EP1117407A1 - Oral dosage formulations comprising (2s, 3s,5r)-2-(3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol and an effective stabilizing amount of alginic acid - Google Patents
Oral dosage formulations comprising (2s, 3s,5r)-2-(3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol and an effective stabilizing amount of alginic acidInfo
- Publication number
- EP1117407A1 EP1117407A1 EP99947420A EP99947420A EP1117407A1 EP 1117407 A1 EP1117407 A1 EP 1117407A1 EP 99947420 A EP99947420 A EP 99947420A EP 99947420 A EP99947420 A EP 99947420A EP 1117407 A1 EP1117407 A1 EP 1117407A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- oral dosage
- dosage form
- discrete oral
- alginic acid
- discrete
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- 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
- A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
Definitions
- This invention relates to discrete oral dosage forms, such as tablets and capsules, comprising (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol ("active agent”) or salts or solvates thereof.
- Alginic acid is described in the Handbook of Pharmaceutical Excipients, pp.
- the present invention provides a discrete oral dosage form comprising a therapeutically effective amount of (2S,3S,5R)-2-(3,5- difluorophenyl)-3,5-dimethyl-2-morpholinol or a physiologically acceptable salt or solvate thereof, or a solvate of said salt, and an effective stabilizing amount of alginic acid.
- the present invention provides a method for preventing or treating attention deficit hyperkinetic disorder or depression, comprising administration of a discrete oral dosage form of this invention.
- the present invention provides the use of a discrete oral dosage form as defined above in the preparation of a medicament for the prevention or 30 treatment of attention deficit hyperkinetic disorder or depression.
- Depression states in the treatment of which the discrete oral dosage form of the present invention is particularly useful are those classified as affective disorders in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition - Revised, American Psychiatric Association, Washington D.C. (1987) (DSM-III-R), including the mood disorders (DSM-III-R, 296.2X to 296.6X), other specific affective disorders (301.13 and 300.40) and bipolar and depressive disorders not otherwise specified (296.70 and 311.00).
- the present invention provides a method for treating addiction to nicotine-containing products, especially tobacco-containing products, comprising administration of a discrete oral dosage form of this invention.
- the present invention provides the use of a discrete oral dosage form as defined above in the preparation of a medicament for the treatment of addiction to nicotine-containing products, especially tobacco-containing products.
- Nicotine-containing products will include tobacco products (e.g. cigarettes, cigars, pipe tobacco, chewing tobacco etc,) and nicotine replacement products, such as nicotine gums, sprays, patches and inhalers and the like.
- Treatment of addiction to such nicotine-containing products includes both partial and complete alleviation of addiction.
- tobacco products, as well as the cessation of the activity, for example smoking this will also include reducing the level or frequency of such activity e.g. reduction of the number of cigarettes smoked in a given period.
- treatment will also involve both cessation of, and a reduction in the level of, usage of such products.
- the present invention provides a method for treating other conditions referred to in U.S. Patent No. 5,104,870, comprising administration of a discrete oral dosage form as defined above.
- Such conditions include the following, with classifications (where indicated) being those adopted in DSM-III-R: anxiety disorders, including phobic neuroses (300.00, 300.21, 300.22, 300.23 and 300.29), anxiety neuroses (300.01, 300.02 and 300.30) and post-traumatic stress disorder (309.89); attention deficit disorders (314.00 and 314.01); eating disorders, including anorexia nervosa (307.10) and bulimia (307.51); personality disorders, including borderline personality disorder (301.83); sexual dysfunctions, including hypoactive sexual desire disorder (302.71), female sexual arousal disorder or male erectile disorder (302.72), inhibited female orgasm (302.73), inhibited male orgasm (302.74), premature ejaculation (302.75), dyspareunia (302.76), vaginismus (306.51) and sexual dysfunction
- narcolepsy-cataplexy syndrome a condition characterised by excessive sleepiness (narcolepsy) often taking the form of sleep attacks, episodes of a seemingly irresistible need to sleep usually lasting for about fifteen minutes or less, together with brief (often lasting less than a minute) periods of loss of muscle tone
- the present invention provides a method for preventing or treating attention deficit hyperkinetic disorder, comprising administration of a discrete oral dosage form of this invention.
