WO2003075824A2 - Process of manufacturing pharmaceutical composition useful for management of tuberculosis - Google Patents
Process of manufacturing pharmaceutical composition useful for management of tuberculosis Download PDFInfo
- Publication number
- WO2003075824A2 WO2003075824A2 PCT/IB2003/000801 IB0300801W WO03075824A2 WO 2003075824 A2 WO2003075824 A2 WO 2003075824A2 IB 0300801 W IB0300801 W IB 0300801W WO 03075824 A2 WO03075824 A2 WO 03075824A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- tuberculosis
- mycobacterium
- management
- prepared according
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
- A61K2039/521—Bacterial cells; Fungal cells; Protozoal cells inactivated (killed)
Definitions
- the invention relates to process for the preparation of formulations comprising a microorganism Mycobacterium w for the treatment of tuberculosis.
- Tuberculosis is a major communicable disease worldwide. It is a major cause of morbidity and mortality worldwide (developing countries as well as developed countries). This is inspite of modern chemotherapy. The modern chemotherapy is widely available and effective. It is an infection caused by mycobacterium tuberculosis. There has been resurgence of tuberculosis recently. Resurgence of tuberculosis is putting lot of pressure on health care system and society. It is believed that almost 2 billion persons are infected with mycobacterium tuberculosis and 3 million persons die each year from the disease.
- Mycobacterium Tuberculosis is slowly growing organism. It is responsible for tuberculosis. It is a chronic disease and needs long term treatment. Inspite of modern day chemotherapy tuberculosis treatment lasts for at least 6 months.
- the treatment comprises of two components i.e. intensive phase and continuation phase.
- intensive phase is to kill microorganisms which are dividing (growing) and render the tissues (sputum) negative of organism. If treatment is stopped at this point them there is a high relapse rate (more than 20%). This is due to organisms which lie dormant and persists in the tissues (persistors).
- the continuation phase is to kill persistors and bring relapse rate as low as possible (less than 5%). Due to longer duration of treatment (more than six months) compliance is a problem. To improve compliance the therapy is given as a directly observed therapy (DOT). This increases the cost of therapy significantly. DOT).
- DOT directly observed therapy
- results of modern chemotherapy in treatment failure cases are not encouraging. It takes a longer time for effective treatment. This is particularly so when organisms are resistant to Rifampicin and Isoniazid.
- the infection with organisms resistant to rifampicin and INH are also known as multidrug resistant tuberculosis. This is a most challenging infection to manage. For this group of patients there is a need to provide an additional novel therapy.
- the therapy should be effective to reduce the burden of treatment failure cases.
- the therapy should also be effective in management of treatment failure cases including MDR tuberculosis.
- UK patent 2236480 describes tuberculosis vaccine.
- the UK patent describes vaccine to provide protection against tuberculosis. It describes its efficacy in animals (mice and guinea pigs) in preventing tuberculosis. It also describes its safety when used in animals.
- therapeutic agents comprising of Mycobacterium w or its components/fractions as an active agent are capable of achieving this goal.
- Use of such compositions are found to improve sputum conversion at least by 4 weeks. They also improve cure rate and relapse rate.
- compositions made from 'Mycobacterium w' are found to be useful in management of tuberculosis. It is observed that administration of mycobacterium w containing pharmaceutical composition is effective in faster sputum conversion. It also improves time for relief from symptoms. It also improves cure rates as well as relapse rates.
- Mycobacterium w used in the present invention is a non-pathogenic, cultivable, atypical mycobacterium, with biochemical properties and fast growth characteristics resembling those belonging to Runyons group IV class of Mycobacteria in its metabolic and growth properties but is not identical to those strains currently listed in this group. It is therefore thought that (M w ) is an entirely new strain.
- Mw The species identity of Mw has been defined by polymerase chain reaction DNA sequence determination and differentiated from thirty other species of mycobacteria. It however differs from those presently listed in this group in on respect or the other.
- base sequence analysis of a polymorphic region of pattern analysis it has been established that M w is a unique species distinct from many other known mycobacterial species examined which are: M avium, M. intracellulare, M. scrofulaceum, M. kansasii, M. gastri, M. gordonae M. shimoidei, M. malmoense, M. haemophilum, M. terrae, M nonchromogenicum, M. thviale, M. marinum, M. flavescens, M.
