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WO2010078660A1 - Utilisation de proanthocyanidines en tant qu'agent anti-apoptotique et agent antiadhésion bactérienne - Google Patents

Utilisation de proanthocyanidines en tant qu'agent anti-apoptotique et agent antiadhésion bactérienne Download PDF

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Publication number
WO2010078660A1
WO2010078660A1 PCT/CA2010/000044 CA2010000044W WO2010078660A1 WO 2010078660 A1 WO2010078660 A1 WO 2010078660A1 CA 2010000044 W CA2010000044 W CA 2010000044W WO 2010078660 A1 WO2010078660 A1 WO 2010078660A1
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Prior art keywords
cranberry
composition
proanthocyanidins
catheter
bacteria
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English (en)
Inventor
Nathalie Tufenkji
Irwin Adam Eydelnant
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McGill University
Royal Institution for the Advancement of Learning
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McGill University
Royal Institution for the Advancement of Learning
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Publication of WO2010078660A1 publication Critical patent/WO2010078660A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/23—Solid substances, e.g. granules, powders, blocks, tablets
    • A61L2/232—Solid substances, e.g. granules, powders, blocks, tablets layered or coated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L2103/15—
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/30—Compounds of undetermined constitution extracted from natural sources, e.g. Aloe Vera
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

  • the present disclosure relates to a composition comprising proanthocyanidins, a biomaterial comprising proanthocyanidins and the use of proanthocyanidins as an anti-apoptotic, anti-invasion and anti-adhesive bacterial agent.
  • HAI hospital acquired infection
  • CAUTI Catheter Associated Urinary Tract Infections
  • a non-antibiotic target of interest is the prevention of initial bacterial adhesion to surfaces. After bacteria attach to a surface they often begin to grow and develop into complex microbial communities known as biofilms. It is the development of biofilm that generally results in HAI and patient complications.
  • an anti-infectious composition comprising proanthocyanidins extracted from cranberry and a carrier, the composition preventing adhesion and propagation of bacteria.
  • an anti-infectious composition comprising proanthocyanidins extracted from cranberry and a carrier, the composition preventing invasion of bacteria in a cell, infection and apoptosis of the cell.
  • cranberry is of the species Vaccinium macrocarpon.
  • bacteria are Gram-positive or Gram- negative, such as for example but not limited to Escherichia coli, Pseudomonas or Enterococcus faecalis.
  • the proanthocyanidins prevent biofilm formation.
  • composition described herein further comprises a therapeutic agent, such as for example, but not limited to, an antibacterial agent or an antibiotic.
  • composition described herein also has anti-inflammatory property.
  • the material is a heart valve, a stent, an artificial limb, an angioplasty balloon, a shunt, a scalpel or a catheter.
  • the catheter is a urinary catheter or a central line catheter, is made of a polymer, and more precisely it can also be made of latex, silicone or Teflon.
  • the material is a packaging material, such as for example but not limited to a food packaging material or a cosmetic packaging material.
  • proanthocyanidins extracted from cranberry in the manufacture of a medicament to prevent apoptosis of cells.
  • the medicament is for improving the condition of a patient suffering from cardiovascular disease, liver disorder, kidney disorder or complication of heart transplant.
  • proanthocyanidins extracted from cranberry in the manufacture of a material free of bacteria.
  • proanthocyanidins extracted from cranberry for improving the condition of a patient suffering from cardiovascular disease, liver disorder, kidney disorder or complication of heart transplant.
  • proanthocyanidins extracted from cranberry for preventing apoptosis of cells.
  • proanthocyanidins further improve the condition of a patient suffering from cardiovascular disease, liver disorder, kidney disorder or complication of heart transplant.
  • It is also provided a method for improving the condition of a patient comprising administering to the patient proanthocyanidins extracted from cranberry, the condition being cardiovascular disease, liver disorder, kidney disorder or complication of heart transplant.
  • Fig. 1A illustrates the results of adhesion experiments conducted with latex microspheres on different biomaterials wherein in the image on the left, latex microspheres (white dots) have adhered onto a polycarbonate (PC) surface (2.5 % w/v in chloroform); in the image on the right, microspheres (white dots) have adhered onto a polycarbonate surface (2.5 % w/v in chloroform) that was first modified with proanthocyanidins (PACs), whereby the PACs were embedded into the polycarbonate; both surfaces (PC on the left and PAC-PC on the right) were exposed to latex microspheres at a concentration of 10 8 particles/mL, and microscope images were taken of the materials to allow enumeration of attached microspheres.