- the present invention provides the use of a discrete oral dosage form as defined above in the preparation of a medicament for the prevention or treatment of attention deficit hyperkinetic disorder.
- the discrete oral dosage form may be further used in human medicine: to alleviate symptoms of withdrawal consequent upon the cessation of illicit drug abuse; to potentiate the analgesia induced by morphine or a like opiate analgesic, for example in the care and treatment of terminally-ill cancer patients; to prevent functional impairment and drowsiness following administration of a drowsiness- inducing benzodiazepine tranquillizer - suitable indications for concomitant administration of a said compound or salt and such a benzodiazepine include a) treatment of mixed anxiety and depression in situations where functional impairment or drowsiness is undesirable, and b) treatment of anxiety in situations where functional impairment or drowsiness is undesirable; to prevent memory loss following administration of a benzodiazepine tranquillizer; to restore mental functioning acutely impaired consequent upon ethanol ingestion; to suppress prolactin release or secretion, for example in the suppression of lactation post partum or in the treatment of galactorrhoea, hyper
- the discrete oral dosage forms of this invention contain a therapeutically effective amount of the active agent or a physiologically acceptable salt or solvate thereof or a solvate of said salt.
- the amount needed to be therapeutically effective is calculated based on the weight of the active agent itself and not any associated counter ions or solvent.
- the active agent is typically prepared as its hydrochloride salt, but the desired amount is usually based on the amount of active agent not including the weight of associated HC1.
- the active agent (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2- morpholinol, as well as its hydrochloride salt, is known and can be prepared by known techniques, particularly as described in U.S. Patent No. 5,104,870 (Kelley et al.).
- the discrete oral dosage forms of this invention comprise at least 0.1 mg of active agent, or a salt or solvate thereof calculated to give at least 0.1 mg of active agent.
- the discrete oral dosage forms of this invention comprise at least 0.1 % by weight of alginic based on total weight of the tablet or capsule, preferably at least 2 % by weight, and most preferably at least 5 % by weight alginic acid.
- Particularly preferred alginic acid is alginic acid NF.
- % by weight or “weight %”, or “wt %”, “% w/w”, or like terms, means a percentage by weight, based on the total weight of the composition. Unless otherwise indicated, percentages herein are given as percent by weight of the total weight of a discrete oral dosage form.
- Alginic acid may be obtained from any suitable source, such as Mendell. In general, the molecular weight is not critical, but is typically from 20,000 to 200,000. Typically the pH of the alginic acid is 1.5 to 3.5 for a 3% weight/volume aqueous dispersion.
- the discrete oral dosage forms of this invention further comprise standard excipients such as binder, filler, lubricant, disintegrant, or glidant.
- the discrete oral dosage forms of this invention may also contain stabilizers in addition to the alginic acid.
- Filler sometimes also referred to as carrier, may be any suitable filler.
- the filler is selected from the group consisting of mannitol, sucrose, lactose, and microcrystalline cellulose fillers. Lactose, particularly lactose monohydrate, is most preferred.
- the discrete oral dosage forms contain from 40 to 95 % by weight, more preferably from 55 to 90 % by weight, of filler.
- the discrete oral dosage forms of this invention contain from 1 to
- Disintegrants may be any suitable disintegrant.
- Preferred disintegrants are glucopyranose compounds.
- Suitable glucopyranose compounds are typically a poly- ⁇ - or poly- ⁇ -glucopyranose compound in which some of the hydroxyl groups have been converted to carboxy alkyl (e.g., carboxymethyl) ether moieties.
- carboxy alkyl ether moieties may be in the form of a pharmaceutically acceptable salt (e.g., a sodium salt).
- the glucopyranose compound is a sodium starch glycolate. Sodium starch glycolate is described in the Handbook of Pharmaceutical Excipients, pg. 462-466 (American Pharmaceutical Association 2d Ed. 1994).