- the object of the present invention is to provide a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for the treatment of tuberculosis.
- Yet another object of the present invention is to provide a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for decreasing relapse rate of tuberculosis.
- Yet another object of the present invention is to provide a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for quicker symptomatic relief in tuberculosis.
- Mw Mycobacterium w'
- Yet another object of the present invention is to provide a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for faster regaining of normal health in tuberculosis.
- Mw Mycobacterium w'
- Yet another object of the present invention is to provide a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for improvement of sputum conversion rate in tuberculosis.
- Mw Mycobacterium w'
- Yet another object of the present invention is to provide a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for faster sputum conversion in patients suffering from tuberculosis.
- Mw Mycobacterium w'
- Yet another object of the present invention is to provide a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for use along with chemotherapeutic agents.
- Yet another object of the present invention is to provide a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for treatment of all categries of tuberculosis including treatment failure as well as MDR tuberculosis.
- Mw Mycobacterium w'
- Yet another object of the present invention is to provide a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for reduction in duration of treatment of tuberculosis.
- compositions, the method of preparation, HPLC characteristic its safety and tolerability, methods of use and outcome of treatments are described in following examples.
- the following are illustrative examples of the present invention and scope of the present invention should not be limited by them.
- Each dose of 0.1 ml of therapeutic agent contains:
- Each dose of 0.1 ml of therapeutic agent contains: Mycobacterium w., (heat killed) 0.50 x 10 9 Sodium Chloride I. P. ... . 0.90% w/v
- Each dose of 0.1 ml of therapeutic agent contains: Mycobacterium w., (heat killed) 0.50 x 10 9 Sodium Chloride I. P. ... . 0.90% w/v Thiomerosal I. P. ... . 0.01% w/v
- Each dose of 0.1 ml of therapeutic agent contains
- Each dose of 0.1 ml of therapeutic agent contains Chloroform Extract of 1x10 10 Mycobacterium w Sodium Chloride I. P. ... . 0.90% w/v Thiomerosal I. P, ... . 0.01 % w/v
- Each dose of 0.1 ml of therapeutic agent contains Acetone Extract of 1x10 10 Mycobacterium w
- Each dose of 0.1 ml of therapeutic agent contains Ethanol Extract of 1x10 10 Mycobacterium w Sodium Chloride I. P. ... . 0.90% w/v
- Each dose of 0.1 ml of therapeutic agent contains
- Mycobacterium w (heat killed) 0.5x10 7
- Extract of mycobacterium w obtained 1x10 3 Mycobacterium w by disruption, solvent extraction or enzymatic extraction.
- Example 2 The Process of preparing a pharmaceutical composition
- Mycobacterium w is cultured on solid medium like L J medium or liquid medium like middle brook medium or sauton's liquid medium.
- middle brook medium is enriched. It can be preferably enriched by addition of glucose, bactotryptone, and BSA. They are used in ratio of 20:30:2 preferably.
- the enrichment medium is added to middle brook medium. It is done preferably in ratio of 15:1 to 25:1 more preperably in ratio of 20:1.
- the inner contact parts of the vessel should be properly cleaned to avoid any contamination. Fill up the vessel with 0.1 N NaOH and leave as such for 24 H to remove pyrogenic materials and other contaminants. The vessel is then cleaned first with acidified water, then wit ordinary water. Finally, the vessel is rinsed with distilled water (3 times) before preparing medium.
- the bioreactor containing 9L distilled water is sterilized with live steam(indirect). Similarly the bioreactor is sterilized once more with Middlebrook medium.
- the other addition bottles, inlet/outlet air filters etc. are autoclaved (twice) at 121°C for 15 minutes. Before use, these are dried at 50° C oven.
- the pallet so obtained is washed minimum three times with normal saline. It can be washed with any other fluid which is preferably isotonic.
- Pyrogen free normal saline is added to pallet. Any other pyrogen free isotonic fluid can be used as a pharmaceutical carrier.
- the carrier is added in amount so as get to desired concentration of active in final form.
- preservative is added.
- Preferred preservative is thiomesol which is used in final concentration of 0.01 % w/v.
- Terminal sterilization can done by various physical methods like application of heat or ionizing radiation or sterile filtration.
- Heat can be in the form of dry heat or moist heat. It can also be in the form of boiling or pasturisation.
