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WO2012020790A1 - Agent anti-infectieux - Google Patents

Agent anti-infectieux Download PDF

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Publication number
WO2012020790A1
WO2012020790A1 PCT/JP2011/068257 JP2011068257W WO2012020790A1 WO 2012020790 A1 WO2012020790 A1 WO 2012020790A1 JP 2011068257 W JP2011068257 W JP 2011068257W WO 2012020790 A1 WO2012020790 A1 WO 2012020790A1
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WIPO (PCT)
Prior art keywords
liposome
solution
tris
vancomycin
group
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PCT/JP2011/068257
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English (en)
Japanese (ja)
Inventor
賢 石井
哲也 蔵本
陽生 船尾
政彦 平井
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Keio University
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Keio University
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Priority to JP2012528698A priority Critical patent/JPWO2012020790A1/ja
Publication of WO2012020790A1 publication Critical patent/WO2012020790A1/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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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

Definitions

  • the present invention relates to a therapeutic agent for infectious diseases.
  • a sugar chain-modified liposome in which a sugar chain is bound to a liposome has been developed (Japanese Patent Laid-Open No. 2003-226638).
  • This sugar chain-modified liposome is used for therapeutic drug delivery system (Japanese Patent Laid-Open No. 2003-226638) for locally delivering a drug or gene to an affected area by recognizing a target cell / tissue such as cancer, or a fluorescent marker.
  • WO2007 / 091661 pamphlet molecular imaging
  • an object of the present invention is to provide a drug suitable for a drug delivery system using a sugar chain-modified liposome, particularly a drug for treating infectious diseases.
  • One embodiment of the present invention is a sugar chain-modified liposome whose outer surface is modified with a tris (hydroxyalkyl) alkylamino group and a sialyl Lewis X group, which is a liposome containing vancomycin.
  • the tris (hydroxyalkyl) alkylamino group is preferably a tris (hydroxymethyl) methylamino group.
  • a further embodiment of the present invention is a pharmaceutical composition containing any of the liposomes described above, particularly an infectious disease therapeutic agent.
  • a further embodiment of the present invention is a method for treating a patient with an infectious disease, wherein the liposome according to any one of the above is administered to the patient.
  • the liposomes may be stored for at least one week after production. In addition, it is preferable to preserve
  • a further embodiment of the present invention is a method for using the liposome according to any one of the above in the production of a pharmaceutical composition, particularly an infectious disease therapeutic agent.
  • Another embodiment of the present invention is a method for producing a pharmaceutical composition, wherein vancomycin is contained in a sugar chain-modified liposome whose outer surface is modified with a tris (hydroxyalkyl) alkylamino group and a sialyl Lewis X group.
  • the tris (hydroxyalkyl) alkylamino group is preferably a tris (hydroxymethyl) methylamino group.
  • a step of formulating the sugar chain-modified liposome containing vancomycin into an infectious disease therapeutic agent may be included.
  • the particle size distribution of liposomes encapsulating vancomycin (the horizontal axis represents the particle size [nm], the vertical axis represents the ratio [%]) is measured immediately after production and at 4 ° C. for one year after production. It is a figure which shows the result measured after preserve
  • the solid line is the measurement result immediately after production, and the dotted line is the measurement result after one year of production.
  • pouring a bacterium into an animal performed the intravenous injection of the vancomycin inclusion
  • FIG. 3 the graph which quantified the light-emission quantity by the bacteria shown in FIG. 3 is shown.
  • the outer surface is modified with a tris (hydroxyalkyl) alkylamino group and a sialyl Lewis X group, and contains vancomycin.
  • Examples of the lipid constituting the liposome of the present invention include phosphatidylcholines, phosphatidylethanolamines, phosphatidic acids, gangliosides or glycolipids or phosphatidylglycerols, cholesterol, and the like.
  • phosphatidylcholines dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, etc.