  • PC polycarbonate
  • PACs proanthocyanidins
  • Fig. 1 B illustrates an histogram of polycarbonate (PC) control material versus PACs incorporated polycarbonate (PAC-PC) showing samples challenged with latex microspheres (lanes 1 and 2) and uropathogen E. faecalis 29212 (lane 3) with a significant reduction of adhesion observed.
  • PC polycarbonate
  • PAC-PC polycarbonate
  • Fig. 2 illustrates PACs' cytoprotective effects by SEM microscopy images of Madin-Darby canine kidney cells (MDCK) exposed to Pseudomonas aeruginosa for two hours in phosphate buffered saline (PBS) (left panel) and MDCK cells exposed to Pseudomonas aeruginosa for two hours in PACs supplemented PBS (75 ug/ml; right panel).
  • MDCK Madin-Darby canine kidney cells
  • PBS phosphate buffered saline
  • FIG. 3 illustrates the proliferative effects of cranberry extracted PACs on MDCK cells incubated in PBS for 3 hours in the presence of various concentrations of cranberry extracted PACs (panel 1 : 0 ⁇ g/ml of PACs; panel 2: 25 ⁇ g/ml of PACs; panel 3: 50 ⁇ g/ml of PACs; panel 4: 75 ⁇ g/ml of PACs , panel 5: 100 ⁇ g/ml of PACs, panel 6: 150 ⁇ g/ml of PACs), imaged by epifluorescence microscopy using Live/Dead staining.
  • Fig. 4 illustrates representative fluorescence microscope images of bacteria adhered to (A) a polycaprolactone (PCL) coated glass disk (control) and (B) PCL-2.5wt%PAC coated glass disk, following an adhesion experiment conducted in a parallel-plate flow cell (PPFC), the images showing considerably greater adhesion on the control (clean) material than the polymer containing cranberry PAC.
  • PCL polycaprolactone
  • PPFC parallel-plate flow cell
  • Fig. 5 illustrates a comparison of the number of adhered bacteria to polycaprolactone (PCL) coated glass disks (lanes 2) versus PCL-2.5wt% PAC glass disks (lanes 1), on three different parallel-plate flow cell (PPFC) experiments.
  • PCL polycaprolactone
  • PPFC parallel-plate flow cell
  • FIG. 6 illustrates the effect of cranberry derived PACs on adhesion and invasion of four bacterial pathogens to kidney epithelial cells: E. faecalis (EF), P. aeruginosa (PA), E. coli O157:H7 (EC1), and E. coli CFT073 (EC2) pre- incubated in DMEM with or without PAC (50 ⁇ g/ml) for 1 hour (data presented as fold-change from untreated conditions; p ⁇ 0.01 , Student's two-tailed t-test; error bars indicate 95% confidence intervals).
  • E. faecalis EF
  • PA P. aeruginosa
  • EC1 E. coli O157:H7
  • EC2 E. coli CFT073
  • Fig. 7 illustrates the effect of cranberry derived PACs on invasion of MDCK cells by E. coli O157:H7
  • CLSM images of A) MDCK cells infected with E. coli O157:H7
  • Fig. 8 illustrates a FTIR spectra for PAC, PCL, and PCL-2.5wt%PAC composite, the peaks specific to PAC which can be observed in the composite spectrum have been identified at 1610, 1524, and 825 cm '1 .
  • Fig. 9 illustrates a release profile of proanthocyanidins from polycaprolactone films in water plotted as a function of time.
  • Fig. 10 illustrates a release profile of proanthocyanidins from polycaprolactone films in PBS plotted as a function of time.
  • Fig. 11 illustrates a percentage release profile of proanthocyanidins from polycaprolactone films in water plotted as a function of time.
  • Fig. 12 illustrates a percentage release profile of proanthocyanidins from polycaprolactone films in PBS plotted as a function of time.
  • Fig. 13 illustrates Differential Scanning Calorimetry (DSC) results for assessing the thermal properties of clean PCL and PAC-embedded PCL films.
  • PACs are isolated as described in Howell et al. (2005, Phytochemistry, 66: 2281- 2291).
  • cranberry has been administered in the treatment of bacterial infections, particularly for urinary tract infection (UTI).
  • UTI urinary tract infection
  • PACs are one group of bioactive molecules that have been identified. These are large molecules present in several different foods including chocolate, red wine, and blueberries.
  • PACs also known as procyanidin oligomeric proanthocyanidins (OPC), pycnogenol, leukocyanidin and leucoanthocyanin
  • OPC procyanidin oligomeric proanthocyanidins
  • pycnogenol pycnogenol
  • leukocyanidin leucoanthocyanin
  • leucoanthocyanin are a class of flavanols.
  • Proanthocyanidins are essentially polymer chains of flavonoids such as catechins.
