WO2004037275A1 - Conjugues d'acide biliaire et particules formees a l'aide de ces conjugues - Google Patents

Conjugues d'acide biliaire et particules formees a l'aide de ces conjugues Download PDF

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Publication number
WO2004037275A1
WO2004037275A1 PCT/EP2003/010580 EP0310580W WO2004037275A1 WO 2004037275 A1 WO2004037275 A1 WO 2004037275A1 EP 0310580 W EP0310580 W EP 0310580W WO 2004037275 A1 WO2004037275 A1 WO 2004037275A1
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Prior art keywords
conjugate
liposomes
structural unit
particles
particle
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PCT/EP2003/010580
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German (de)
English (en)
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Gerhard PÜTZ
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Wieland, Heinrich
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Priority to AU2003275978A priority Critical patent/AU2003275978A1/en
Publication of WO2004037275A1 publication Critical patent/WO2004037275A1/fr

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    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6911—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome

Definitions

  • the present invention relates to conjugates containing a bile acid or bile acid salt component.
  • the invention further relates to particles, in particular liposomes or similar vesicular particles, which comprise such conjugates or which are formed, inter alia, with these conjugates.
  • Such conjugates and particles which comprise or contain the conjugates are particularly well suited for therapeutic applications, in particular for target-specific and especially liver-specific therapy.
  • target- or cell type-specific liposomes have been constructed in which an internalizing receptor serves as a cellular target protein for the binding of the liposomes on the cell surface.
  • This approach enables the liposomes bound in this way to enter the cell via receptor-mediated endocytosis.
  • Geho et. al. in US Pat. No. 4,603,044 describe such a targeted drug delivery system (trageted drug delivery) which is to be bound to hepatobiliary receptors.
  • a vesicle is linked to a conjugate consisting of a connector molecule, a bridge molecule and a target molecule.
  • the target molecule is said to have an intended receptor molecule Hepatocytes interact.
  • An iminodicarboxyl acid residue as a connector molecule, a “bridging ion”, especially a chromium complex as a bridge molecule, and a target molecule that is identical to the connector molecule are proposed for the structure, wherein other target molecules for binding to the desired receptor are also conceivable.
  • the object of the present invention is to provide an improved system for targeted therapy.
  • the conjugate according to the invention has the following components:
  • the conjugate consequently has the structure (a) - (b), with this the preferred structure (a) - (c) - (b).
  • a conjugate with components (a) and (b) and optionally (c) is capable of hepatocyte-specific proteins transporting bile salt, such as Na +, which mainly transports cholyltaurine (CT) / Cholyltaurine co-transporting polypeptide (Ntcp) and various organic anion transporting polypeptides (Oatp 1-x), which was confirmed by inhibition of bile acid transport by the special conjugate according to the invention.
  • FIG. 1 shows an example of a conjugate according to an embodiment of the invention, in which a lipid structural unit is linked via a linker structural unit to a structural unit of a bile acid salt;
  • FIG. 2A schematically shows the possible structure of a bile salt-bearing liposome according to an embodiment of the invention
  • FIG. 2B shows an enlarged detail in area X of FIG. 2A
  • FIG. 3 shows the inhibition of the uptake of natural bile salts in hepatocytes by particles carrying bile salts using the example of liposomes.
  • FIG. 4 shows a typical organ distribution when using particles carrying the conjugate according to the invention using the example of liposomes in comparison to liposomes without the conjugate; 5A to C show the binding of the inventive contact jugate-bearing particles using the example of liposomes, in which a fluorescent model substance had been incorporated, on hepatocyte primary cultures, and FIG. 5D shows a comparison with liposomes without the conjugate, in each case as a fluorescence-microscopic image of the hepatocytes.
  • lipid of the structural unit (a) of the conjugate means any fat molecule or a fat-like substance which is preferably found in natural cells. With lipid structure units occurring in natural cells, immunological defense reactions can advantageously be suppressed better. Phospholipids, especially phosphoglycerides, are particularly advantageous. A phospho-diester linkage can conveniently be used for the covalent connection to the structural unit (b) or - in the preferred case the intermediate linker - (c). The use of phosphoglycerides as a lipid structural unit in the conjugate is very advantageous, since when the particles described in more detail below, in particular with liposomes, are built up, the conjugate is stably anchored via a phosphoglyceride with long-chain acyl residues.