  • phosphatidylethanolamines dimyristoyl phosphatidylethanolamine, Dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, etc.
  • phosphatidic acids such as dimyristoyl phosphatidic acid, dipalmitoyl phosphide.
  • Atidic acid, distearoyl phosphatidic acid, dicetyl phosphoric acid, etc. are gangliosides, ganglioside GM1, ganglioside GD1a, ganglioside GT1b, etc.
  • glycolipids are galactosylceramide, glucosylceramide, lactosylceramide, phosphatide, globoside.
  • phosphatidylglycerols dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol and the like are preferable.
  • the tris (hydroxyalkyl) alkylamino group may be covalently bonded directly to the lipid layer, but is preferably covalently bonded to the lipid layer via a linker.
  • a linker can be appropriately selected by those skilled in the art, but a linker protein composed of a protein is preferable.
  • the linker protein is not particularly limited, and examples thereof include serum albumin such as human serum albumin (HSA) and bovine serum albumin (BSA).
  • the two alkyl groups of the tris (hydroxyalkyl) alkylamino group may be independently selected from methyl, ethyl, butyl, propyl (normal propyl or isopropyl), etc., but tris (hydroxymethyl), both of which are methyl
  • the methylamino group is most preferred.
  • Vancomycin is a glycopeptide antibiotic and may be a pharmacologically acceptable salt, and is usually administered in the form of hydrochloride, but the salt is not particularly limited.
  • the liposome may include reagents other than vancomycin, drugs, and the like.
  • reagents other than vancomycin, drugs, and the like for example, in order to trace the position of the liposome, a fluorescent dye or the like may be included in the liposome.
  • Antibiotics other than vancomycin and antibacterial agents may be included.
  • the liposome itself can be produced according to a known method, and examples thereof include a thin film method, a reverse layer evaporation method, an ethanol injection method, and a dehydration-rehydration method. Moreover, it is also possible to adjust the particle diameter of the liposome using an ultrasonic irradiation method, an extrusion method, a French press method, a homogenization method, or the like.
  • the production method of the liposome of the present invention will be specifically described.
  • phosphatidylcholines, cholesterol, phosphatidylethanolamines, phosphatidic acids, gangliosides or glycolipids, or phosphatidylglycerols A mixed micelle of a lipid and a surfactant sodium cholate is prepared.
  • phosphatidylethanolamines function as hydrophilization reaction sites
  • gangliosides or glycolipids or phosphatidylglycerols function as linker protein binding sites.
  • Liposomes are produced by ultrafiltration of the mixed micelles thus obtained.
  • the liposome surface is made hydrophilic by using a divalent reagent for crosslinking and tris (hydroxyalkyl) aminoalkane on the lipid phosphatidylethanolamine of the liposome membrane.
  • a divalent reagent for crosslinking and tris (hydroxyalkyl) aminoalkane on the lipid phosphatidylethanolamine of the liposome membrane For example, using a lipid such as dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, a liposome solution obtained by a conventional method, bissulfosuccinimidyl suberate Disuccinimidyl glutarate, dithiobissuccinimidyl propionate, disuccinimidyl suberate, 3,3'-dithiobissulfosuccinimidyl propionate, ethylene glycol bissuccinimidyl succ
  • the tris (hydroxyalkyl) aminoalkane is reacted with the bound divalent reagent to bind the tris (hydroxyalkyl) alkylamino group to the liposome surface.
  • the tris (hydroxyalkyl) aminoalkane is most preferably tris (hydroxymethyl) aminomethane (also simply referred to as tris).
  • sialyl Lewis X is further bound to the liposome.
  • This bonding is preferably via a linker.
  • the linker is a protein as an example.
  • the liposome is oxidized with NaIO 4 , Pb (O 2 CCH 3 ) 4 , NaBiO 3 or the like.
  • one end of the crosslinking divalent reagent is bonded to as many groups as possible of the amino group of the linker protein.
  • the reducing end of sialyl Lewis X is glycosylated with an ammonium salt such as NH 4 HCO 3 or NH 2 COONH 4 , and the added amino group and one unbound end of the divalent reagent for crosslinking on the liposome are combined.
  • an ammonium salt such as NH 4 HCO 3 or NH 2 COONH 4
  • a tris (hydroxyalkyl) aminoalkane is bonded to the unbound end of the divalent reagent on the linker protein that is left unreacted without the sugar chain being bound.
  • Bivalent reagents for crosslinking include bissulfosuccinimidyl suberate, disuccinimidyl glutarate, dithiobissuccinimidyl propionate, disuccinimidyl suberate, 3,3'-dithiobissulfos Cuxinimidyl propionate, ethylene glycol bissuccinimidyl succinate, ethylene glycol bissulfosuccinimidyl succinate and the like can be used.
