WO2005042013A1 - Agente immunoterápico útil para el tratamento combinado de la tuberculosis en associación con otros fármacos - Google Patents
Agente immunoterápico útil para el tratamento combinado de la tuberculosis en associación con otros fármacos Download PDFInfo
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- WO2005042013A1 WO2005042013A1 PCT/ES2004/000482 ES2004000482W WO2005042013A1 WO 2005042013 A1 WO2005042013 A1 WO 2005042013A1 ES 2004000482 W ES2004000482 W ES 2004000482W WO 2005042013 A1 WO2005042013 A1 WO 2005042013A1
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- Prior art keywords
- immunotherapeutic agent
- treatment
- tuberculosis
- weeks
- drugs
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
- A61K2039/541—Mucosal route
- A61K2039/543—Mucosal route intranasal
-
- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
Definitions
- the present invention relates to a method for preparing an immunotherapeutic agent useful for the combined treatment of tuberculosis in association with other drugs, based on cell wall fragments of a virulent strain of Mycobacterium tuberculosis-complex, and in the immunotherapeutic agent obtainable by said procedure.
- Tuberculosis is a chronic infectious disease caused by the bacilli Mycobacterium tuberculosis-comp ex. (MTB-C), which currently include the species M. tuberculosis, M. bovis, M. microti and M. africanum.
- MTB-C Mycobacterium tuberculosis-comp ex.
- BCG Bacillus Calmette-
- Said type of prolonged treatment could favor the development of microorganisms resistant to said drugs in the case of not performing the treatment until the end and, in addition, the said drugs act only at the moment when the bacillus has an active metabolism, that is when It is in the growth phase, but not when it is in a non-active phase.
- An attempt to solve the problems raised, as described in US4724144, is the use of an immunotherapeutic agent based on dead cells. of M.vaccae as an adjunct to the treatment of tuberculosis together with the administration of other drugs, for example, rifampicin and isoniazid.
- the authors of the present invention have discovered a method that allows preparing a new immunotherapeutic agent useful for the combined treatment of tuberculosis in association with other drugs, comprising cell wall fragments of a virulent strain of MTB-C, capable of increasing the efficacy of the associated drugs by generating an effective immune response against bacilli that are not in the active metabolism phase, which also reduces the risk of resistance.
- the object of the present invention is a method for obtaining an immunotherapeutic agent comprising cell wall fragments of a virulent strain of MTB-C, which is useful in the combined treatment of tuberculosis in association with other drugs. Also part of the object of the present invention are the immunotherapeutic agent obtainable according to the above procedure and the use thereof for the preparation of a medicament for the combined treatment of tuberculosis in association with other drugs. Another additional object is the pharmaceutical compositions containing said immunotherapeutic agent.
- an immunotherapeutic agent comprising cell wall fragments of a virulent strain of Mycobacterium tuberculosis-corc ⁇ lex (MTB-C), said method characterized in that it comprises the following stages: - the culture of the virulent strain MTB-C for a period of time equal to or greater than three weeks and, subsequently, - the homogenization of cell culture in the presence of a non-ionic surfactant.
- the virulent strain can be any virulent strain of MTB-C, since the bacillus of tuberculosis is very stable and the appearance of mutations in immunogenic compounds has not been described.
- H37Rv One of the strains most used by researchers in this field, considered as a virulent reference strain, is called H37Rv which, for example, can be freely acquired in the National Collection of Type Cultures (NCTC), London, Great Britain (number of deposit NC007416).
- the virulent strain can be grown by inoculation in culture media well known to the person skilled in the art. It may be a solid medium, such as Middlebrook type 7H10 or type 7H11 agar, or a liquid medium, for example Sauton culture medium or Proskauer-Beck culture medium.
- the culture should be carried out for a period of time equal to or greater than three weeks, preferably between 3 and 4 weeks.
- the temperature of the culture is preferably maintained between 34 ° C and 38 ° C.
- the plates are scratched to obtain the colonies, avoiding the extraction of medium (agar) at the same time.
- the culture has been carried out in the liquid phase, the cells are concentrated and washed using conventional techniques known to those skilled in the art, such as centrifugation.