  • the lipid structural unit (a) is preferably constructed as a diacyl phosphoglyceride, where the acyl residue can be, for example, a saturated fatty acid residue such as lauryl, myristyl, palmitinyl, stearinyl, arachinyl or an unsaturated fatty acid residue such as palmitoleyl, oleyl, linolyl, lindenyl and arachidonyl.
  • C12 to C18 acyl residues in particular C16 to C18 acyl residues, are particularly suitable.
  • the acyl radicals can be selected independently of one another.
  • a bile acid or a bile acid salt serves as the structural unit (b), the salt form being, for example, the Na, the K, the ammonium salt, the salt of an amino acid or an organic amine or the like. Unless otherwise stated, the terms bile acid and bile acid salt are used synonymously below.
  • the structural unit (b) has the steroid characteristic of bile acid Basic structure, for example in the form of a 5 ⁇ -cholanic acid derivative.
  • the cholanic acid derivative is preferably modified on the 24C carboxylate with nitrogen-containing bases such as glycine or taurine.
  • Modification with taurine is particularly advantageous because the -S0 3 H group forms a permanently charged sulfate group at the end of the bile salt opposite the lipid structure unit after dissociation and thereby an undesired insertion of the hydrophobic cholane framework area into a particle, especially into a liposome membrane - bran, difficult or prevented. Moreover, the non-hepatocyte-specific insertion of the hydrophobic framework region into the membranes of cells can be made more difficult or prevented by the negative charge.
  • a functional group in the 24C radical and one or more hydroxyl groups in the 3-, 7- or 12-position of the cholane skeleton can be considered for linking the structural units (a) and (b).
  • a suitable functionalization can also be introduced at other points for linking.
  • the linkage is therefore preferably via the 3-hydroxy position of the steroid structure of bile acid.
  • the 7- and 12-positions of the steroid skeleton of bile acid may or may not be hydroxylated, or they may be modified by other structural units.
  • Particularly suitable bile acids are taurocholic acid and especially lithotaurocholic acid and their salts.
  • the structural unit (b) can be directly covalently linked to the structural unit (a) may be connected, for example via an ester linkage such as a phosphorus diester linkage with the phosphoglyceride described above.
  • an ester linkage such as a phosphorus diester linkage with the phosphoglyceride described above.
  • linker structural unit (c) between the structural units (a) and (b). This linker molecule can itself consist of one or more structural units.
  • Suitable structural units are, for example, alone or in combination, a polyalkylene glycol group with n polarization units, where n is an integer such as di-, tri- or tetramethylene glycol or polyethylene glycol, a dicarboxylate group such as succinyl and the like.
  • FIG. 1 A specific example of a conjugate according to the invention is shown in FIG. 1 in the form of a schematic structure.
  • the respective structural units (a) - (c) - (b) are indicated.
  • the structural representation only serves to illustrate a possible structure, but is not to be understood as restrictive, since according to the invention any variations are possible within the scope of the respective structural unit (a), (b) and, if appropriate, (c).
  • a particle comprises the special conjugate described above.
  • Suitable particles are microparticulate carriers or transport vehicles of suitable size, which are preferably designed such that therapeutic agents are bound or included on and / or in the particle.
  • the particle can be of natural or artificial origin or an artificial modification of natural vehicles.
  • the functional component (b) is easily integrated into the hydrophobic areas of the particle via the lipid component (a) and anchored there in a stable manner.
  • the particle composition suitably contains 0.1-50% by weight, preferably 0.5-5% by weight and in particular 0.75-2% by weight, based on the total amount of the particle components, e.g. the liposome mixture, the conjugate according to the invention.
  • Particularly preferred particle carriers for the conjugate according to the invention are liposomes.
  • the lipid-containing conjugate of the invention in particular in combination with the preferred diacylphosphoglycerides described above, a particularly stable anchoring of the functional component (b) to the liposomes is possible.
