WO2003075825A2 - Procede applicable au traitement de la tuberculose - Google Patents

Procede applicable au traitement de la tuberculose Download PDF

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Publication number
WO2003075825A2
WO2003075825A2 PCT/IB2003/000802 IB0300802W WO03075825A2 WO 2003075825 A2 WO2003075825 A2 WO 2003075825A2 IB 0300802 W IB0300802 W IB 0300802W WO 03075825 A2 WO03075825 A2 WO 03075825A2
Authority
WO
WIPO (PCT)
Prior art keywords
mycobacterium
tuberculosis
treatment
pharmaceutical composition
effective
Prior art date
Application number
PCT/IB2003/000802
Other languages
English (en)
Other versions
WO2003075825A3 (fr
Inventor
Bakulesh Mafatlal Khamar
Original Assignee
Modi, Rajiv, Indravadan
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Modi, Rajiv, Indravadan filed Critical Modi, Rajiv, Indravadan
Priority to AU2003209534A priority Critical patent/AU2003209534A1/en
Priority to GB0400094A priority patent/GB2392839A/en
Priority to KR10-2003-7015464A priority patent/KR20050008452A/ko
Publication of WO2003075825A2 publication Critical patent/WO2003075825A2/fr
Publication of WO2003075825A3 publication Critical patent/WO2003075825A3/fr

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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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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

Definitions

  • the invention relates to the method of treating tuberculosis comprises use of 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 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. triviale, M. marinum, M. flavescens, M.
  • the object of the present invention is to provide the method of treating tuberculosis comprising administration of 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 the method of treating tuberculosis comprising administration of 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 the method of treating tuberculosis comprising administration of 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 the method of treating tuberculosis comprising administration of 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 the method of treating tuberculosis comprising administration of 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 the method of treating tuberculosis comprising administration of 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 the method of treating tuberculosis comprising administration of a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for use along with chemotherapeutic agents.
  • Mw Mycobacterium w'
  • Yet another object of the present invention is to provide the method of treating tuberculosis comprising administration of 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 the method of treating tuberculosis comprising administration of a pharmaceutical composition containing 'Mycobacterium w' (Mw) with or without constituents obtained from Mw for reduction in duration of treatment of tuberculosis.
  • Mw Mycobacterium w'
  • 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:
  • 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 Methanol 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 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 Sodium Chloride I. P. ... . 0.90% w/v
  • 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 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
  • 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. It is preferable to autoclave the final product.
  • 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.
  • H Preparation of constituents of Mycobacterium w.
  • the constituents of Mycobacterium w can be prepared for the purpose of invention by:
  • 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.
  • a group of patients was treated with standard chemotherapy(Rifampicin, INH, Pyrizinamide, ethambutol), the other group was given standard chemotherapy with intradermal Mycobacterium w.
  • Mycobacterium w was given at baseline, on day 15, day 30 and day 45. In all patients sputum was evaluated on day 15, day 30 and day45 and day 60. The sputum conversion was found to be enhanced by at least 30 days. Sputum conversiuon rate at day 30 in group receiving Mycobacterium w was comparable or better to the sputum conversion rate at day 60 in a group not receiving Mycobacterium w.
  • 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.
  • Mycobacterium w derived pharmaceutical composition is helpful in reducing the relapse rate considerably. This is of great significance. Since it relapses are responsible for recurrent disease, emergance of MDR TB and persistence of infection in a society.
  • 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 composition possess potent antitubercular activity and provides better results earlier.
  • 24 sputum smear positive cases of pulmonary tuberculosis with treatment failure were included in study. They were all put on category -II anti-tubercular treatment; their weight and clinical symptoms were recorded, out of these 24 patients every alternate patient at random was also given injection of Mycobacterium w intradermally over the deltoid region initially and repeated every fortnight.
  • 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)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Mycology (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Communicable Diseases (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un procédé applicable au traitement de la tuberculose et faisant intervenir une utilisation d'un micro-organisme, en l'occurrence 'Mycobactérium w', pour le traitement de la tuberculose.
PCT/IB2003/000802 2002-03-08 2003-03-04 Procede applicable au traitement de la tuberculose WO2003075825A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2003209534A AU2003209534A1 (en) 2002-03-08 2003-03-04 The method of treating tuberculosis
GB0400094A GB2392839A (en) 2002-03-08 2003-03-04 Use of Mycobacterium w in the treatment of tuberculosis
KR10-2003-7015464A KR20050008452A (ko) 2002-03-08 2003-03-04 결핵의 치료방법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN235/MUM/2002 2002-03-08
IN235MU2002 2002-03-08

Publications (2)

Publication Number Publication Date
WO2003075825A2 true WO2003075825A2 (fr) 2003-09-18
WO2003075825A3 WO2003075825A3 (fr) 2003-11-13