- the homogenization of the cells is carried out in a buffer medium at a neutral pH, it being important for the purposes of the present invention that said homogenization be carried out in the presence of a non-ionic surfactant that favors obtaining finely divided cell wall particles and emulsifies, at least in part, unwanted lipid fractions.
- Homogenization can be carried out by sonication by ultrasound, or by using small balls of approximately 1 mm in diameter, for example, of silica or silica-zirconium, together with a mechanical homogenizer.
- a mechanical homogenizer that can be used, for example, is the BEADBEATER model of Biospec.
- the buffered medium is constituted, for example, by PBS buffer (phosphate buffer saline).
- the type of nonionic surfactant used is not critical, although it is preferably selected from the group of ethoxylated alkylphenols and ethoxylated sorbitan esters.
- the nonionic surfactant is selected from the ethoxylated octylphenols. More preferably, ethoxylated octylphenols with 7-8 moles of ethylene oxide are used, which are commercially available under the name of, for example, TRITON X-114.
- the non-ionic surfactant content in the homogenization stage is between 1 and 5% by weight with respect to the total homogenate.
- the homogenized mass which already contains the desired cell wall fragments, is subjected to a conventional treatment in order to separate said fragments from the non-fragmented cells and the solubilized components.
- the product resulting from the homogenization is gently centrifuged at a speed of less than 5,000 rpm to remove the non-fragmented cells as sediment.
- the resulting supernatant is centrifuged at a higher centrifugation rate, for example greater than 15,000 rpm, to remove the solubilized elements, which are concentrated in the supernatant liquid, while the cell wall fragments are concentrated in the sediment.
- a higher centrifugation rate for example greater than 15,000 rpm
- the sediment obtained which contains the cell wall fragments, is dispersed in PBS buffer and is subjected to a chemical process, for example by treatment with formalin, or physical, for example by autoclaving or pasteurization treatment, which ensures total inactivation of MTB-C cells that could have remained viable after the fragmentation and purification process.
- a chemical process for example by treatment with formalin, or physical, for example by autoclaving or pasteurization treatment, which ensures total inactivation of MTB-C cells that could have remained viable after the fragmentation and purification process.
- the dispersion of cell wall fragments in PBS buffer is distributed in vials and lyophilized at a temperature between -15 ° C and -25 ° C and with a vacuum between 0.1 and 0.5 mbar.
- Vials containing MTB-C cell wall fragments that constitute the immunotherapeutic agent of the invention are obtained and stored at -70 ° C.
- compositions can also be prepared from the immunotherapeutic agent of the invention, also object of the invention, which can be formulated in the form of an oil-in-water (O / W) emulsion or in the form of liposomes.
- Pharmaceutical compositions in the form of liposomes are preferred.
- Liposome formation can be performed using conventional techniques, well known to the expert. For example, liposomes can be formed by mixing lyophilized cell wall fragments and auxiliary lipids for the formation of liposomes in an aqueous medium, and subjecting the mixture to a standard homogenization procedure, for example, by using a high stirrer. speed. Auxiliary lipids for manufacturing liposomes are widely known to those skilled in the art.
- phospholipids with neutral and / or negative net charge, and sterols are included.
- the phospholipids used can be, for example: phosphatidylcholine, phosphatidylserine and phosphatidylinositol.
- the major component of liposomes is phosphatidylcholine, which can be synthesized or isolated from natural sources.
- a frequently used commercial product is soy lecithin.
- the sterols used in the preparation of liposomes can be, among others, cholesterol and bile salts.
- liposomes are formed using a mixture of soy lecithin and sodium cholate.
- liposomes may contain additives that improve their stability, for example: vitamin E, which acts as an antioxidant for lipids.
- the liposomes obtained have a size distribution in which 99.9% are smaller than 1 meter.
- the liposomes can be subjected to lyophilization to thereby obtain the immunotherapeutic agent object of the invention in the form of lyophilized liposomes.
- the use of the immunotherapeutic agent for the preparation of a medicament for the combined treatment of tuberculosis in association with other drugs is also part of the object of the invention.
- the immunotherapeutic agent object of the invention is administered parenterally.
