EP1343504A2 - Pharmaceutical formulation of gepirone for oral administration - Google Patents
Pharmaceutical formulation of gepirone for oral administrationInfo
- Publication number
- EP1343504A2 EP1343504A2 EP01995688A EP01995688A EP1343504A2 EP 1343504 A2 EP1343504 A2 EP 1343504A2 EP 01995688 A EP01995688 A EP 01995688A EP 01995688 A EP01995688 A EP 01995688A EP 1343504 A2 EP1343504 A2 EP 1343504A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- gepirone
- amount
- pharmaceutical formulation
- formulation
- polymer matrix
- 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- Withdrawn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
- QOIGKGMMAGJZNZ-UHFFFAOYSA-N gepirone Chemical compound O=C1CC(C)(C)CC(=O)N1CCCCN1CCN(C=2N=CC=CN=2)CC1 QOIGKGMMAGJZNZ-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 229960000647 gepirone Drugs 0.000 title claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 26
- 238000013265 extended release Methods 0.000 claims abstract description 13
- 238000009472 formulation Methods 0.000 claims abstract description 12
- 239000011159 matrix material Substances 0.000 claims abstract description 9
- 229920000642 polymer Polymers 0.000 claims abstract description 9
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 6
- 150000001720 carbohydrates Chemical class 0.000 claims abstract description 5
- 208000015114 central nervous system disease Diseases 0.000 claims abstract description 4
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 238000000034 method Methods 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000654 additive Substances 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000009491 slugging Methods 0.000 description 3
- 241000237858 Gastropoda Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- -1 glidants Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102220487426 Actin-related protein 2/3 complex subunit 3_K15M_mutation Human genes 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000001034 iron oxide pigment Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012735 once-a-day formulation Substances 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
Classifications
-
- 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
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- the invention relates to a pharmaceutical formulation for oral administration with extended release properties comprising an amount of gepirone hydrochloride, an amount of a cellulosic polymer matrix and an amount of microcrystalline cellulose.
- Such pharmaceutical formulations are described in EP 700 680 for use in the treatment of CNS disorders such as anxiety, depression and panic disorders.
- Gepirone is a drug which induces undesirable effects when high peak levels are reached. An even distribution of drug levels in blood is desirable to have a suitably tolerated therapeutic dose level. It was reported that optimal treatment of major depressive disorder was obtained with daily doses of up to 100 mg gepirone HCl (Wilcox et al;
- This invention makes a pharmaceutical formulation according to the opening paragraph available in which the amount of the pharmaceutically acceptable cellulosic polymer matrix is from 70 to 85 wt %, the amount of carbohydrate binder is from 7 to 10 wt % and the amount of gepirone hydrochloride is from 13 to 21 wt %.
- the formulation may optionally contain further pharmaceutically acceptable additives, such as glidants, lubricants and colorants.
- the invention makes a once per day medical treatment available with gepirone HCl in a pharmaceutical formulation for oral administration having the above-defined composition.
- This treatment is useful and well- tolerated by those patients treated for depression or a related central nervous system disorder, who are started on a treatment regime beginning with doses of about 20 mg gepirone HCl per day, and which is gradually built up to 60-100 mg gepirone HCl per day.
- a pharmaceutical formulation for oral administration is usually a tablet or a capsule. Contrary to what would have been the weight of an 80 mg tablet according to EP 700 680, tablets according to the present invention can have a total weight of at most 450 mg. Despite the high relative amount of gepirone HCl over the cellulosic polymer matrix material and also over the carbohydrate binder, oral formulations, in particular tablets, could still be made with acceptable dissolution properties of gepirone and sufficient stability during production and handling.
- a pharmaceutically acceptable cellulosic polymer matrix has the function of retaining gepirone HCl so that an extended release effect is obtained.
- Suitable matrixes include hydroxyalkylsubstituted alkylcelluloses having a viscosity of 15,000 cps to 100,000 cps. Hydroxymethyl propylcellulose (HPMC) of grades K15M and K100M is preferred and grade K100M, Premium (Methocel) is in particular preferred.
- HPMC Hydroxymethyl propylcellulose
- the amounts of components in the pharmaceutical formulation of the invention are expressed as weight percentage (wt %) of the total weight of the formulation, which is usually a tablet.