- Ionizing radiation can be ultraviolet or gamma rays or mircrowave or any other form of ionizing radiation.
- the organisms are checked for acid fastness after gram staining.
- iii.lnactivation test This is done by culturing the product on L J medium to find out any living organism.
- the cultured organisms are infected to Balb/c mice. None of the mice should die and all should remain healthy and gain weight. There should not be any macroscopic or microscopic lesions seen in liver, lung spleen or any other organs when animals are killed upto 8 weeks following treatment.
- the organism is subjected to following biochemical tests:
- the organism gives negative results in urease, tween 80 hydrolysis and niacin test. It is positive by nitrate reduction test.
- the cell disruption can be done by way of sonication or use of high pressure fractionometer or by application of osmotic pressure ingredient.
- the solvent extraction can be done by any organic solvent like chloroform, ethanol, methanol, acetone, phenol, isopropyl alcohol, acetic acid, urea, hexane etc.
- the enzymatic extraction can be done by enzymes which can digest cell wall/membranes. They are typically proteolytic in nature. Enzyme liticase and pronase are the preferred enzymes.
- cell constituents of Mycobacterium w can be used alone in place of mycobacterium w organisms or it can be added to the product containing mycobacterium w.
- HPLC analysis was done using a waters system high performance liquid chromatography apparatus
- Solvent A HPLC grade methanol.
- the HPLC gradient initially comprised 98%(v/v) methanol (solvent B).
- the gradient was increased linearly to 80%.
- EXAMPLE 4 Following examples provides methods of use as well as efficacy of Mycobacterium w derived pharmaceutical composition in treatment of tuberculosis.
- Mycobacterium w containing pharmaceutical compositions are useful in better and faster sputum conversion
- the group of patients receiving Mycobacterium w had weight gain of more than 2 kg while none of the patients in a group not receiving Mycobacterium w had weight gain more than 0.5 kg by 6 weeks.
- Mycobacterium w containing pharmaceutical compositions are useful in quick sputum conversion, quicker symptomatic relief and feeling of well being.
- Multi drug resistant (MDR) tuberculosis is a difficult to manage problem.
- the treatment lasts much longer as it is difficult to achieve faster sputum conversion in this group of patients.
- the Mycobacterium w was evaluated in a group of patients having MDR as demonstrated by sputum culture evaluation. They were treated by ciprofloxacin, kanamycin, ethionamide, ethambutol, Pyrizinamide. In a randomised way half of patients received 0.1 ml of Mycobacterium w derived pharmaceutical composition intradermally at interval of one week.
- the group of patients receiving Mycobacterium w were found to be sputum negative by the end of two months while all the patients in a group not receiving Mycobacterium w were sputum positive at the end of two months. By three months only 15% of subjects were found to be sputum negative in a group not receiving Mycobacterium w.
- Mycobacterium w derived pharmaceutical compositions are effective in management of multi drug resistant tuberculosis.
- a group of patients with freshly diagnosed pulmonary tuberculosis and bacterial load of 1+ as demonstrated by microscopy of sputum were randomly assigned to receive modern chemotherapy or modern chemotherapy with pharmaceutical composition derived from Mycobacterium w given intradermally.
- Mycobacterium w containing pharmaceutical compositions are useful in quick sputum conversion, quicker feeling of well being and improved health (weight gain ).