- isoniazid and rifampicin are preferred for the combined treatment with the therapeutic agent of the invention.
- the association of the immunotherapeutic agent of the invention with the antituberculosis drugs for the combined treatment of the disease can be carried out simultaneously or sequentially, that is to say by simultaneously administering the drugs and the immunotherapeutic agent, or by prior administration. of the drugs followed by the administration of the immunotherapeutic agent.
- Example 1 - - Obtaining the immunotherapeutic agent About 80-100 Middlebrook agar plates of type 7H11 are inoculated with an H37Rv culture supplied by the National Collection of Type Cultures (NCTC), London, Great Britain (deposit number NC007416).
- the concentration of colony forming units inoculated on each plate is 10 5 -10 6 CFU.
- the plates are incubated for 21 days (3 weeks) at a temperature between 34 ° C and 38 ° C. After the incubation period, the colonies of the agar plates are removed using a spatula, being careful not to remove medium of cultivation Between 15 and 18 g of crude extract are obtained.
- the crude extract is dispersed in approximately 20 mL of PBS buffer containing 4% by weight of TRITON X-114. About 35 mL of 1mm diameter silica-zirconium balls are added and mechanical homogenization is carried out with the BEADBEATER homogenizer, from Biospec.
- the homogenization process is continued until the staining of a sample with the Ziehl-Neelsen technique detects less than 5 whole bacilli after observing 100 fields at 1000 magnifications.
- the product resulting from the homogenization is separated from the silica-zirconium balls by decantation. These are washed with the PBS buffer solution containing 4% by weight of TRITON X-114, and the wash waters are combined with the product, obtaining a total volume of about 80-100 mL.
- the product resulting from the homogenization plus the wash waters is centrifuged at 3,000 rpm for 30 minutes in a centrifuge refrigerated at 4 ° C, to remove the non-fragmented cells in the sediment.
- the supernatant is preserved. Then, said supernatant is centrifuged at 15,100 rpm (equivalent to 27,000 g) for 60 minutes at 4 ° C, obtaining an off-white sediment, containing the cell wall fragments. The sediment is preserved, and the yellowish supernatant is removed. The sediment is first washed with PBS buffer (3 x 3 mL), redispersed in 3 mL of said buffer solution, flush to 20 mL with PBS buffer and centrifuged again at 15,100 rpm for 60 minutes at 4 ° C. reject the supernatant obtained. The washing and centrifuging operation is repeated again, so that the supernatant obtained is completely transparent and rejected.
- PBS buffer 3 x 3 mL
- the sediment which contains the cell wall fragments, is washed with PBS buffer (3x3 mL) and redispersed in 12 mL of PBS buffer. After the centrifugation and washing process, the dispersion of the cell wall fragments in PBS buffer in a container is combined and pasteurized by treatment at 65 ° C for 1 hour. The mixture is then cooled rapidly in an ice bath, and the dispersion of cell wall fragments in cryotubes is distributed at a rate of 1 mL per cryotube.
- the dispersion of cell wall fragments contained in the cryotubes is frozen at -70 ° C and subjected to a lyophilization process at a temperature between -15 and -22 ° C and at a vacuum between 0.188 and 0.400 mbar. Between 1 and 1.5 g of immunotherapeutic agent are obtained.
- Example 2 Obtaining liposomes of the immunotherapeutic agent Weigh between 740 and 770 mg of the product obtained in Example 1 in a beaker to which 20 mL of a pharmaceutical grade soy lecithin dispersion in ethanol (1 kg) is added of lecithin in 1 liter of absolute ethanol), and 7 mL of a solution of pharmaceutical grade sodium coolant in water (200 g of sodium cholate in 1 liter of double distilled water). The pH is adjusted to a value between 7.7 and 8 with a solution of HC1 0.997 N.
- the liposomes are prepared by homogenization with a high speed stirrer.
- the liposome dispersion thus obtained is diluted to 10% with double-distilled water and the pH is adjusted to a value between 7.1 and 7.3 with a solution of HC1 0.0997 N.
- the liposome dispersion in cryotubes is distributed to 0.5 mL per tube and frozen at -80 ° C.