  • Proanthocyanidins are a class of polyphenol ⁇ compounds found in several plant species composed of flavan-3-ol most commonly linked through either 4 -> 6 or 4 -> 8.
  • Procyanidins are the most common classes that have chains of catechin, epicatechin, and their gallic acid esters. Structural isomers exist including the formation of second interflavanoid bonds by C-O oxidative coupling forming A-type oligomers. B-type oligomers are singly linked and are more abundant in nature.
  • Proanthocyanidin trimers derived from Vaccinium macrocarpon exhibit bioactivity against pathogenic P-fimbriated E. coli to uroepithelial cells. Specifically these trimers exhibit A-type interflavanoid linkages that are absent in proanthocyanidins isolated from other sources.
  • the trimers epicatechin- (4 ⁇ f6)-epicatechin-(4 ⁇ f8, 2 ⁇ f(f7)-epicatechin, epicatechin-(4 ⁇ f8, 2 ⁇ f(f7)- epicatechin-(4 ⁇ f8)-epicatechin, and epicatechin-(4 ⁇ f8)-epicatechin-(4 ⁇ f8, 2 ⁇ f(f7)-epicatechin are known to exhibit significantly greater activity than weakly active epicatechin-(4 ⁇ f8, 2 ⁇ f(f7)-epicatechin (procyanidin A2) and inactive epicatechin monomers and their dimers epicatechin-(4 ⁇ f8)-epicatechin (procyanidin B2).
  • PACs produced by cranberries have a particular structure that has been demonstrated to prevent the adhesion of bacteria to the cells found in the internal lining of the urinary tract, thereby preventing the onset of UTI (Howell et al., 2005, Phytochemistry, 66: 2281-2291).
  • Whole cranberry proanthocyanidin fraction demonstrates complex series of oligomers with both A-type (containing at least one double linkage) and B-type (exclusively single linked) oligomers.
  • the A-type oligomers found in cranberry have only a single double linkage per oligomer as opposed to those found in other species with multiple double linkages.
  • Blueberry in contrast only exhibits B-type proanthocyanidins. Peanuts and cinnamon have A-type linkages.
  • High molecular weight PACs have a significant higher binding efficiency to lipopolysaccharides (LPS) on various strains of pathogenic bacteria than PACs derived from tea and grapes (Delehanty et al., 2007, Journal of Natural Products, 70: 1718-1724).
  • LPS lipopolysaccharides
  • This LPS binding potential has been exploited for the development of new materials in the removal of LPS from solution.
  • Derivatives from Vaccinium species were found to bind the pili of N. meningitidis with greater efficiency than a wide range of extracts derived from other berry sources, with implication in the prevention of infection (Toivanen et al., 2009, Journal of Agricultural and Food Chemistry, 57: 3120-3127).
  • cranberry derived proanthocyanidins when embedded in a material, effectively prevent the adhesion of both Gram- positive and Gram-negative pathogenic bacteria to commonly used biomaterial surfaces, independent of anti-bacterial mechanisms. This is an important finding as by preventing adhesion instead of killing bacteria, these compounds reduce the risk of propagating new resistant bacterial strains. The observed reduction ranged from 50% to 90% (Fig. 1 B), indicating a strong potential for prolonging the non-infected lifespan of the tested materials when PACs are embedded in the carrier material.
  • Fig. 4 shows representative fluorescence microscope images of a PCL-2.5wt%PAC coated glass disk, and PCL coated glass disk, following the full PPFC experiment described hereinabove.
  • the adhesion data recited in Table 1 hereinbelow is presented as the average number of bacteria adhering to the biomaterials surfaces.
  • the ratio of adhered bacteria between the control and the treatment represents the fold reduction in bacterial adhesion (see Fig. 5).
  • Bacterial adhesion was shown to be 5.5 times greater on the PCL coated glass disks than on the PCL-2.5wt% PAC glass disks.
  • PACs activity when embedded and/or coated into a material such as a biomaterial result in a reduction in adhesion of bacteria due to steric interference by PACs adsorbed to the surface.
  • Mammalian (kidney) cells maintained normal stretched morphology when challenged with bacteria (P. aeruginosa) in the presence of PACs as seen in Fig. 2, supporting PACs cytoprotective effects.
  • cranberry- derived PACs can be use to prevent infections related to a broad range of indwelling devices (e.g., heart valves, stents, artificial limbs, etc) and medical conditions.