  • vancomycin is encapsulated in the liposome by adding vancomycin to form the liposome.
  • This vancomycin-containing sugar chain-modified liposome can be stored for a long period of time, and can be administered after storage for at least 7 days, stored for at least 1 month, and stored for at least 3 months. Or may be administered after storage for at least one year.
  • the storage may be performed at 25 ° C. or less, but is preferably performed at 20 ° C. or less, more preferably at 15 ° C. or less, further preferably at 10 ° C. or less, and further at 4 ° C. or less. In any case, it must be 0 ° C. or higher, and it is most preferable to carry out at 4 ° C.
  • This pharmaceutical composition may further contain a pharmaceutically acceptable carrier and the like.
  • Pharmaceutically acceptable carriers include, for example, antioxidants, preservatives, colorants, flavors, diluents, emulsifiers, suspending agents, solvents, fillers, extenders, buffers, diluents, excipients Examples include, but are not limited to, agents and pharmaceutical adjuvants.
  • the pharmaceutical composition can be easily formulated by those skilled in the art by considering pH, isotonicity, stability, administration method, tissue to be administered, and the like.
  • a pharmaceutically acceptable carrier for example, it is blended with a pharmaceutically acceptable carrier, and is orally or parenterally as a liquid preparation such as a solid preparation such as a tablet, capsule, granule, powder or powder, syrup, suspension or solution.
  • a liquid preparation such as a solid preparation such as a tablet, capsule, granule, powder or powder, syrup, suspension or solution.
  • the dose and frequency of administration of this drug are easily determined by those skilled in the art in consideration of the purpose of use, target disease (type, severity, etc.), patient age, weight, gender, medical history, treatment history, etc. can do.
  • the drug of the present invention contains vancomycin, which is an antibiotic, a patient suffering from an infectious disease for which vancomycin is effective is an administration target. Therefore, it is preferable to use widely as a therapeutic agent for infectious diseases, and it is not limited to the type of infecting bacteria or the infection location.
  • Free BS 3 was removed by ultrafiltration (NMWL: 300,000), 1.5 mL of 132 mg / mL Tris solution (CBS buffer, pH 8.5) was added, and the mixture was stirred at room temperature for 2 hours, followed by 4 ° C. And stirred overnight. Free Tris was removed by ultrafiltration (NMWL: 300,000), and the buffer was replaced with TAPS buffer (pH 8.4) to obtain 50 mL of a liposome solution. 0.054 g of sodium metaperiodate was dissolved in 1.25 mL of TAPS buffer (pH 8.4) and added to the liposome solution and stirred overnight at 4 ° C.
  • Sodium metaperiodate was removed by ultrafiltration (NMWL: 300,000) and the buffer was replaced with PBS buffer (10 mM sodium hydrogen phosphate-sodium dihydrogen phosphate / 150 mM sodium chloride, pH 8.0). 10 mL of 10 mg / mL HSA solution (PBS buffer, pH 8.0) was added and reacted at room temperature for 2 hours to obtain 50 mL of a liposome solution. 15.5 mg of sodium cyanoborate was dissolved in 125 ⁇ L of PBS buffer (pH 8.0), added to the liposome solution, and stirred at 4 ° C. overnight. Free sodium cyanoborate and free HSA were removed by ultrafiltration (NMWL: 300,000), and the buffer was exchanged with CBS buffer (pH 8.5) to obtain 50 mL of a liposome solution.
  • PBS buffer 10 mM sodium hydrogen phosphate-sodium dihydrogen phosphate / 150 mM sodium chloride, pH 8.0
  • PBS buffer
  • sialyl Lewis X sugar chain (SLX) (Calbiochem) was dissolved in purified water so that the final concentration was 4 mg / mL, and then ammonium bicarbonate was dissolved until saturation, and reacted at 37 ° C. for 3 days. After cooling with ice, the solution was filtered through a 0.45 ⁇ m filter to obtain a 4 mg / mL aminated SLX solution.
  • DTSSP DTSSP
  • PIERCE DTSSP
  • Free DTSSP was removed by ultrafiltration (NMWL: 300,000), 4 mg / mL aminated SLX solution was added so that the final concentration of SLX was 50 ⁇ g / mL, stirred at room temperature for 2 hours, and then 132 mg / mL.
  • 500 ⁇ L of mL Tris solution (CBS buffer, pH 8.5) was added and stirred at 4 ° C. overnight.
  • HEPES buffer pH 7.2
  • Example 2 Measurement of liposome stability
  • the particle size and the zeta potential of the liposome prepared in Example 1 were determined by diluting the liposome solution 50 times with purified water to obtain Zeta Sizer Nano (Nano-ZS) (MALVERN). ).