- the immunotherapeutic agent, object of the invention is obtained in the form of liposomes.
- Example 3. Effectiveness of the immunotherapeutic agent as an adjuvant to drug treatment
- Female mice 6 to 8 weeks of age of the BALB / c, 129 / Sv, C57BL / 6 and DBA / 2 types are used. of specific pathogens.
- a virulent strain of Mycobacterium tuberculosis is grown in medium
- Proskauer-Beck until a logarithmic middle phase, and is stored in 1 mL aliquots at -70 ° C until use.
- Mice are infected by aerosol by placing them in a Middelbrook aerosol infection apparatus that provides an approximate inoculum of 10-50 viable bacilli in the lungs.
- Bacillary concentration that is, the number of viable bacilli, is determined by incubating serial dilutions of homogenates of the left lung and spleen in Middelbrook 7H11 agar. Homogenization of the left lung and spleen are carried out in the presence of 1 mL of PBS buffer.
- the dose of the liposome immunotherapeutic agent, object of the invention was administered at week 13.
- the animals were sacrificed and the conce Bacillary injections in the left lung and in the spleen.
- Bacillary concentrations, determined according to the method described in the introduction to section C, were significantly lower in the lungs of vaccinated animals, while in the spleen, the results compared to the Control group were not statistically different.
- the results, expressed in CFU / mL, are shown in Table 1: Table 1
- mice treated intranasally and intraperitoneally with the liposome immunogenic agent, object of the invention, simultaneously with the treatment with isoniazid have a bacillus number in the lungs considerably lower than in mice that have only been treated with the isoniazid antibiotic.
- the number of bacilli determined includes those in the active phase and those in the non-active phase
- treatment with the liposome immunogenic agent would allow a reduction in the time of treatment with the antibiotic, since it is reduced considerably the number of bacilli that can pass into an active phase over time.
- mice treated subcutaneously with the liposome immunogenic agent, object of the invention after a treatment with the antibiotics isoniazid and rifampicin, have a bacillus number in the lungs considerably lower than in mice that have only been treated with antibiotics
- the same conclusion in section I) can be applied in this case.
- mice treated with a single dose of the liposome immunogenic agent intranasally, simultaneously with a treatment with the isoniazid antibiotic have a significantly lower number of bacilli in the lungs than mice that have only been treated with the antibiotic. .
- the same conclusion in section I) can be applied in this case.
- the bacillary concentration was significantly lower in the vaccinated animals after the administration of the 3 doses (corresponding to week 28), compared to the Control group.
- Table 4 Table 4
- mice treated intranasally with three doses of the liposome immunogenic agent, object of the invention, simultaneously with a treatment with the isoniazid antibiotic have a bacillus number in the lungs considerably lower than in mice that have only been treated with the antibiotic.
- the same conclusion in section I) can be applied in this case.
- infected mice were maintained without any treatment.
- infected mice were treated only with the isoniazid antibiotic at a rate of 25 mg / kg and day for 5 days a week for 4 weeks and rifampicin at a rate of 10 mg / kg and day for 5 days a week for 4 weeks, from week 9 after infection.
- infected mice were only treated with three 180 ⁇ g doses of liposome immunotherapeutic agent administered subcutaneously at weeks 9, 11 and 15 after infection.
- treatment with the isoniazid antibiotic started at week 9 and lasted for 4 weeks.
- treatment with rifampin was started, which ended at week 17.
- three doses of liposome immunotherapeutic agent were administered, object of the invention.
- all animals were sacrificed and bacillary concentrations in the left lung were determined. The results obtained for the lung, are expressed in log 10 CFU / mL, are shown in Table 6: Table 6
- the combined treatment of the antibiotics isoniazid and rifampicin with the liposome immunotherapeutic agent, object of the invention leads to a considerably greater reduction in the number of bacilli than the use of any of the two factors (antibiotics and liposome immunotherapeutic agent) by themselves.
- the number of bacilli determined includes those in the active phase and those in the non-active phase
- the combined treatment of the liposome immunogenic agent in association with other drugs would allow a reduction in the treatment time with said drugs , since the number of bacilli that can pass into an active phase over time is considerably reduced.