  • Formation of a biofilm begins with the attachment of free-floating microorganisms to a surface, tissue or cells for example. These first colonists adhere to the surface initially through weak, reversible van der Waals forces. If the colonists are not immediately separated from the surface, they can anchor themselves more permanently using cell adhesion structures such as pili. The first colonists facilitate the arrival of other cells by providing more diverse adhesion sites and beginning to build the matrix that holds the biofilm together. Some species are not able to attach to a surface on their own but are often able to anchor themselves to the matrix or directly to earlier colonists. Once colonization has begun, the biofilm grows through a combination of cell division and recruitment. The final stage of biofilm formation is known as development, and is the stage in which the biofilm is established and may only change in shape and size. The development of a biofilm may allow for the aggregate cell colony(ies) to be increasedly antibiotic resistant.
  • the catheter system disclosed herein or other material can be made of numerous polymers. Alternatively, it can be made of flexible latex, silicone, or Teflon tubing embedded with cranberry derived proanthocyanidins (PACs). It is the PACs embedded into the material that prevents initial bacterial adhesion and increases the infection-free lifespan of the catheter and thereby protects the patient.
  • Catheter diameter ranges from 4 mm to 10 mm with a standard size of 4.6 mm.
  • Terminal balloons vary in size from 5 cm 3 to 30 cm 3 as required for different applications.
  • a dual channel design allows for balloon inflation with sterile water or saline solution.
  • the catheter system disclosed herein represents a more economical alternative to antiseptic catheter present in the market today, with a cost reduction of $2.00 to $3.00 or more per unit.
  • PACs treated catheters offer a novel approach. It is disclosed herein that PACs inhibit bacterial adhesion to surfaces independent of anti-bacterial mechanisms, a significant advantage since the potential for more resistant bacteria is reduced.
  • the anti-adhesive properties of PACs disclosed herein can also be used for a wide range of specialized industries to protect surfaces from bacterial colonization and biofilm formation.
  • the anti-adhesive properties of PACs disclosed herein can be embedded into any material where sterility is a concern.
  • PACs such as a natural food preservative if embedded into packaging materials.
  • Other applications include cleaning products such as cleaning brushes, sponges or utensils.
  • a material referred herein is intended to mean any material, natural or man-made, such as a biomaterial, metals, food preparation surfaces, wherein PACs can be coated on, incorporated in and/or embedded therein without limitation to.
  • Biomaterials are intended to mean material that can contain whole or part of a living structure or biomedical device which performs, augments, or replaces a natural function. It is also intended herein to include all materials used as packaging materials for food preservation or cosmetic products.
  • such biomaterial is a heart valve, a stent, an artificial limb, an angioplasty balloon, a shunt, a scalpel, and a catheter.
  • the catheter can be for example biodegradable, as known in the art (US application publication nos. 2009/311337; 2009/299465; 2009/299292).
  • cranberry derived proanthocyanidins PACs
  • PACs cranberry derived proanthocyanidins
  • An anti-apoptotic effect is intended to mean the prevention of apoptosis of bacteria and/or cell, apoptosis being a type of cell death in which a series of molecular steps in a cell leads to its death.
  • cranberry derived proanthocyanidins for the mitigation of kidney cell infection by selected uro- and entero-pathogens is described herein with an adhesion/invasion assay and confocal microscopy.
  • This study demonstrated that PACs effectively reduce invasion of canine kidney cells by pathogenic bacteria: E. coli CFT073 and O157:H7, E. faecalis 29212, and P. aeruginosa 10145.
  • An invasion by bacteria of a cell is intended to mean the penetration of the bacteria into the cell by phagocytosis or fusion with the cell, allowing the infection by the bacteria, the bacteria growing and dividing in the cell cytoplasm and gaining entry to neighbouring cells by bursting through and digesting membranes.
  • This new area of application of the PACs is fundamental as these compounds will prevent cellular inflammatory response and improve resistance to apoptosis. Their anti-inflammatory and anti-apoptotic effects will reduce the incidence of chronic illnesses such as cardiovascular diseases, liver/kidney disorders and others complications following heart transplant. The increased totipotency/proliferation effect of PACs on healthy mammalian cells will impact positively human well-being.
  • PACs according to the disclosure herein can also be used in the medical field as part of a composition to protect patients from the harmful effects of inflammation and cell death.
  • the present disclosure provides the use of a natural product which is safe, non-toxic, and available in large quantities for a range of applications mentioned herein.
  • this is an exciting advance over existing technology as cranberry derived proanthocyanidins also reduce adhesion of bacteria to abiotic surfaces thereby serving as a 'two-for-one' strategy in clinical applications.
  • the relatively low cost of PACs per application creates an economically viable solution to alleviate clinical expenditures.
  • an anti-apoptotic and/or anti-bacterial composition comprising PACs formulated in different forms such as powder form, pills, softchews and food beverages.