- the glucopyranose compound is a low pH glucopyranose compound.
- low pH is generally meant that a 3.3% aqueous dispersion of the compound exhibits a pH of from 1 to 5.
- the molecular weight is not critical, but is typically from 500,000 to 1,000,000.
- An example of a suitable low pH compound is available as EXPLOTAB® LOW pH from Mendell (a Penwest Company; 2981 Route 22, Patterson, NY, USA 12563-9970). See also, EXPLOTAB® Low pH Sodium Starch Glycolate Product Sheet (Mendell 1996).
- Other suitable glucopyranose compounds include low pH croscarmellose sodium (see, for example, Handbook of Pharmaceutical Excipients, pg. 141).
- the discrete oral dosage forms of this invention contains from 0.1 to 5 percent of a lubricant.
- Lubricants that may be employed in carrying out the present invention include, but are not limited to, glyceryl behenate, magnesium stearate, and stearic acid. Glyceryl behenate and magnesium stearate are preferred. Magnesium stearate is particularly preferred.
- the discrete oral dosage form may be prepared by any suitable method of pharmacy that includes the step of bringing into association the active agent, the alginic acid, and any other ingredients. Typically a filler or carrier is used and is first mixed with the alginic acid and one or more of the optional ingredients such as lubricant, stabilizer, and/or disintegrant.
- the formulations of the invention are prepared by uniformly and intimately admixing the active agent hydrochloride salt with solid paniculate carrier, alginic acid and optional ingredients, and then, if necessary, shaping the resulting mixture.
- a tablet may be prepared by compressing or molding a powder or granules containing the active compound, with one or more optional ingredients.
- Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
- Capsules may be prepared by filling a two piece hard gelatin capsule with the active agent, carrier, and accessory ingredients.
- Oral dosage forms of the present invention are useful as antidepressants in the prevention or treatment of depression, obesity, and attention deficit disorder, or aiding in smoking cessation, in subjects, particularly humans, in need thereof, and for all the uses described in U.S. Patent No. 5,104,870.
- NF National Formulary grade
- mg milligrams
- the active agent hydrochloride salt can be prepared as described in the '870 patent.
- Tablets were prepared containing the equivalent of 1 mg of active agent.
- the active agent hydrochloride salt was weighed so as to give a calculated amount of 1 mg per tablet of free base.
- the tablets were prepared by sifting each component except magnesium stearate and silicon dioxide through a # 20 mesh screen. The sifted components were added to a V-shell blender and mixed for 15 minutes. The magnesium stearate and silicon dioxide were sifted through a # 20 mesh screen and added to the V-shell blender. The contents were mixed for a period of 5 additional minutes. The blend was compressed on a rotary tablet press fitted with 8.6mm round tooling, uppers scored and lowers, plain, at approximately 250 mg per tablet. The composition of the tablets is summarized below in Table 1.
- Tablets containing 1.25 mg of active agent were prepared as in Comparative Example C 1 except stearic acid and sodium starch glycolate were used as the lubricant and disintegrant, respectively and Comparative Example C2 contained 4.8 wt% of ascorbic acid and Comparative Example C3 contained 4.8 wt % of citric acid.
- the theory was that the pH and/or antioxidant effects of these carboxylic acids would stabilize the formulations. The results of stability testing are summarized below in Table 3.
- active agent HC1 The active agent hydrocloride salt
- active agent HC1 was first sieved through a US Standard 30 mesh hand screen to remove any large lumps from the article.
- the active agent HC1 was milled with centrifugal mill fitted with a 0.5 mm screen.
- the desired amount of milled active agent HC1 was then sieved with a vibratory screener fitted with a US Standard 14-mesh stainless steel screen.
- the active agent HC1 was then charged to V-blender.
- a 5 cubic foot blender was used in the manufacture of the 1.25 mg tablets, whereas a 3 cubic foot blender was used in the manufacture of the 0.25 mg and 0.5 mg tablets strengths.
- a one cubic foot blender was used to blend the 5 mg tablets.