  • the amount of lipid was calculated by quantifying cholesterol, which is a constituent lipid of the liposome.
  • Cholesterol E-Test Wako (Wako Pure Chemicals, catalog number 439-17501) was used for lipid quantification.
  • the 200 mg / dL cholesterol standard solution attached to the kit was diluted with purified water and used. 10 ⁇ L of the sample or standard solution was added to 300 ⁇ L of the coloring solution attached to the kit and stirred.
  • lipid content (mg / mL) cholesterol content (mg / mL) ⁇ 4.51 (conversion factor).
  • Micro BCA TM Protein Assay Reagent kit (PIERCE, Code. No. 23235BN) was used to measure the amount of HSA bound to or encapsulated in liposomes.
  • BSA 2 mg / mL albumin
  • a standard solution a standard substance (2 mg / mL: albumin) was diluted with a PBS buffer solution to prepare solutions of 0, 0.25, 0.5, 1, 2, 3, 4, 5 ⁇ g / 50 ⁇ L. Liposomes were diluted 20 times with PBS buffer to prepare test samples.
  • vancomycin inclusion was measured by bioassay immediately after production and one year after production (stored at 4 ° C.). The method will be described in detail below.
  • Bacillus subtilis was inoculated into a Nutrient agar medium (containing 1x Nutrient Broth (Difco), 1.5% agar powder (SAJ)) and cultured at 35 ° C for 16 to 24 hours. Single colonies were inoculated into 100 mL of Nutrient medium and cultured at 35 ° C. for 16-24 hours.
  • Nutrient® Broth (Difco) was dissolved in 300 mL of purified water, 4.5 g of agar powder was added, and autoclaved.
  • Vancomycin hydrochloride was dissolved in HEPES buffer (pH 7.2) to prepare a vancomycin standard solution of 5 to 500 ⁇ g / mL (titer). As a control, only HEPES buffer was used. 60 ⁇ L of the liposome sample or vancomycin standard solution was mixed with 570 ⁇ L of methanol / chloroform solution (1: 1), vortexed, and 50 ⁇ L each was put into the perforated agar plate. The perforated agar plate was cultured at 35 ° C. for 16 to 20 hours, and the diameter of the formed inhibition circle was measured with a digital caliper.
  • the liposome encapsulating vancomycin was stored at 4 ° C. for at least one year, the particle size distribution was not much changed, the average particle size was hardly changed, there was no leakage, and the titer was It was stable.
  • the absorbance (680 nm) was almost constant for at least one year, and there was no leakage of Cy5.5 contained in the liposomes.
  • the zeta potential indicating the surface charge of the liposome was -30 mV or less for at least one year, and the liposome had stable dispersibility. There was no change in the amount of lipid or protein for at least one year.
  • the prednisolone phosphate encapsulated in the liposome was measured by an absorbance method. As a detector, Ultrospec 6300pro (Amersham Biosciences) was used. Dilute prednisolone phosphate standard solution (10 mg / mL, methanol / chloroform solution (1: 1)) with methanol / chloroform solution (1: 1), 0.05, 0.1, 0.25, 0.5, A prednisolone phosphate solution having a concentration of 1.0 mg / mL was prepared. The liposome solution was diluted 10-fold with a methanol / chloroform solution (1: 1) to prepare a test sample.
  • the absorbance at 260 nm was measured, and the amount of prednisolone phosphate encapsulated in the liposome was calculated based on a calibration curve prepared from a standard solution.
  • the leakage of prednisolone phosphate was confirmed by removing the prednisolone phosphate leaked from the liposomes by ultrafiltration (NMWL: 300,000) after standing for 7 days in a refrigerated state and measuring by an absorbance method.
  • Pravastatin encapsulated in liposomes was measured by an absorbance method.
  • Ultrospec 6300pro Ultrospec 6300pro (GE Healthcare) was used.
  • a standard solution a standard substance (1 mg / mL pravastatin) was diluted with a PBS buffer solution to prepare pravastatin solutions having respective concentrations of 0, 25, 50, 100, 125, 250, 500, 750, and 1000 ⁇ g / mL. 180 ⁇ L of methanol / chloroform solution (1: 1) was added to each test tube into which 20 ⁇ L of the standard solution and the sample solution were dispensed.
  • pravastatin leakage was determined by removing pravastatin leaked from the liposome by ultrafiltration (NMWL: 300,000) after standing for 3 months in a refrigerated state, and measuring the amount of pravastatin in the liposome by an absorbance method. confirmed.
  • Cisplatin encapsulated in liposomes was measured by flameless atomic absorption spectrophotometry (FAAS).
  • FAAS flameless atomic absorption spectrophotometry
  • AA-6700 Atomic absorption Flame emission spectrophotometer (Shimadzu Corporation) was used for FAAS.