  • the composition comprises also a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • carrier also known as adjuvant or vehicle, refers to a carrier, adjuvant or vehicle that may be administered to a subject, incorporated into a composition of the present invention, and which does not destroy the pharmacological activity thereof.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, the following: ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems ("SEDDS"), surfactants used in pharmaceutical dosage forms such as TweensTM or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool
  • Cyclodextrins such as ⁇ -, ⁇ - and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives may also be used to enhance delivery of the compositions of the present invention.
  • compositions disclosed herein may contain other therapeutic agents, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • pharmaceutical additives for example, excipients, binders, preservatives, stabilizers, flavors, etc.
  • compositions disclosed herein may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrastemal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
  • suitable means for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrastemal injection or infusion techniques (e.g., as sterile injectable aqueous or non-
  • compositions may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
  • the present compounds may also be delivered through the oral cavity by sublingual and/or buccal administration.
  • Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used.
  • Exemplary compositions include those formulating the present compositions with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicelTM) or polyethylene glycols (PEG).
  • Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., GantrezTM), and agents to control release such as polyacrylic copolymer (e.g., CarbopolTM 934).
  • HPC hydroxy propyl cellulose
  • HPMC hydroxy propyl methyl cellulose
  • SCMC sodium carboxy methyl cellulose
  • GantrezTM maleic anhydride copolymer
  • agents to control release such as polyacrylic copolymer (e.g., CarbopolTM 934).
  • Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • composition as disclosed herein may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human from about 0.1 to 500 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 5 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion and clearance, drug combination, and severity of the particular condition.
  • Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to anti-apoptotic and/or anti-bacterial dependence or apoptotic and/or bacterial associated disorders.
  • terapéuticaally effective amount refers to an amount that is sufficient to effect a therapeutically or prophylactically significant reduction of a disease or condition when administered to a typical subject of the intended type.
  • PACs or composition comprising PACs to a subject
  • typically the PACs, formulation, or composition should be administered in a therapeutically effective amount.
  • compositions disclosed herein may be employed alone or in combination with other suitable therapeutic agents useful in promoting anti- apoptotic, anti-invasive and anti-bacterial effects.
  • PCL polycaprolactone
  • PCL-2.5wt% PAC composite Solutions of neat polycaprolactone (PCL) and PCL-2.5wt% PAC composite are prepared.
  • Four glass disks, 14 mm in diameter (Biosurface Technologies), are washed with soap and rinsed thoroughly with distilled deionised water, then dried under ultrapure nitrogen.
  • the disks are stored in sterile Petri dishes until use.
  • the disks are then mounted on a spin coater (WS- 400B-86NPP-LITE, Laurell Technologies Corporation), and spin coated for 5 minutes, at 3000 rpm, with an average of 175 ⁇ l of solution using a glass syringe.
  • WS- 400B-86NPP-LITE Spin coater
  • the gram negative bacteria E. coli D21 are used.
  • the bacterial cell suspensions are prepared from pure cultures, previously maintained at -80 0 C in Luria-Bertani Lennox broth (20 g/l) supplemented with 30% glycerol. Subsequently, cultures are streaked onto agar plates and incubated overnight (12h) at 37°C. The plates are stored for up to 7 days in the fridge at 4 0 C. For each experiment, a single colony of bacteria is inoculated into 150 ml of regular LB broth, and incubated at 200 rpm and 37°C for 4h.
  • the cell suspension is centrifuged at 7000 rpm for 10 minutes (SS-34 rotor, Kendro) at 4°C. Then, the LB broth is decanted and the pellet is resuspended in 30 ml of phosphate buffered saline (PBS). The centrifugation and resuspension are repeated twice more to remove all LB broth and metabolites.
  • the concentration of the cell suspension is determined using a volume of 0.02 ⁇ l of the suspension in a Helber bacteria counting chamber (SV400, ProSciTech), after which the suspension is diluted to the desired final concentration of 1.85x10 8 CFU/ml in PBS.
  • the PCL and PCL-PAC coated glass disks are carefully placed in a dual channel parallel plate flow cell (PPFC), each channel containing 2 disks coated with the same material.
  • the disks are then covered with thin microscope slides, previously washed with soap and Dl water, and dried under ultrapure nitrogen.
  • the PPFC is then closed, and two 20 ml syringes containing 85% ethanol are connected to it. All of these procedures are conducted under a biological safety cabinet (BSC) to reduce the risks of bacterial contamination.
  • BSC biological safety cabinet
  • the flow chambers are first rinsed with 85% ethanol contained in the previously connected syringes, at a flow rate of 2 ml/min.
