Hyperbactericidal surfaces

Details Hyperbactericidal surfaces Hyperbactericidal surfaces

1999-02-01

2001-11-13

Levy, Neil S. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Biocides; animal or insect repellents or attractants

C424S405000, C514S197000, C514S198000, C514S199000, C514S200000, C514S642000, C514S643000

Reexamination Certificate

active

06316015

ABSTRACT:

The present invention relates to a process for producing a surface with permanent antibiotic, bactericidal, fungicidal or viricidal properties, to surfaces which can be obtained by the production process, and to their use in the medical, cosmetics, food, hygiene or industrial fluids industries.
Throughout the present text, the terms “antibiotic”, “cytotoxic”, “bactericidal” molecules or substances should be deemed to include not only the bactericidal property itself, but also a viricidal, fungicidal or in general any bio-active substance which is cytotoxic to any living cell the elimination of which is desired.
Bactericidal surfaces already exist, in particular for medical use, for example gloves or fabrics. Non covalent mixtures of the surfaces and bactericidal substances have been described; a particular example is a pair of gloves incorporating a liquid medium containing an effective pharmacological agent between two layers of latex (French patent 87 11753); a further example is an emulsion of micro-droplets stabilised by a block copolymer (French patent number 93 15561, dated Dec. 23, 1993).
Medical implants or catheters have also been coated with an antibiotic or a mixture of antibiotics; the bonding with the support is ionic and the antibiotic is simply adsorbed on the substrate (International patent application WO 93 17746).
European patent EP-A-0 348 462 describes contact lenses constituted by an acrylic polymer the surface of which is modified by grafting organic molecules with the desired properties (UV resistance, selective cytotoxicity, etc . . . ). This molecule comprises a silane group which is reactive towards the carboxyl groups of the acrylic polymer chains. The modified surface of such lenses comprises a multilayer of the selected chemical group with a range of thicknesses: 50 to 100 Å in some cases (Table 1, column 4), 2000 to 6000 Å in other cases when the lens is modified to endow it with particular properties.
Depositing organic molecules on glass or silica substrates by grafting a monolayer has been described in Appl. Phys. Lett., 62, 2256 (1993), Sciences et Avenir, 567, 87 (1994) and in La Recherche, 275 (26), 460 (1995); applications for such modified surfaces are in the fields of self-lubricating surfaces, ultra-thin electrical insulators and stay-clean windows.
Antibiotic surfaces are of particular importance in the battle against the development of nosocomial infections in a hospital environment; the availability of materials the surface of which are cytotoxic and which could inhibit the development of bacteria which come into contact with those materials would be of great interest. These would include surgical instruments, catheters, and also crockery, doors and windows, wall coverings, ceramics etc . . . Further, the appearance of bacterial strains which have become resistant to normal doses of antibiotics necessitates the use of ever increasing concentrations of cytotoxic products. Thus the number of antibiotic molecules per unit surface area must be as high as possible.
The present invention provides a surface endowed with antibiotic, antiseptic, viricidal or fungicidal properties constituted by a mineral or organic solid substrate, the surface of which has been coated, using suitable chemical means, with a homogeneous, dense monolayer of molecules with these bio-active properties. Said molecules are fixed to the substrate by covalent bonds, which endows the active layer with a permanent and irreversible character.
The modified substrate of the invention is characterized in that the antibiotic molecules are fixed to the surface by covalent bonds via one or more “spacers”.
The spacer molecules are generally alkyl chains, composed of a series of 2 to 18 carbon atoms, and with functional groups at each extremity to enable an irreversible covalent bond to be formed firstly with a surface site of the solid substrate, and secondly with the bio-active molecule.
The spacer of the invention preferably has the formula
A
1
—(CH
2
)
n
—A
2
,
where:
A
1
is
where Z=H, OH or Cl; or SiY
3
where Y
3
is Cl or an alkoxy group containing 1 to 3 carbon atoms;
the number n of methylene groups forming the alkyl chain is in the range 2 to 24;
A
2
is selected from the following residues: CH
3
, CH═CH
2
, OH, halogen or
where Z=H, OH or Cl.
In the above formula, n is preferably in the range 5 to 18. Too short a spacer would run the risk of too high a rigidity while if it were too long, there would be a risk of the aliphatic chain folding back on itself, which would lead to less effective coupling with the antibiotic.
The substrates to be modified are either mineral surfaces, in particular silica based (sand, glass beads, glass wool), or organic substrates, depending on the desired use in fields as disparate as those cited above. Non limiting examples of organic substrates are polyethylene, polyvinyl chloride (PVC), polyacrylates, polymethacrylates, polypropylene, polyamides, polyurethanes, acrylonitrile-butadiene-styrene (ABS), saturated or unsaturated polyesters such as polyethylene terephthalate (PET), polycarbonates, polyacrylamides, Teflon® (PTFE), polysiloxanes, polysaccharides or any polymer or copolymer which can be grafted with a spacer containing two reactive extremities. The substrate can also be a metal or its oxide such as aluminium (Al), tin (Sn) or indium (In).
Some of the substrates used, in particular organic substrates, contain naturally reactive functions, either in their side chains such as PVC (Cl), polyacrylate (—COOH), polyamide (—CO—NH
2
) or polyhydroxymethylsiloxane (Si—H), or in their main chain such as polyurethane (—NH—CO—O—), polycarbonate (—O—CO—O—), or polyesters (—CO—O—).
In other compounds, however, the reactive functions have to be generated in situ using standard activation methods such as chemical oxidation or plasma treatment, using techniques described by L. Penn et al., (“Polymers for Advanced Technologies” (1994), 5: 809-817); this is the case, for example, for polyethylene and for numerous other polymers or copolymers.
In addition to the polymers cited above, any polymer containing reactive groups in its framework, or at its surface, or containing groups which can be transformed into a reactive group, are good candidates as a substrate for the surfaces of the invention. The surface is, of course, selected depending on the antibiotic or cytotoxic use which it is desired to develop.
The shapes of the surfaces can also vary depending on the desired use.
In biological or medical fields, flat or almost flat surfaces are encountered in bottles, pouches, flasks or other components; they can be tubular surfaces such as in catheters, syringes, needles, etc . . . ; or in hollow or solid microfibres. Hollow microfibres are used, for example, in renal dialysis cartridges or in hollow fibre systems for culturing animal cells.
Spherical surfaces are encountered in beads or micro-beads and can have any diameter which is appropriate for the desired use, in particular between a few microns and several millimetres. Examples of the use of beads are in children's sandpits, in the abrasive contained in toothpaste, and in systems for purifying water by contact with particles with a high specific surface area to decontaminate a solution by simple stirring with no risk of releasing the antibiotics into the medium.
When decontaminating industrial fluids (cutting fluid for machine tools, etc . . . ), the surfaces can be solid fibres assembled into a filtering cartridge.
Antibiotics which can be used for producing the surfaces of the invention are necessarily antibiotics which preferably act on the cell wall; antibiotics which act on a transcription or translation level are of less interest in the present case since covalent fixing does not allow the antibiotic to penetrate into the bacterium under the conditions which subsist when in solution.
In particular, these antibiotics can be those containing a &bgr;-lactam nucleus such as penicillins, cephalosporins, monobactams, thienamycins, &bgr;-lactamase inhibitors,

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