  • a lamp current 120 ° C. for 30 seconds, 250 ° C. for 10 seconds, 700 ° C. for 20 seconds, 700 ° C. for 5 seconds, 2600 ° C. for 3 seconds Processed sequentially.
  • a platinum standard solution (1 mg / mL Pt) was diluted with purified water to prepare platinum solutions having respective concentrations of 12.5, 25, 50, 100, and 200 ng / mL, and a calibration curve was prepared.
  • the liposome solution was diluted 10,000 times with purified water to prepare a test sample. Conversion from the obtained platinum amount to the cisplatin amount was calculated from the molecular weight of platinum and cisplatin by the following formula.
  • the leakage of cisplatin was confirmed by removing CDDP leaked from the liposome by ultrafiltration (NMWL: 300,000) after standing in a refrigerated state for 3 months and measuring the amount of CDDP in the liposome by FAAS. did.
  • Cisplatin amount platinum amount (measured value) ⁇ 300 (cisplatin molecular weight) / 195 (platinum molecular weight)
  • Micro BCA TM Protein Assay Reagent kit (PIERCE, Code. No. 23235BN) was used to measure IgG encapsulated in liposomes.
  • 2 mg / mL albumin (BSA) attached to the kit was used.
  • BSA albumin
  • a standard solution a standard substance (2 mg / mL: albumin) is diluted with a PBS buffer solution to prepare solutions having respective concentrations of 0, 0.25, 0.5, 1, 2, 3, 4, 5 ⁇ g / 50 ⁇ L. did.
  • IgG-encapsulated liposomes were diluted 20 times with PBS buffer to prepare a test sample.
  • IgG leaked from the liposome was removed by ultrafiltration (NMWL: 300,000), and the amount of IgG in the liposome was measured using a BCA kit. Was confirmed.
  • Liposomes encapsulating vancomycin were very stable for at least one year when stored at 4 ° C., whereas pravastatin and cisplatin were detected to leak 6% after 3 months. Prezonisolone phosphate and IgG were Seven days later, as much as 30% and 12% leaks were detected.
  • Example 3 Administration of vancomycin (VCM) -encapsulated liposome to mouse infection model
  • VCM vancomycin
  • a soft tissue infection model includes methicillin-resistant Staphylococcus aureus (MRSA Xen31 strain, Caliper life Sciences) (Am J Otolaryngol. 2010 Apr 29, expressing 5 ⁇ L of luciferase in the shallow gluteus muscle of BALB / c mice. published online) was used with a highly reproducible model injecting 8 ⁇ 10 7 CFU (Colony Forming Units) / ⁇ L.
  • MRSA was cultured in LB (Luria Bertani) medium at 37 ° C., then dispensed and stored at ⁇ 30 ° C.
  • FIG. 2 shows liposome-injected mice (FIGS. 2C, D, E, F) and control mice (FIGS. 2A, B) on day 5 (FIGS. 2A, C, D, E) and day 7 (FIGS.
  • VCM and VCM / Lypo the results of administration of VCM and VCM-encapsulated liposomes are denoted as VCM and VCM / Lypo, respectively.
  • MRSA and Lypo the image which observed bacterial dynamics and liposome dynamics was described as MRSA and Lypo, respectively, and the image which superposed
  • VCM-encapsulated liposomes in an infectious disease model has a markedly higher therapeutic effect than the administration of vancomycin solution alone.
  • Example 4 Administration of vancomycin (VCM) -encapsulated liposomes to a mouse infection model
  • VCM-encapsulated liposomes were administered immediately after injection of bacteria into an animal (initial animal model of infection), and the pharmaceutical effect was determined.
  • the VCM-encapsulated liposome has a therapeutic effect even in a small amount of 8 ⁇ g of VCM.
  • Example 4 even if the VCM-encapsulated liposome is administered after the bacteria have formed a sufficient infection site in the adult body, there is a sufficient therapeutic effect, and even if the dose of the VCM-encapsulated liposome is smaller, the therapeutic effect is also achieved. Indicates that there is.
  • MRSA Xen31 strain methicillin-resistant Staphylococcus aureus (MRSA Xen31 strain, Caliper life Sciences) (Am J Otolaryngol) expressing 5 ⁇ L of luciferase in the shallow gluteus muscle of BALB / c mice was used. 2010 Apr 29, published online) was used as a highly reproducible model injecting 8 ⁇ 10 7 CFU (Colony Forming Units) / ⁇ L. MRSA was cultured in LB (Luria Bertani) medium at 37 ° C., then dispensed and stored at ⁇ 30 ° C.
  • LB Lia Bertani
  • VCM-encapsulated liposomes in an infectious disease model was found to have a therapeutic effect with a minute dose of about 10,000 times less than the normal dose of VCM, more than the normal dose. This is due to the high specific accumulation property of the liposome prepared in Example 1 in the infected lesion.
  • a drug suitable for a drug delivery system using a sugar chain-modified liposome, particularly a drug for treating infectious diseases.