  • the PPFC is covered in aluminium foil to reduce light incidence, and two 5 ml syringes with solutions of LIVE/DEAD BacLight TM bacterial viability kit (Invitrogen) prepared from 100 ⁇ l of green-fluorescent SYTO® 9 staining reagent, and 100 ⁇ l of red-fluorescent propidium iodide staining reagent, completed to 5 ml with Dl water, are attached to the PPFC.
  • the staining reagents are injected at a rate of 0.5 ml into the PPFC, and the system is incubated for 15 minutes in the dark at room temperature.
  • FIG. 4 shows representative fluorescence microscope images of a PCL-2.5wt%PAC coated glass disk, and PCL coated glass disk, following the full PPFC experiment described hereinabove.
  • the adhesion data recited in Table 1 is presented as the average number of bacteria adhering to the biomaterials surfaces, with the standard deviation from the sample presented in between parentheses.
  • the ratio of adhered bacteria between the control and the treatment represents the fold reduction in bacterial adhesion (see Fig. 5).
  • the average fold reduction was found to be 5.5; namely, bacterial adhesion is 5.5 times greater on the PCL coated glass disks than on the PCL-2.5wt% PAC glass disks.
  • the number of bacteria was shown to be significantly higher on the PCL coated coupons than on the PCL-2.5wt%PAC coated coupons.
  • a Student one-tailed t-test was used to compare the means of the two treatments and a value of p ⁇ 0.01 was chosen to show a statistically significant difference. Table 1
  • Dry PAC extract purified by HPLC (Marucci Center for Blueberry and Cranberry Research, Rutgers University) is ground using a mortal and pestle then solubilized in deionized (Dl) (MiIIi-Q) water to obtain a PAC stock solution (1.5 mg/mL).
  • PAC stock solution is filtered through a 0.45 m syringe filter prior to experimentation.
  • the average molecular weight of PAC used is ⁇ 15 kDa.
  • E. coli CFT073 ATCC 700928, uropathogenic E. faecalis ATCC 29212, environmental isolate P. aeruginosa 10145, and enteropathogenic E. coli O157:H7 ATCC 700927 are used.
  • E. coli CFT073 is a Gram negative clinical isolate from the blood and urine of a woman with acute pyelonephritis and its complete genome has been sequenced.
  • E. faecalis 29212 is a well-characterized Gram-positive uropathogenic bacterium isolated from urine. P.
  • aeruginosa is a common Gram-negative opportunistic pathogen that typically infects the pulmonary tract and urinary tract.
  • E. coli O157:H7 is a Gram-negative enterohemorrhagic strain of E. coli that causes acute gastroenteritis. Pure cultures are maintained at -8O 0 C in Luria-Bertani Lennox broth (20 g/l) supplemented with 30% glycerol. Cultures are streaked onto LB agar plates, then incubated 24 h at 37°C. For each experiment, a single colony from a fresh plate was used to inoculate 15 ml of LB broth (in a 50 mlenmeyer flask).
  • Cultures are incubated at 37 0 C for 18 h at 200 rpm, then harvested by centrifugation at 5860 g for 15 min (SS-34 rotor, Kendro) at 4°C.
  • the growth media is decanted and the pellet is resuspended in Dulbecco's Modified Eagle Medium (DMEM). Centrifugation and resuspension are repeated one additional time to remove any traces of growth media and metabolites.
  • the concentration of cells is determined with a Helber (SV400, Proscitech) bacteria counting chamber and the suspensions are diluted accordingly to achieve a multiplicity of infection of 50:1 in DMEM with or without PAC supplementation (50 g/ml).
  • Madin-Darby Canine Kidney (MDCK) cells are cultured in DMEM containing 4.5 g/l glucose, 10% fetal bovine serum (FBS, Invitrogen) supplemented with 10 mM Hepes, 100 U/ml of penicillin, 100 g/ml streptomycin and non-essential amino acids. The cells are incubated under conventional cell culture conditions at 37 0 C in a humidified incubator containing 5% CO ⁇ . One day prior to experimentation, MDCK cells are seeded on glass coverslips in 24- well culture plates, then incubated 24 hr to 80% confluency.
  • FBS fetal bovine serum
  • MDCK cells are washed in phosphate buffered saline (PBS, Sigma- Aldrich) then infected with the respective bacteria at a multiplicity of infection of 50:1 for 3 hrs at 37°C.
  • PBS phosphate buffered saline
  • TAB total associated bacteria
  • MDCK cells are washed with PBS and lysed in 0.1% TritonTM X-100 (Sigma). Supernatant is diluted in maximum recovery diluent (Fisher) and plated in triplicate on LB agar plates for bacteria enumeration.