  • the production of such liposome particles is particularly simple since the conjugate according to the invention can easily be used as a starting material and only needs to be mixed with other lipid components suitable for liposomes, such as normal phosphoglycerides, cholesterol, lecithin or the like.
  • the liposome mixture in addition to the conjugate according to the invention, which is suitably used in a proportion of 0.1 to 50 mol%, preferably 0.5 to 5 mol%, can contain up to 99.9 mol% of normal phospholipids and if desired, contain 0.1 to 80 mol% of cholesterol and optionally further constituents.
  • Suitable normal phospholipids can be selected from the following group: Phospholipids with long-chain saturated fatty acid residues of C16 and above, in particular C16-C18 such as DPPC and DSPC, preferably in a proportion of 20 to 40 mol%, or of long-chain unsaturated fatty acid residues such as POPC and DNPC, preferably in a proportion of 10 to 30 mol%, since these favor the storage of the liposomes at 4 ° C without transition into the liquid crystalline phase; and phospholipids with medium saturated chain lengths (C8-C14) such as DMPC, preferably in a proportion of 20 to 40 mol%, or with medium unsaturated chain lengths such as D yPC, preferably in a proportion of 20 to 90 mol% and in particular from 40 to 80 mol% because these favor a fusion with cell membranes.
  • C16-C18 such as DPPC and DSPC
  • POPC and DNPC long-chain unsaturated fatty acid residues
  • the liposome mixture preferably contains from 10 to 90 mol%, more preferably from 20 to 60 mol%, of cholesterol. While the main components of the liposome mixture are neutral in total, such as the uncharged cholesterol or the zwitterionic diacylphosphocholine, one or more negatively charged phospholipids can additionally be added to the liposome mixture.
  • the structural unit (b) of the conjugate contained in the liposome can protrude outwards and bind better to a transport protein.
  • a negative total charge of the liposome also leads to a slower opsonization in vivo and thus to an increased length of time of the liposomes in the blood.
  • Suitable negatively charged lipids are, for example, phosphatidylglycerol, DSPG, DMPG and glutyryl-DSPG, since it ensures a particularly long half-life of the liposomes in the blood.
  • the negatively charged lipid component of the liposomes can preferably be present in a proportion of 1 to 50 mol%, more preferably 4 to 15 Mol% are added.
  • FIG. 2A shows a schematic representation of the possible structure of a liposome carrying bile salt
  • FIG. 2B shows section X of FIG. 2A enlarged.
  • the hydrophilic residues in the bile salt structural unit (b) of the conjugate according to the invention (3-litho-cholyltaurine-distearoyl-phosphoethanolamine) point, for example, inwards and outwards of the double-walled liposome membrane, while the lipid structural unit (a) of the conjugate is stable in the liposomes - membrane is integrated and thus anchored.
  • the bile salt structural unit (b) points essentially outwards.
  • the size of the particle according to the invention can generally be in the nanometer range up to the micrometer range.
  • the average particle size is suitably in the range from 10 nm to 10 ⁇ m, more preferably from 40 to 200 nm and in particular from 100 to 150 nm.
  • the particle preferably further comprises a fusion peptide known per se, e.g. those described in WO 99/39742 A, such as the 25-amino acid N-terminal sequence of the surfactant associated protein B, in order to promote the fusion with the cellular membrane after the binding of the particle to the transporter of the hepatocyte and thus the content of the particle easier to discharge into the cell plasma.
  • the fusion peptide can be tailored via tailored amino acid sequences, e.g. via hydrophobic amino acids, or suitable modifications, e.g. via covalent links, firmly connected to the particle or anchored there, e.g. in WO 99/39742 A and by Pecheur et al. (Biochemistry 36, 3773-3781 (1997) and Biochemistry 37, 2361-2371 (1998).
  • the particles in particular the liposomes, can preferably also be a sterically stabilized, ie a so-called Have “stealth component”, for example lipid-bound polyethylene glycol (PEG) or lipid-bound glutaryl, in order to prolong the half-life of the particles against the immune system in circulation in vivo.
  • a so-called Have “stealth component” for example lipid-bound polyethylene glycol (PEG) or lipid-bound glutaryl
  • the particle according to the invention can preferably comprise a therapeutic agent or a pharmaceutical composition or a diagnostic agent for use in the medical field.
  • Suitable therapeutic agents are, for example, cytostatics, antibiotics, antivirals, antimycotics, gene therapy substances such as DNAs or antisense molecules, antibodies, cytokines, interferons, radionuclides and the like.
  • Suitable diagnostic agents are, for example, contrast agents, radioactive isotropes, NMR imaging agents and the like.