- the desired amounts of lactose monohydrate, modified spray dried, alginic acid and sodium starch glycolate, low pH were also sieved with the vibratory screener fitted with a US Standard 14 mesh stainless steel screen and added to the blender.
- the V-blender was then rotated for 20 minutes.
- the proper amount of glyceryl behenate was screened with a vibratory screener fitted with a US Standard 14 mesh stainless steel screen and added to the blender.
- the V-blender was rotated for an additional 5 minutes.
- NT Not Tested The data show that alginic acid stabilizes the active agent HC1 in these tablets at a variety of active agent strengths and at a variety of temperature and humidity conditions.
- Tablets were made containing 2 different amounts of active agent.
- the active agent HC1 was weighed so as to deliver 0.25 mg and 5 mg, of active agent per tablet for Examples 5 and 6 respectively.
- Each of the tablets contained 10% by weight of alginic acid.
- Lactose Monohydrate, NF Modifies Spray Dried (wt % %)) 8877..6611 80.84
- Tablets were made containing 2 different amounts of active agent.
- the active agent HCl was weighed so as to deliver 10 mg and 5 mg, of active agent per tablet for Examples 7 and 8 respectively.
- Each of the tablets contained 2.5% by weight of alginic acid.
- Tablets were manufactured as in Examples 1-4 except the tablet diameter was increased to 6.5 mm, and the tablet weight was increased to 150 mg and 135 mg for formulations 7 and 8, respectively. These tablets were not film-coated.
- the composition of the tablets is summarized below in Table 8.
- Lactose Monohydrate, NF Modifies Spray Dried (wt %) 83.84 57.74
- Tablets were stored in open and closed vials to assess stability in both configurations. Stability results are summarized below in Table 9, the data for L.C. are wt % and the data for Total Impurity are area %..
- Tablets were made containing 2 different amounts of microcrystalline cellulose.
- the active agent HCl was weighed so as to deliver 7.5 mg, of active agent per tablet for Examples 9 and 10.
- Each of the tablets contained 5% by weight of alginic acid.
- Tablets were manufactured as listed above the tablet diameter was 6.5 mm and the tablet weight was 135 mg. These tablets were not film-coated.
- the compositions of the tablets are summarized below in Table 10.
- Lactose Monohydrate, NF Modifies Spray Dried (wt %) 78.11 73.11
- Tablets were stored in open and closed vials to assess stability in both configurations. Results of stability testing are summarized below in Table 1 1, the data for L.C. are wt % and the data for Total Impurity are area %.
- Tablets were made containing 2 different amounts of microcrystalline cellulose.
- the active agent HCl was weighed so as to deliver 1.25 mg, of active agent per tablet for Examples 1 1 and 12.
- Each of the tablets contained 5% by weight of alginic acid. Tablets were manufactured as listed above except the tablet diameter was 6.5 mm and the tablet weight was 135 mg. These tablets were not film-coated.
- the compositions of the tablets are summarized below in Table 12.
- Lactose Monohydrate, NF Modifies Spray Dried (wt %) 83.44 78.44
- Tablets were stored in open and closed vials to assess stability in both configurations.