  • Invasion assays followed the same infection protocol, with the exception that after infection, MDCK cells are incubated for 1 hr in gentamiacin (100 ⁇ g/ml, Sigma-Aldrich) to eliminate extracellular bacteria prior to lysis and plating. Control experiments determined these conditions as sufficient for complete elimination of all bacteria examined.
  • MDCK cells infected with E. coli O157:H7, prior to TritonTM-X lysis are washed with PBS, fixed in 2.5% paraformaldehyde (Fluka) for 15 minutes, washed again using PBS, then blocked and permeabilized with 4% bovine serum albumin/0.1 % TritonTM-X/PBS (BPBS) for 30 min.
  • Infected MDCK cells are incubated for 1 hr with fluorescein- labeled antibody directed to E. coli O157:H7 (Kirkegaard and Perry Laboratories), washed with PBS, incubated with Texas-Red phalloidin
  • a solvent casting method is used to produce neat polymer and composite films.
  • 1g of PCL is dissolved in 10 ml of chloroform.
  • the PAC powder is added to the polymer solution in the following concentrations for the composite films: PCL-2.5wt% PAC and PCL-5wt% PAC.
  • the glass vials are covered in aluminium foil to reduce light incidence.
  • the solutions are then sonicated (Ultrasonic Cleaner FS20, Fisher Scientific) for 1 h to obtain a homogeneous dispersion of the PAC in the polymer solution.
  • the solutions are cast and the solvent is allowed to evaporate in a dark room for 48h.
  • a Differential Scanning Calorimetry method is used to assess the thermal properties of the PCL film, as well as of the composite film of PCL- 2.5wt% PAC and PCL-5wt% PAC.
  • the tests are performed using a Perkin- Elmer Pyris Diamond Differential Scanning Calorimeter (Perkin-Elmer Instruments). Samples for each material weighing on average 5.5 mg ⁇ 0.1 are used. All samples are first brought to a temperature of -50°C and held at that temperature for 1 minute, after which they are heated up to 100 0 C at a rate of 20°C/minute, and again held at that temperature for 1 minute. The samples are subsequently cooled back to -5O 0 C at the same rate. This heat/cool cycle is repeated three times. All tests are carried out under ultrapure nitrogen.
  • a release study is conducted to quantify the behaviour of PAC when soaked in either water or PBS.
  • a 137 mM NaCI, 2.7 nmM KCI, and 1OmM PBS solution (Sigma Aldrich, pH 7.40 ⁇ 0.02 at 25°C) is prepared using ultrapure water (18.2 M ⁇ -cm).
  • 9 sterile plastic vials are filled with 20 ml of this solution; another 9 sterile plastic vials are filled with 20 ml of ultrapure water. All vials are then covered in aluminium foil and incubated for 12h at 37°C ⁇ 0.5.
  • One polymer or composite coupon is added to each vial, to obtain the following design:
  • the ATR spectra for PAC, neat PCL, and the PCL-PAC composite can be seen in Fig. 8.
  • the presence of PACs could be observed in the composite material spectrum, more specifically at 1610, 1524, and 825 cm “1 .
  • the peaks at 1695-1735 cm “1 associated with carbonyl stretching, as well as the peaks at 2800-3000 cm "1 , typical for CH 2 symmetrical and asymmetrical stretching of the PCL backbone are still strongly present, suggesting that the PACs and PCL are not covalently bonding.
  • PCL-5wt%PAC release profiles for PCL-5wt%PAC are almost identical for both water and PBS, as well as for PCL-2.5wt%PAC.
  • the final maximal concentrations of PACs in ultrapure water (after 21 days), for the PCL-2.5wt%PAC coupons is of 0.036mg/ml ⁇ 0.003, and of 0.082 mg/ml ⁇ 0.005 for the PCL-5wt%PAC coupons.
  • the concentrations after 21 days are of 0.043mg/ml ⁇ 0.004 for the PCL-2.5wt%PAC coupons, and of 0.082mg/ml ⁇ 0.010 for the PCL- 5wt%PAC coupons.

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Abstract

La présente invention concerne l'utilisation de proanthocyanidines, en particulier celles isolées de canneberge, en tant qu'agent anti-apoptotique et antibactérien, la propriété antibactérienne étant en outre due aux propriétés antiadhésives de PAC lorsqu'elles sont incluses dans un matériau.