  • conjugate according to the invention and the particle according to the invention comprising it are therefore particularly well suited for use in therapy and diagnostics in medicine, in particular in hepatocyte-related diseases such as hepatitis or liver cell carcinoma.
  • the conjugate according to the invention and a particle and / or a therapeutic or diagnostic agent are combined in separate complements of a kit.
  • the kit preferably comprises, in separate compliments, a liposome preparation in which the conjugate according to the invention is enclosed in the liposomes, and separately the therapeutic or diagnostic agent.
  • the liposome preparation can then be loaded with the therapeutic or diagnostic agent before use.
  • the activated bile salt derivative was precipitated by adding 50 ml of ether, the precipitate was separated from the supernatant after a short centrifugation and dissolved in a mixture of 10 ml of CHCl 3 , 5 ml of MeOH and 200 ⁇ l of water.
  • Liposomes were produced in a modified form using the extrusion method of MacDonald et al. , Biochim. Biophys. Acta. 1061, 297-303. (1991).
  • the individual lipids, which should be contained in the liposome membrane, were in a defined concentration in chloroform (POPC, DPPC, DNPC, DMPC, DMyPC, cholesterol) or in a mixture of chloroform, methanol and dist. Dissolved water in the ratio 1/1 / 0.02 (v / v / v) (DSPG, DMPG, 3-LCT-DSPE). These stock solutions were stored at -20 ° C. For the production of liposomes of the desired lipid composition, the corresponding aliquots of the lipid stock solutions were transferred to a 25 ml round-bottomed flask. The lipid composition of the liposomes used in mol% is given in Table 1.
  • the composition of the buffer used corresponded to that of the perfusion buffer used for hepatocyte isolation. No glucose was used to increase the shelf life of the liposomes.
  • the liposome buffer was filtered through a membrane with a pore diameter of 220 ⁇ m.
  • the desired amount of liposome buffer was added to the dried lipid mixture and the mixture was stirred for 15 minutes at 40 ° C. and 50 rpm using a rotary evaporator. By adding 10-20 glass beads (710 - 1018 microns) the resuspen- lipids are accelerated considerably.
  • the amount of liposome buffer added was chosen so that the suspension obtained contained 10-40 mg lipid / ml.
  • the lipid suspension was centrifuged at 1000 xg for 30 seconds and then left at room temperature for 2 hours. Finally, the resulting multilamellar vesicles were pressed 13 times through a polycarbonate membrane (LFM-200, Milsch equipment) with a pore diameter of 200 nm using a LiposoFast ® extrusion apparatus (Milsch Equipment, Laudenbach, Germany) and then 21 times through two superimposed polycarbonate membranes (LFM-100, milk equipment) with a pore diameter of 100 nm.
  • LFM-200 LiposoFast ® extrusion apparatus
  • the size of the liposomes produced was determined by means of PCS (photon correlation spectroscopy) (C. Washington, 1992, in M.H. Rubinstein, ed., Ellis Horwood, Ltd., London, England.). The results of mean diameters (measured from 9 individual preparations each, the mean values and the standard deviation are given) for the bile salt-bearing liposomes and the control liposomes are shown in Table 2.
  • the liposomes produced with an average diameter of approximately 120 nm can be used very well both in vitro and in vivo for the investigation of the binding of bile salt-bearing liposomes to hepatocytes.
  • the possible structure for the bile salt-bearing liposome is shown in FIG. 2A to illustrate the size relationships (the size shown should correspond to a liposome diameter of 100 nm).
  • the liposome membrane 1 has so-called bile salt layers 2.
  • 2B shows a modeled, enlarged section of the membrane of such a bile salt-bearing liposome.
  • the results illustrate a specific binding of the bile salt-bearing liposomes to bile salt-transporting proteins of the hepatocytes.
  • Uptake of the liposomes modified according to the invention via a receptor-mediated endocytosis was practically not observed.
  • a lysosomal pathway can thus be prevented or at least strongly suppressed.
  • the long-lived liposomes were prepared as described in Example 2, but using the lipid composition given in Table 3.
  • Liposomes labeled with [ 3 H] cholesteryl hexadecyl ether were used to study the organ distribution of long-lived liposomes.
  • Male albino rats of the Wistar S 300 strain (approx. 200 g) were anesthetized by intraperitoneal injection of a 2% Nembutal ® solution (1.5 ml / kg body weight). The amount of long-lived liposomes injected was calculated so that the PC concentration in the serum of the rats was 2 mM liposomal PC.
  • the corresponding amount of stock liposome solution was mixed with 1% by volume of a sterile 125 mM CaCl 2 solution and injected into the vein of the hind leg over a period of about 1 min using a cannula. After 90 minutes, the rats' abdominal cavity was opened and the kidneys and spleen were removed. A blood sample was taken from the heart and placed in a prepared 1.5 ml reaction vessel containing EDTA to prevent coagulation. To separate the erythrocytes, the blood sample was centrifuged at 2000 xg for 2 min. 3 aliquots of 200 ⁇ l each were transferred from the supernatant to 20 ml liquid scintillation vials.