- alkyl as used here means a branched or unbranched saturated unsubstituted carbon chain. In view of the required viscosities, the alkyl groups referred to in this paragraph do not comprise more than 6 carbon atoms.
- pharmaceutically acceptable for suitable additives for use in carrying out the invention refers to requirements set for pharmaceutical auxiliaries in general. These requirements with regard to safety and noninterference with the active principle in pharmaceutical formulations are generally known to the skilled person. A standard compilation of pharmaceutically acceptable carriers and excipients can be found in the Handbook of Pharmaceutical excipients (2 nd edition edited by A. Wade and P. J. Weller; Published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London in 1994).
- Additives to a pharmaceutical formulation such as carriers, binders, glidants, lubricants and colorants are used for example in order to obtain certain cohesiveness, coloration and flowability of the tablets.
- magnesium stearate, colloidal silicon dioxide and iron oxide pigments are used.
- Glidants and lubricants are agents reducing the adhesiveness of the powder mixture or tablets during production. Methods of use of such additives are known in the art of making pharmaceutical compositions as for example described in chapter 19 of Remington's Pharmaceutical Sciences (18th edition Editor A.R. Gennaro; Mack Publishing Comp; Easton, Pennsylvania).
- Binders are agents used to impart cohesive properties to a pharmaceutical composition resulting in minimal loss from the pharmaceutical composition during production and handling.
- Carbohydrate binders are for example cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, sugars, starches, amylopectin, dextrin, maltodextrin, gums and alginates.
- Microcrystalline cellulose, and in particular Avicel pH 101, is a preferred binder for use in this invention.
- a formulation according to the invention has a release rate of gepirone from the formulation such that about 18 to 24 hours are required to attain from about 90 to about 95% absorption of gepirone.
- Oral pharmaceutical formulations according to the present invention can be prepared by methods known in the art, e.g. as described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture). Some caution in handling the compressed high strength formulations of this invention is advisable in order to avoid breaking and cracks in tablets.
- Gepirone may be prepared by any method known in the art. Typically the compound is prepared by the methods described in US patent No. 4,423,049. Pharmaceutical extended release compositions containing gepirone are disclosed in EP 700 680. The contents of these documents are incorporated herein by reference.
- Active pre-mixture Transfer the colloidal silicon dioxide, NF, colorant (40 mg: Euroxide Yellow E 7056; 60 mg:Euroxide Yellow E 7055; 80 mg: Euroxide yellow E 7055 and Euroxide Red E 7016), gepirone HCl powder and 20% of hydroxypropyl methylcellulose USP in 2 cu.
- Ft. planetary mixer Hobart mixer
- Mix ingredients for 15 minutes in a planetary mixer Hobart Mixer.
- Label as 'Active Pre-Mix'. Blend for slugging
- V'-blender without an I-bar Transfer the Active Pre-Mix in a 10 cu. Ft. "V'-blender without an I-bar, while passing through #12 mesh screen and transfer the balance of 80% HPMC, microcrystalline cellulose, NF and 50% of magnesium stearate, NF in the V-blender without an I-bar. Blend ingredients in the V-blender without an I bar for 24 minutes and label as "Blend for Slugging".