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Abstract

Le but de la présente invention est de fournir un médicament approprié pour un système d'administration de médicament utilisant des liposomes glycosylés, particulièrement un agent anti-infectieux. L'agent anti-infectieux est préparé en incluant de la vancomycine dans les liposomes glycosylés, la surface externe des liposomes glycosylés étant modifiée par un groupe tris(hydroxyméthyl)méthylamino et un groupe de Lewis X sialylé.
PCT/JP2011/068257 2010-08-11 2011-08-10 Agent anti-infectieux Ceased WO2012020790A1 (fr)

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JP2012528698A JPWO2012020790A1 (ja) 2010-08-11 2011-08-10 感染症治療薬

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06345663A (ja) * 1993-06-08 1994-12-20 Sumitomo Pharmaceut Co Ltd バンコマイシン含有リポソーム製剤
JP2003226638A (ja) * 2002-01-30 2003-08-12 National Institute Of Advanced Industrial & Technology 標的指向性リポソーム
WO2005011632A1 (fr) * 2003-08-01 2005-02-10 National Institute Of Advanced Industrial Science And Technology Liposome dirige sur une cible, enterique et a absorption commandee possedant une chaine de sucre, ainsi que remede contre le cancer contenant ce liposome et diagnostic mettant en oeuvre ce liposome
JP2006514016A (ja) * 2002-11-26 2006-04-27 ギリアード サイエンシーズ， インコーポレイテッド リポソーム処方物
WO2009055568A2 (fr) * 2007-10-23 2009-04-30 Transave, Inc. Préparations de vancomycine liposomales

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009148169A1 (fr) * 2008-06-06 2009-12-10 片山化学工業株式会社 Technique de traitement de tumeurs utilisant un complexe ammine-platine à haute concentration encapsulé dans un liposome

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06345663A (ja) * 1993-06-08 1994-12-20 Sumitomo Pharmaceut Co Ltd バンコマイシン含有リポソーム製剤
JP2003226638A (ja) * 2002-01-30 2003-08-12 National Institute Of Advanced Industrial & Technology 標的指向性リポソーム
JP2006514016A (ja) * 2002-11-26 2006-04-27 ギリアード サイエンシーズ， インコーポレイテッド リポソーム処方物
WO2005011632A1 (fr) * 2003-08-01 2005-02-10 National Institute Of Advanced Industrial Science And Technology Liposome dirige sur une cible, enterique et a absorption commandee possedant une chaine de sucre, ainsi que remede contre le cancer contenant ce liposome et diagnostic mettant en oeuvre ce liposome
WO2009055568A2 (fr) * 2007-10-23 2009-04-30 Transave, Inc. Préparations de vancomycine liposomales

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DARIA NICOLOSI ET AL.: "Encapsulation in fusogenic liposomes broadens the spectrum of action of vancomycin against Gram-negative bacteria", INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, vol. 35, no. 6, June 2010 (2010-06-01), pages 553 - 558, XP027000734 *
ZUZANNA DRULIS-KAWA ET AL.: "Liposomes as delivery systems for antibiotics", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 387, 15 March 2010 (2010-03-15), pages 187 - 198, XP026888460, DOI: doi:10.1016/j.ijpharm.2009.11.033 *

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