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Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/577,840 US8246944B2 (en) | 2003-10-31 | 2004-10-29 | Immunotherapeutic agent for the combined treatment of tuberculosis in association with other drugs |
KR1020067008014A KR101146469B1 (ko) | 2003-10-31 | 2004-10-29 | 다른 약물과 공동으로 결핵의 복합 치료에 유용한면역치료제 |
JP2006537326A JP4998988B2 (ja) | 2003-10-31 | 2004-10-29 | 他の抗結核薬と組み合わせて使用する結核治療に有効な免疫療法治療剤 |
NZ546715A NZ546715A (en) | 2003-10-31 | 2004-10-29 | Useful immunotherapeutic agent for the combined treatment of tuberculosis in association with other drugs. |
BRPI0415695A BRPI0415695B8 (pt) | 2003-10-31 | 2004-10-29 | agente imunoterápico útil para o tratamento combinado de tuberculose em associação com outras drogas |
AU2004285305A AU2004285305B2 (en) | 2003-10-31 | 2004-10-29 | Useful immunotherapeutic agent for the combined treatment of tuberculosis in association with other drugs, method of obtention and pharmaceutical compositions |
AT04791401T ATE428442T1 (de) | 2003-10-31 | 2004-10-29 | Immuntherapeutikum für die kombinierte behandlung von tuberkulose mit anderen pharmazeutika |
DK04791401T DK1690549T3 (da) | 2003-10-31 | 2004-10-29 | Immunoterapeutisk middel, som anvendes til den kombinerede behandling af tuberkulose sammen med andre lægemidler |
DE602004020663T DE602004020663D1 (de) | 2003-10-31 | 2004-10-29 | Immuntherapeutikum für die kombinierte behandlung von tuberkulose mit anderen pharmazeutika |
PL04791401T PL1690549T3 (pl) | 2003-10-31 | 2004-10-29 | Środek immunoterapeutyczny do stosowania w połączeniu z innymi lekami do skojarzonego leczenia gruźlicy |
EP04791401A EP1690549B1 (en) | 2003-10-31 | 2004-10-29 | Immunotherapic agent which is used for the combined treatment of tuberculosis together with other pharmaceuticals |
CA2543659A CA2543659C (en) | 2003-10-31 | 2004-10-29 | Useful immunotherapeutic agent for the combined treatment of tuberculosis in association with other drugs |
IL175030A IL175030A (en) | 2003-10-31 | 2006-04-20 | A storage agent used in combination with tuberculosis and other drugs |
HK07104774.7A HK1098362A1 (en) | 2003-10-31 | 2007-05-04 | Immunotherapic agent which is used for the combined treatment of tuberculosis togetheir with other pharmaceuticals |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200302551A ES2231037B1 (es) | 2003-10-31 | 2003-10-31 | Agente inmunoterapico util para el tratamiento combinado de la tuberculosis en asociacion con otros farmacos. |
ESP200302551 | 2003-10-31 |
Publications (1)
Publication Number | Publication Date |
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WO2005042013A1 true WO2005042013A1 (es) | 2005-05-12 |
Family
ID=34530979
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/ES2004/000482 WO2005042013A1 (es) | 2003-10-31 | 2004-10-29 | Agente immunoterápico útil para el tratamento combinado de la tuberculosis en associación con otros fármacos |
Country Status (21)
Country | Link |
---|---|
US (1) | US8246944B2 (es) |
EP (1) | EP1690549B1 (es) |
JP (1) | JP4998988B2 (es) |
KR (1) | KR101146469B1 (es) |
CN (1) | CN100490894C (es) |
AT (1) | ATE428442T1 (es) |
AU (1) | AU2004285305B2 (es) |
BR (1) | BRPI0415695B8 (es) |
CA (1) | CA2543659C (es) |
DE (1) | DE602004020663D1 (es) |
DK (1) | DK1690549T3 (es) |
ES (2) | ES2231037B1 (es) |
HK (1) | HK1098362A1 (es) |
IL (1) | IL175030A (es) |
MA (1) | MA28121A1 (es) |
NZ (1) | NZ546715A (es) |
PL (1) | PL1690549T3 (es) |