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01995688A EP1343504A2 (en) | 2000-12-08 | 2001-11-30 | Pharmaceutical formulation of gepirone for oral administration |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP00204388 | 2000-12-08 | ||
| EP00204388 | 2000-12-08 | ||
| EP01995688A EP1343504A2 (en) | 2000-12-08 | 2001-11-30 | Pharmaceutical formulation of gepirone for oral administration |
| PCT/EP2001/014189 WO2002045753A2 (en) | 2000-12-08 | 2001-11-30 | Oral extended release formulation of gepirone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1343504A2 true EP1343504A2 (en) | 2003-09-17 |
Family
ID=8172397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP01995688A Withdrawn EP1343504A2 (en) | 2000-12-08 | 2001-11-30 | Pharmaceutical formulation of gepirone for oral administration |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP1343504A2 (cs) |
| JP (1) | JP2004517083A (cs) |
| KR (1) | KR20040018314A (cs) |
| CN (1) | CN1479620A (cs) |
| AR (1) | AR031461A1 (cs) |
| AU (1) | AU2002226371A1 (cs) |
| BR (1) | BR0115976A (cs) |
| CA (1) | CA2436692A1 (cs) |
| CZ (1) | CZ20031589A3 (cs) |
| EC (1) | ECSP034627A (cs) |
| HU (1) | HUP0401021A2 (cs) |
| IL (1) | IL155855A0 (cs) |
| MX (1) | MXPA03005099A (cs) |
| NO (1) | NO20032581L (cs) |
| PL (1) | PL362445A1 (cs) |
| RU (1) | RU2003120446A (cs) |
| SK (1) | SK6942003A3 (cs) |
| WO (1) | WO2002045753A2 (cs) |
| ZA (1) | ZA200303915B (cs) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004028507A1 (en) * | 2002-09-24 | 2004-04-08 | Akzo Nobel N.V. | Method to improve pharmaceutical tablets having a matrix of cellulose ether |
| AU2004324868B2 (en) * | 2004-11-05 | 2010-04-29 | Fabre Kramer Holdings Inc | High-dosage extended-release formulation of gepirone |
| MY198454A (en) * | 2017-07-26 | 2023-08-29 | Abbott Lab | Nutritional Tablets and Methods of Making the Same |
| CN109745323A (zh) * | 2017-11-01 | 2019-05-14 | 四川科瑞德制药股份有限公司 | 氮哌酮类化合物提高副交感神经活性的用途 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5478572A (en) * | 1994-09-06 | 1995-12-26 | Bristol-Myers Squibb Co. | Gepirone dosage form |
-
2001
- 2001-11-30 CZ CZ20031589A patent/CZ20031589A3/cs unknown
- 2001-11-30 PL PL01362445A patent/PL362445A1/xx not_active Application Discontinuation
- 2001-11-30 BR BR0115976-3A patent/BR0115976A/pt not_active Application Discontinuation
- 2001-11-30 RU RU2003120446/15A patent/RU2003120446A/ru not_active Application Discontinuation
- 2001-11-30 CN CNA018201792A patent/CN1479620A/zh active Pending
- 2001-11-30 SK SK694-2003A patent/SK6942003A3/sk unknown
- 2001-11-30 AU AU2002226371A patent/AU2002226371A1/en not_active Abandoned
- 2001-11-30 KR KR10-2003-7007555A patent/KR20040018314A/ko not_active Withdrawn
- 2001-11-30 MX MXPA03005099A patent/MXPA03005099A/es unknown
- 2001-11-30 CA CA002436692A patent/CA2436692A1/en not_active Abandoned
- 2001-11-30 HU HU0401021A patent/HUP0401021A2/hu unknown
- 2001-11-30 EP EP01995688A patent/EP1343504A2/en not_active Withdrawn
- 2001-11-30 JP JP2002547535A patent/JP2004517083A/ja not_active Withdrawn
- 2001-11-30 IL IL15585501A patent/IL155855A0/xx unknown
- 2001-11-30 WO PCT/EP2001/014189 patent/WO2002045753A2/en not_active Application Discontinuation
- 2001-12-07 AR ARP010105683A patent/AR031461A1/es not_active Application Discontinuation
-
2003
- 2003-05-20 ZA ZA200303915A patent/ZA200303915B/en unknown
- 2003-05-28 EC EC2003004627A patent/ECSP034627A/es unknown
- 2003-06-06 NO NO20032581A patent/NO20032581L/no not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0245753A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0401021A2 (hu) | 2004-09-28 |
| NO20032581D0 (no) | 2003-06-06 |
| KR20040018314A (ko) | 2004-03-03 |
| MXPA03005099A (es) | 2004-02-12 |
| AU2002226371A1 (en) | 2002-06-18 |
| NO20032581L (no) | 2003-06-06 |
| SK6942003A3 (en) | 2003-10-07 |
| ZA200303915B (en) | 2004-08-20 |
| BR0115976A (pt) | 2003-12-30 |
| IL155855A0 (en) | 2003-12-23 |
| CA2436692A1 (en) | 2002-06-13 |
| WO2002045753A2 (en) | 2002-06-13 |
| JP2004517083A (ja) | 2004-06-10 |
| ECSP034627A (es) | 2004-09-28 |
| AR031461A1 (es) | 2003-09-24 |
| CZ20031589A3 (cs) | 2003-11-12 |
| PL362445A1 (en) | 2004-11-02 |
| WO2002045753A3 (en) | 2002-08-29 |
| CN1479620A (zh) | 2004-03-03 |
| RU2003120446A (ru) | 2005-02-20 |
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