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Microbiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2003-7015465A KR20050008453A (ko) | 2002-03-08 | 2003-03-04 | 결핵 관리에 유용한 약제학적 조성물의 제조방법 |
AU2003209533A AU2003209533A1 (en) | 2002-03-08 | 2003-03-04 | Process of manufacturing pharmaceutical composition useful for management of tuberculosis |
BR0303367-8A BR0303367A (pt) | 2002-03-08 | 2003-03-04 | Células de mycobacterium w, veìculo farmaceuticamente aceitável, preservativo, ruptura de mycobacterium w, extração de solvente, enzimas usadas para a extração enzimática de células de mycobacterium w, adjuvante, composição farmacêutica, tensoativo, e, concentração de tensoativo do processo de fabricar uma composição farmacêutica para a administração de tuberculose |
JP2003574100A JP2005519941A (ja) | 2002-03-08 | 2003-03-04 | 結核の管理のために有用な医薬組成物の製造方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN236MU2002 | 2002-03-08 | ||
IN236/MUM/2002 | 2002-03-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003075824A2 true WO2003075824A2 (en) | 2003-09-18 |
WO2003075824A3 WO2003075824A3 (en) | 2003-12-24 |
Family
ID=27799868
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2003/000801 WO2003075824A2 (en) | 2002-03-08 | 2003-03-04 | Process of manufacturing pharmaceutical composition useful for management of tuberculosis |
Country Status (5)
Country | Link |
---|---|
JP (1) | JP2005519941A (pt) |
KR (1) | KR20050008453A (pt) |
AU (1) | AU2003209533A1 (pt) |
BR (1) | BR0303367A (pt) |
WO (1) | WO2003075824A2 (pt) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2400560A (en) * | 2002-01-29 | 2004-10-20 | Rajiv Indravadan Modi | Method of providing prophylaxis for tuberculosis in hiv positive individuals |
GB2389532B (en) * | 2001-12-10 | 2004-10-27 | Bakulesh Mafatlal Khamar | The method of treating cancer |
EP2131858A2 (en) * | 2007-03-20 | 2009-12-16 | Cadila Pharmaceuticals Limited | P38 inhibitors |
US8932608B2 (en) | 2007-04-12 | 2015-01-13 | Mico Bio, Inc. | Tuberculosis vaccine and method of using same |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2170083A4 (en) * | 2007-06-28 | 2011-09-28 | Cadila Pharmaceuticals Ltd | PROTEIN KINASE ACTIVATED BY A MITOGENIC MODULATOR |
FR2979826B1 (fr) * | 2011-09-08 | 2013-12-27 | Univ Bordeaux Segalen | Composition anti-inflammatoire |
KR101696514B1 (ko) * | 2014-08-18 | 2017-01-24 | 서울대학교산학협력단 | 신규한 온도 민감성 마이코박테리아 균주 및 이를 포함하는 마이코박테리아 감염증에 대한 백신 조성물 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3567585A (en) * | 1963-07-12 | 1971-03-02 | Ciba Geigy Corp | Process for obtaining bcg-cultures |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4843842B1 (pt) * | 1970-07-17 | 1973-12-21 |
-
2003
- 2003-03-04 WO PCT/IB2003/000801 patent/WO2003075824A2/en active Application Filing
- 2003-03-04 BR BR0303367-8A patent/BR0303367A/pt not_active Application Discontinuation
- 2003-03-04 KR KR10-2003-7015465A patent/KR20050008453A/ko not_active Application Discontinuation
- 2003-03-04 AU AU2003209533A patent/AU2003209533A1/en not_active Abandoned
- 2003-03-04 JP JP2003574100A patent/JP2005519941A/ja active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3567585A (en) * | 1963-07-12 | 1971-03-02 | Ciba Geigy Corp | Process for obtaining bcg-cultures |
Non-Patent Citations (1)
Title |
---|
DATABASE WPI Week 197401, Derwent Publications Ltd., London, GB; AN 1974-01695V/01 & JP 48 043 842 B (MARUYAMA S) 21 December 1973 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2389532B (en) * | 2001-12-10 | 2004-10-27 | Bakulesh Mafatlal Khamar | The method of treating cancer |
GB2400560A (en) * | 2002-01-29 | 2004-10-20 | Rajiv Indravadan Modi | Method of providing prophylaxis for tuberculosis in hiv positive individuals |
EP2131858A2 (en) * | 2007-03-20 | 2009-12-16 | Cadila Pharmaceuticals Limited | P38 inhibitors |
EP2131858A4 (en) * | 2007-03-20 | 2011-11-23 | Cadila Pharmaceuticals Ltd | P38 INHIBITORS |
US8932608B2 (en) | 2007-04-12 | 2015-01-13 | Mico Bio, Inc. | Tuberculosis vaccine and method of using same |
US9636391B2 (en) | 2007-04-12 | 2017-05-02 | Mico Bio, Inc. | Tuberculosis vaccine and method of using same |
Also Published As
Publication number | Publication date |
---|---|
KR20050008453A (ko) | 2005-01-21 |
AU2003209533A1 (en) | 2003-09-22 |
WO2003075824A3 (en) | 2003-12-24 |
JP2005519941A (ja) | 2005-07-07 |
BR0303367A (pt) | 2004-07-20 |
AU2003209533A8 (en) | 2003-09-22 |
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