  • the liver was perfused with 10 ml of the cell buffer indicated below and then removed. Kidneys and spleen were each treated with 10 ml of ice-cold cell buffer, the liver was mixed with 15 ml of ice-cold cell buffer, and the organs were then homogenized. The total volume of the homogenate was determined and 3 aliquots of 200 ⁇ l each were transferred to 20 ml liquid scintillation vials. In each of the 20 ml liquid scintillation vials 1 ml of Biolute S ® (tin) was added and the samples were fed to the liquid scintillation measurement as described.
  • Biolute S ® tin
  • FIG. 4 The result of organ distribution after 90 minutes of infusion is shown in FIG. 4.
  • the long-lived, bile salt-bearing liposomes hatchched columns
  • the control liposomes black column
  • the spleen and kidney are practically not affected.
  • Liposomes containing 0.3 mol% of the fluorescent dye Ph 2 -DiOC18 were used to investigate the accumulation of long-lived liposomes on liver hepatocytes.
  • the fluorescence intensities of the liposome preparations were determined by fluorescence spectroscopy, and suspensions with control liposomes and bile salt-bearing liposomes with the same fluorescence intensity were always used for the studies using confocal laser scanning microscopy.
  • the excitation of the Ph 2 -DiOC18-carrying liposomes was carried out using an argon laser at a wavelength of 488 nm
  • the fluorescence signal was detected at a wavelength of 505 nm.
  • the hepatocytes were cultivated with collagen type
  • the cell culture medium located above the cells was then removed as completely as possible, and 150 ⁇ l of a liposome suspension according to the invention prepared as described in Example 2 and containing 2 mM liposomal PC were added to the cells. After incubating the cells at 37 ° C. for 5 minutes, the liposome suspension was aspirated as completely as possible, and the cells were carefully washed 3 times with 150 ⁇ l of cell buffer each. Then 150 ul cell culture medium was added to the cells and the flow chamber was inserted into the confocal laser microscope.
  • the image was taken with a confocal laser scanning microscope (LSM 510 UV; ZEISS, Jena, Germany; recording speed: 2.24 ⁇ s / pixel; pixel size in the x and y direction: 0.2 - 0.4 ⁇ m; distance the cutting planes in the z direction: 0.05 ⁇ m to 0.15 ⁇ ; setting the pinhole so that the half-maximum z resolution was between 0.5 and 1 ⁇ m at full width)
  • the hepatocytes were left in the culture dish for cultivation and carefully 3 times with each
  • FIG. 5 shows the results of the binding of liposome aggregates to the hepatocyte surface
  • FIG. 5A showing the binding of bile salt-bearing liposomes after 5 minutes
  • FIG. 5B showing the binding of bile salt-bearing liposomes after 6 hours
  • FIG. 5C an enlarged section from FIG. 5B and 5D shows the comparison with control liposomes after 6 h.
  • Fluorescent liposome aggregates appear in the form of brightly fluorescent dots (see arrows in FIGS. 5B and 5C). The specific binding to hepatocytes is clearly visible (cf. FIGS. 5B and C compared to FIG. 5D).
  • the liposomes were infused analogously to that described in Example 4. After perfusion of the liver, small pieces of the individual liver lobes were removed with a scalpel. The removed pieces of liver were placed on a thin cork disc and immediately frozen in liquid N 2 . Ultrathin sections of the liver tissue were made from the frozen pieces of liver using a microtome. These were viewed under the fluorescence microscope.
  • liposomes which contained a suitable fusion peptide (SBP25) (WO 99/39742 A).
  • SBP25 peptide was chemically synthesized, purified by high-performance liquid chromatography and has the following amino acid sequence: Ac-Phe-Pro-Ile-Pro-Leu-Pro-Tyr-Cys-Trp-Leu-Ala-Arg-Ala- Leu-Ile-Lys-Arg-Ile-Gln-Ala-Met-Ile-Pro-Lys-Gly-NH 2 (HPLC purity 87%).
  • the liposomes were prepared as described in Example 2 by extrusion, using the lipid composition given in Table 4. SBP25 was dissolved in methanol, and 0.04 ⁇ mole SBP25 per ⁇ mol phospholipid was added to the respective mixture of lipids dissolved in organic solvents to prepare SBP25-bearing liposomes. The organic solvent was then removed. The following buffer (pH 7.6) was used for the resuspension of the lipids:
  • the non-encapsulated lipid was separated using gel permeation chromatography.
  • the liposome suspensions were brought to a volume of 1 ml, and the subsequent separation of the liposomes and the non-encapsulated fluorescent dextran was carried out under hydrostatic pressure.
  • the liposome suspensions contained 2 mM liposomal PC. After 2 h, 5 h or 20 h, the liposome suspensions were removed, the cells were washed and then viewed under a fluorescence microscope.