PCT/CA2010/000044 2009-01-12 2010-01-12 Utilisation de proanthocyanidines en tant qu'agent anti-apoptotique et agent antiadhésion bactérienne Ceased WO2010078660A1 (fr)

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Cited By (10)

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FR2959938A1 (fr) * 2010-05-12 2011-11-18 Gunter Haesaerts Sonde urinaire comportant des proanthocyanidines et son mode d'utilisation
WO2013177275A1 (fr) * 2012-05-25 2013-11-28 The United States Of America, As Represented By The Secretary Of Agriculture Composition d'oligosaccharide de type xyloglucane d'airelles
EP2647286A4 (fr) * 2011-01-22 2014-01-08 Az Co Ltd Procédé de désinfection, dispositif de désinfection et agent désinfectant utilisant la lumière
WO2016146806A1 (fr) * 2015-03-19 2016-09-22 Uropharma Lmited Composition médicinale pour le traitement d'une infection des voies urinaires
WO2016196674A1 (fr) * 2015-06-01 2016-12-08 Robert Caron Lutte contre les biofilms au moyen de bacillus subtilis et de proantocyanidines de vaccinium macrocarpon
EP3129038A2 (fr) * 2014-04-11 2017-02-15 Institut National de la Santé et de la Recherche Médicale (INSERM) Utilisation de proanthocyanidine de canneberge pour le traitement de la colonisation bactérienne de l'oropharynge
WO2017096484A1 (fr) * 2015-12-11 2017-06-15 The Royal Institution For The Advancement Of Learning/Mcgill University Utilisation de composés phénoliques dérivés de canneberge en tant qu'agent de synergie antibiotique contre des bactéries pathogènes
US12234578B2 (en) 2020-01-29 2025-02-25 Wisconsin Alumni Research Foundation Tannin composite fibers
US12303564B2 (en) 2021-03-19 2025-05-20 Wisconsin Alumni Research Foundation Composite chitosan-tannin-active agent compositions and methods of making and using same
EP4496895A4 (fr) * 2022-03-21 2026-01-07 Tintoria Piana Us Inc Compositions contenant une teneur élevée en proanthocyanidines et leurs procédés de préparation et d'utilisation

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2959938A1 (fr) * 2010-05-12 2011-11-18 Gunter Haesaerts Sonde urinaire comportant des proanthocyanidines et son mode d'utilisation
EP2647286A4 (fr) * 2011-01-22 2014-01-08 Az Co Ltd Procédé de désinfection, dispositif de désinfection et agent désinfectant utilisant la lumière
US8999236B2 (en) 2011-01-22 2015-04-07 Az Co., Ltd. Disinfection method and disinfection device
WO2013177275A1 (fr) * 2012-05-25 2013-11-28 The United States Of America, As Represented By The Secretary Of Agriculture Composition d'oligosaccharide de type xyloglucane d'airelles
CN104507485A (zh) * 2012-05-25 2015-04-08 美利坚合众国（由农业部长代表） 蔓越莓木葡聚糖低聚糖组合物
US9314494B2 (en) 2012-05-25 2016-04-19 The United States Of America, As Represented By The Secretary Of Agriculture Cranberry xyloglucan oligosaccharide composition
CN104507485B (zh) * 2012-05-25 2018-10-09 美利坚合众国（由农业部长代表） 蔓越莓木葡聚糖低聚糖组合物
EP3129038A2 (fr) * 2014-04-11 2017-02-15 Institut National de la Santé et de la Recherche Médicale (INSERM) Utilisation de proanthocyanidine de canneberge pour le traitement de la colonisation bactérienne de l'oropharynge
WO2016146806A1 (fr) * 2015-03-19 2016-09-22 Uropharma Lmited Composition médicinale pour le traitement d'une infection des voies urinaires
US10772901B2 (en) 2015-03-19 2020-09-15 Uropharma Limited Medicinal composition for treating urinary tract infection (UTI)
AU2016232101B2 (en) * 2015-03-19 2020-10-08 Synesis Llc Medicinal composition for treating urinary tract infection (UTI)
WO2016196674A1 (fr) * 2015-06-01 2016-12-08 Robert Caron Lutte contre les biofilms au moyen de bacillus subtilis et de proantocyanidines de vaccinium macrocarpon
WO2017096484A1 (fr) * 2015-12-11 2017-06-15 The Royal Institution For The Advancement Of Learning/Mcgill University Utilisation de composés phénoliques dérivés de canneberge en tant qu'agent de synergie antibiotique contre des bactéries pathogènes
US12234578B2 (en) 2020-01-29 2025-02-25 Wisconsin Alumni Research Foundation Tannin composite fibers
US12303564B2 (en) 2021-03-19 2025-05-20 Wisconsin Alumni Research Foundation Composite chitosan-tannin-active agent compositions and methods of making and using same
EP4496895A4 (fr) * 2022-03-21 2026-01-07 Tintoria Piana Us Inc Compositions contenant une teneur élevée en proanthocyanidines et leurs procédés de préparation et d'utilisation

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