en not_active Abandoned
  • 2004-11-02 BR BRPI0416154-8A patent/BRPI0416154A/pt not_active IP Right Cessation
  • 2004-11-02 WO PCT/EP2004/012386 patent/WO2005049013A1/en not_active Ceased
  • 2004-11-02 KR KR1020067008517A patent/KR20060097025A/ko not_active Withdrawn
  • 2004-11-02 JP JP2006537238A patent/JP2007509900A/ja active Pending
  • 2004-11-02 EP EP04797529A patent/EP1682122B9/en not_active Revoked
  • 2004-11-02 CN CNA2004800329189A patent/CN1878548A/zh active Pending
  • 2004-11-02 PL PL04797529T patent/PL1682122T3/pl unknown
  • 2004-11-02 PT PT04797529T patent/PT1682122E/pt unknown
  • 2004-11-02 ES ES04797529T patent/ES2303958T3/es not_active Expired - Lifetime
  • 2004-11-02 RU RU2006119329/15A patent/RU2006119329A/ru not_active Application Discontinuation
  • 2004-11-02 AT AT04797529T patent/ATE389399T1/de not_active IP Right Cessation
  • 2004-11-02 AU AU2004290505A patent/AU2004290505B2/en not_active Ceased
• 2008
  • 2008-09-26 US US12/286,039 patent/US20090036432A1/en not_active Abandoned

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