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Abstract

L'invention concerne un conjugué comprenant un motif structural lipidique, un motif structural d'acide biliaire ou de sel biliaire et éventuellement un motif structural de liaison. Selon l'invention, le motif structural lipidique et le motif structural d'acide biliaire ou de sel biliaire sont liés par covalence, éventuellement par l'intermédiaire du motif structural de liaison situé entre eux. Les conjugués selon l'invention permettent de constituer, avec ou sans composants supplémentaires, des particules très utiles, en particulier des liposomes ou des corpuscules vésiculaires analogues. Ces conjugués et les particules qui les contiennent ou qui les comportent par liaison sont en particulier conçus pour des applications thérapeutiques, en particulier pour une thérapie ciblée et, spécifiquement, pour une thérapie hépato-spécifique.
PCT/EP2003/010580 2002-10-25 2003-09-23 Conjugues d'acide biliaire et particules formees a l'aide de ces conjugues WO2004037275A1 (fr)

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AU2003275978A AU2003275978A1 (en) 2002-10-25 2003-09-23 Bile acid conjugates and particles formed therewith

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DE10249890A DE10249890A1 (de) 2002-10-25 2002-10-25 Gallensäurekonjugate und damit gebildete Partikel
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1926499B1 (fr) * 2005-09-21 2014-01-22 PAT GmbH Utilisation de lipides a effet therapeutique et procede de fabrication de lipides a effet therapeutique specifiques aux organes/tissus
WO2014096165A2 (fr) * 2012-12-21 2014-06-26 Bracco Suisse Sa Microvésicules remplies de gaz
WO2020260558A1 (fr) 2019-06-27 2020-12-30 Phenex Pharmaceuticals Ag Dérivés d'acide iso-/isoallo-lithocholique 3-modifiés ou leurs homo-analogues pour la prévention et le traitement de maladies associées à clostridioides difficile

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Publication number Priority date Publication date Assignee Title
US4115313A (en) * 1974-10-08 1978-09-19 Irving Lyon Bile acid emulsions
US6063400A (en) * 1997-07-02 2000-05-16 Sdg, Inc. Targeted liposomal constructs for diagnostic and therapeutic uses
WO2001051003A2 (fr) * 2000-01-10 2001-07-19 Yissum Research Development Company Of The Hebrew University Of Jerusalem Utilisation de conjugues de lipides dans le traitement de maladies

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4115313A (en) * 1974-10-08 1978-09-19 Irving Lyon Bile acid emulsions
US6063400A (en) * 1997-07-02 2000-05-16 Sdg, Inc. Targeted liposomal constructs for diagnostic and therapeutic uses
WO2001051003A2 (fr) * 2000-01-10 2001-07-19 Yissum Research Development Company Of The Hebrew University Of Jerusalem Utilisation de conjugues de lipides dans le traitement de maladies
US20020049183A1 (en) * 2000-01-10 2002-04-25 Saul Yedgar Use of lipid conjugates in the treatment of disease

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1926499B1 (fr) * 2005-09-21 2014-01-22 PAT GmbH Utilisation de lipides a effet therapeutique et procede de fabrication de lipides a effet therapeutique specifiques aux organes/tissus
US8883426B2 (en) 2005-09-21 2014-11-11 Pat Gmbh Use of therapeutically effective lipids and method for producing organ-/tissue-specific therapeutically effective lipids
WO2014096165A2 (fr) * 2012-12-21 2014-06-26 Bracco Suisse Sa Microvésicules remplies de gaz
WO2014096165A3 (fr) * 2012-12-21 2014-10-23 Bracco Suisse Sa Microvésicules remplies de gaz
US10010630B2 (en) 2012-12-21 2018-07-03 Bracco Suisse S.A. Gas-filled microvesicles
WO2020260558A1 (fr) 2019-06-27 2020-12-30 Phenex Pharmaceuticals Ag Dérivés d'acide iso-/isoallo-lithocholique 3-modifiés ou leurs homo-analogues pour la prévention et le traitement de maladies associées à clostridioides difficile

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