- the results of stability testing are summarized below in Table 13, the data for L.C. are wt % and the data for Total Impurity are area %.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10211298P | 1998-09-28 | 1998-09-28 | |
US102112P | 1998-09-28 | ||
PCT/EP1999/007117 WO2000018406A1 (en) | 1998-09-28 | 1999-09-24 | Oral dosage formulations comprising (2s,3s,5r) -2-(3,5- difluorophenyl) -3,5-dimethyl -2-morpholinol and an effective stabilizing amount of alginic acid |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1117407A1 true EP1117407A1 (en) | 2001-07-25 |
Family
ID=22288187
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99947420A Withdrawn EP1117407A1 (en) | 1998-09-28 | 1999-09-24 | Oral dosage formulations comprising (2s, 3s,5r)-2-(3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol and an effective stabilizing amount of alginic acid |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP1117407A1 (ja) |
JP (1) | JP2002525328A (ja) |
KR (1) | KR20010075385A (ja) |
CN (1) | CN1328459A (ja) |
AR (1) | AR022673A1 (ja) |
AU (1) | AU6087399A (ja) |
BR (1) | BR9914096A (ja) |
CA (1) | CA2345638A1 (ja) |
CZ (1) | CZ20011142A3 (ja) |
HU (1) | HUP0103459A2 (ja) |
IL (1) | IL142054A0 (ja) |
MA (1) | MA26693A1 (ja) |
NO (1) | NO20011555D0 (ja) |
PE (1) | PE20001087A1 (ja) |
PL (1) | PL346877A1 (ja) |
TR (1) | TR200100863T2 (ja) |
WO (1) | WO2000018406A1 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU7750100A (en) * | 1999-10-13 | 2001-04-23 | Glaxo Group Limited | Method for the treatment of obesity |
DE102008047910A1 (de) | 2008-09-19 | 2010-03-25 | Molkerei Meggle Wasserburg Gmbh & Co. Kg | Tablettierhilfsstoff auf Laktose- und Cellulosebasis |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4597969A (en) * | 1982-04-05 | 1986-07-01 | Merck Sharp & Dohme | Stabilization of unstable drugs or food supplements |
GB8924528D0 (en) * | 1989-10-31 | 1989-12-20 | Wellcome Found | Heterocyclic pharmaceutical compounds,preparation and use |
-
1999
- 1999-09-23 MA MA25782A patent/MA26693A1/fr unknown
- 1999-09-24 CA CA002345638A patent/CA2345638A1/en not_active Abandoned
- 1999-09-24 JP JP2000571924A patent/JP2002525328A/ja active Pending
- 1999-09-24 TR TR2001/00863T patent/TR200100863T2/xx unknown
- 1999-09-24 CZ CZ20011142A patent/CZ20011142A3/cs unknown
- 1999-09-24 CN CN99813675A patent/CN1328459A/zh active Pending
- 1999-09-24 HU HU0103459A patent/HUP0103459A2/hu unknown
- 1999-09-24 WO PCT/EP1999/007117 patent/WO2000018406A1/en not_active Application Discontinuation
- 1999-09-24 KR KR1020017003874A patent/KR20010075385A/ko not_active Application Discontinuation
- 1999-09-24 AR ARP990104841A patent/AR022673A1/es unknown
- 1999-09-24 BR BR9914096-9A patent/BR9914096A/pt not_active IP Right Cessation
- 1999-09-24 EP EP99947420A patent/EP1117407A1/en not_active Withdrawn
- 1999-09-24 AU AU60873/99A patent/AU6087399A/en not_active Abandoned
- 1999-09-24 PL PL99346877A patent/PL346877A1/xx unknown
- 1999-09-24 IL IL14205499A patent/IL142054A0/xx unknown
- 1999-09-27 PE PE1999000976A patent/PE20001087A1/es not_active Application Discontinuation
-
2001
- 2001-03-27 NO NO20011555A patent/NO20011555D0/no not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO0018406A1 * |
Also Published As
Publication number | Publication date |
---|---|
NO20011555L (no) | 2001-03-27 |
TR200100863T2 (tr) | 2001-07-23 |
MA26693A1 (fr) | 2004-12-20 |
KR20010075385A (ko) | 2001-08-09 |
CN1328459A (zh) | 2001-12-26 |
NO20011555D0 (no) | 2001-03-27 |
IL142054A0 (en) | 2002-03-10 |
CZ20011142A3 (cs) | 2001-09-12 |
PL346877A1 (en) | 2002-03-11 |
WO2000018406A1 (en) | 2000-04-06 |
JP2002525328A (ja) | 2002-08-13 |
AR022673A1 (es) | 2002-09-04 |
BR9914096A (pt) | 2001-07-31 |
PE20001087A1 (es) | 2000-10-20 |
HUP0103459A2 (hu) | 2002-01-28 |
AU6087399A (en) | 2000-04-17 |
CA2345638A1 (en) | 2000-04-06 |
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