PT (1) | PT1690549E (es) |
RU (1) | RU2341287C2 (es) |
WO (1) | WO2005042013A1 (es) |
ZA (1) | ZA200604234B (es) |
Cited By (3)
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---|---|---|---|---|
EP2027865A1 (en) * | 2006-05-12 | 2009-02-25 | National University Corporation Hokkaido University | Liposome having lipid membrane containing bacterial cell component |
JP2010508254A (ja) * | 2006-10-30 | 2010-03-18 | アーチバル ファルマ、エスエル. | 結核の予防ワクチン |
ES2335177A1 (es) * | 2008-09-19 | 2010-03-22 | Archivel Farma, S.L. | Agente inmunoterapeutico apropiado para la profilaxis primaria de la tuberculosis. |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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ES2231037B1 (es) | 2003-10-31 | 2005-12-16 | Archivel Technologies, Sl | Agente inmunoterapico util para el tratamiento combinado de la tuberculosis en asociacion con otros farmacos. |
EP2471511A1 (en) | 2011-01-04 | 2012-07-04 | Archivel Farma, SL | Liposome formulation suitable for treating or preventing tuberculosis |
WO2012093137A1 (en) * | 2011-01-04 | 2012-07-12 | Archivel Farma, Sl | Liposome formulation suitable for treating or preventing tuberculosis |
EP2802345B1 (en) | 2012-01-12 | 2018-03-07 | Archivel Farma, S.l. | Mtb-c vaccine against allergic responses |
ES2758400B2 (es) | 2018-11-02 | 2021-01-20 | Univ Granada | Nanoparticulas biomimeticas mediadas por mamc |
WO2023062066A1 (en) | 2021-10-14 | 2023-04-20 | Archivel Farma, S.L. | Liposome formulations for treatment of active tuberculosis |
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- 2004-10-29 BR BRPI0415695A patent/BRPI0415695B8/pt active IP Right Grant
- 2004-10-29 JP JP2006537326A patent/JP4998988B2/ja not_active Expired - Fee Related
- 2004-10-29 WO PCT/ES2004/000482 patent/WO2005042013A1/es active Application Filing
- 2004-10-29 CN CNB2004800322762A patent/CN100490894C/zh active Active
- 2004-10-29 DK DK04791401T patent/DK1690549T3/da active
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- 2004-10-29 KR KR1020067008014A patent/KR101146469B1/ko active IP Right Grant
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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EP2027865A1 (en) * | 2006-05-12 | 2009-02-25 | National University Corporation Hokkaido University | Liposome having lipid membrane containing bacterial cell component |
JPWO2007132790A1 (ja) * | 2006-05-12 | 2009-09-24 | 国立大学法人 北海道大学 | 細菌菌体成分を含む脂質膜を有するリポソーム |
EP2027865A4 (en) * | 2006-05-12 | 2010-08-18 | Univ Hokkaido Nat Univ Corp | LIPOSOME HAVING A LIPIDIC MEMBRANE CONTAINING A BACTERIAL CELLULAR COMPONENT |
JP2010508254A (ja) * | 2006-10-30 | 2010-03-18 | アーチバル ファルマ、エスエル. | 結核の予防ワクチン |
US9289483B2 (en) * | 2006-10-30 | 2016-03-22 | Archivel Farma, S.L. | Prophylactic tuberculosis vaccine |
ES2335177A1 (es) * | 2008-09-19 | 2010-03-22 | Archivel Farma, S.L. | Agente inmunoterapeutico apropiado para la profilaxis primaria de la tuberculosis. |
WO2010031883A1 (es) * | 2008-09-19 | 2010-03-25 | Archivel Farma, S.L. | Agente inmunoterapéutico apropiado para la profilaxis primaria de la tuberculosis |
US8795719B2 (en) | 2008-09-19 | 2014-08-05 | Archivel Farma, S.L. | Immunotherapeutic agent suitable for the primary prophylaxis of tuberculosis |
RU2544125C2 (ru) * | 2008-09-19 | 2015-03-10 | Арчивель Фарма, С.Л. | Иммунотерапевтическое средство, предназначенное для первичной профилактики туберкулеза |
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