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PCT/IB2003/000802 WO2003075825A2 (fr) 2002-03-08 2003-03-04 Procede applicable au traitement de la tuberculose
PCT/IB2003/000827 WO2003077829A2 (fr) 2002-03-08 2003-03-06 Procede de preparation de composition pharmaceutique

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PCT/IB2003/000827 WO2003077829A2 (fr) 2002-03-08 2003-03-06 Procede de preparation de composition pharmaceutique

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KR (1) KR20050008452A (fr)
AU (2) AU2003209534A1 (fr)
GB (1) GB2392839A (fr)
WO (2) WO2003075825A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006114680A2 (fr) 2005-04-25 2006-11-02 Bakulesh Mafatlal Khamar Adjuvants de vaccins
US20100062026A1 (en) * 2006-11-23 2010-03-11 Cadila Pharmaceuticals Ltd. Poly tlr antagonist

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006111853A2 (fr) * 2005-04-18 2006-10-26 Aurobindo Pharma Limited Formes posologiques solides stables d'un medicament labile en milieu acide
WO2010122583A2 (fr) 2009-04-24 2010-10-28 Rubicon Research Private Limited Compositions pharmaceutiques orales comprenant des substances labiles en milieu acide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985003639A1 (fr) * 1984-02-17 1985-08-29 University College London Preparations biologiques et leur utilisation
GB2236480A (en) * 1989-08-09 1991-04-10 Nat Inst Immunology Tuberculosis vaccine
WO1994006466A1 (fr) * 1992-09-14 1994-03-31 University College London Agent therapeutique obtenu a partir de mycobacterium vaccae et son utilisation pour lutter contre l'infection hiv

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GB2189698A (en) * 1986-04-30 1987-11-04 Haessle Ab Coated omeprazole tablets
US5232706A (en) * 1990-12-31 1993-08-03 Esteve Quimica, S.A. Oral pharmaceutical preparation containing omeprazol
SE9302395D0 (sv) * 1993-07-09 1993-07-09 Ab Astra New pharmaceutical formulation
WO2003063896A1 (fr) * 2002-01-29 2003-08-07 Modi, Rajiv, Indravadan Procede de preparation d'une composition pharmaceutique pour conferer l'immunite contre la tuberculose a des individus hiv-positifs
BR0307262A (pt) * 2002-01-29 2006-12-19 Bakulesh Mafatlal Khamar método de prover profilaxia para tuberculose em indivìduos hiv positivos

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985003639A1 (fr) * 1984-02-17 1985-08-29 University College London Preparations biologiques et leur utilisation
GB2236480A (en) * 1989-08-09 1991-04-10 Nat Inst Immunology Tuberculosis vaccine
WO1994006466A1 (fr) * 1992-09-14 1994-03-31 University College London Agent therapeutique obtenu a partir de mycobacterium vaccae et son utilisation pour lutter contre l'infection hiv

Non-Patent Citations (1)

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Title
SINGH I.G. ET AL.: 'In vitro characterization of T cells from mycobacterium w-vaccinated mice' INFECTION AND IMMUNITY vol. 60, no. 1, January 1992, pages 257 - 263 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006114680A2 (fr) 2005-04-25 2006-11-02 Bakulesh Mafatlal Khamar Adjuvants de vaccins
WO2006114680A3 (fr) * 2005-04-25 2007-08-23 Bakulesh Mafatlal Khamar Adjuvants de vaccins
GB2442408A (en) * 2005-04-25 2008-04-02 Cadila Pharmaceuticals Ltd Vaccine adjuvants
GB2442408B (en) * 2005-04-25 2010-06-30 Cadila Pharmaceuticals Ltd Mycobacterium W as an adjuvant
US8048434B2 (en) * 2005-04-25 2011-11-01 Cadila Pharmaceuticals, Ltd. Vaccine adjuvants
US8277778B2 (en) 2005-04-25 2012-10-02 Cadila Pharmaceuticals Ltd. Vaccine adjuvants
AU2006238906B2 (en) * 2005-04-25 2013-04-11 Cadila Pharmaceuticals Ltd. Vaccine adjuvants
AP2695A (en) * 2005-04-25 2013-07-16 Cadila Pharmaceuticals Ltd Vaccine adjuvants
US20100062026A1 (en) * 2006-11-23 2010-03-11 Cadila Pharmaceuticals Ltd. Poly tlr antagonist
US8333978B2 (en) * 2006-11-23 2012-12-18 Cadila Pharmaceuticals Poly TLR antagonist

Also Published As

Publication number Publication date
WO2003075825A3 (fr) 2003-11-13
WO2003077829A3 (fr) 2003-12-04
WO2003077829A2 (fr) 2003-09-25
AU2003209534A1 (en) 2003-09-22
GB2392839A8 (en) 2004-11-18
AU2003209534A8 (en) 2003-09-22
AU2003208505A1 (en) 2003-09-29
GB2392839A (en) 2004-03-17
GB0400094D0 (en) 2004-02-04
AU2003208505A8 (en) 2003-09-29
KR20050008452A (ko) 2005-01-21

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