WO2004045663A1 - Surgical implant coated with a composition comprising a polyol fatty acid monoester - Google Patents

Surgical implant coated with a composition comprising a polyol fatty acid monoester

Info

Publication number
WO2004045663A1
WO2004045663A1 PCT/EP2003/012760 EP0312760W WO2004045663A1 WO 2004045663 A1 WO2004045663 A1 WO 2004045663A1 EP 0312760 W EP0312760 W EP 0312760W WO 2004045663 A1 WO2004045663 A1 WO 2004045663A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
fatty acid
characterized
coating
wt
implants
Prior art date
Application number
PCT/EP2003/012760
Other languages
French (fr)
Inventor
Heike Lackmann
Christoph Walther
Jörg PRIEWE
Stephen Wohlert
Original Assignee
Ethicon Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L17/00Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06At least partially resorbable materials
    • A61L17/10At least partially resorbable materials containing macromolecular materials
    • A61L17/12Homopolymers or copolymers of glycolic acid or lactic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L17/00Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/14Post-treatment to improve physical properties
    • A61L17/145Coating
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/04Macromolecular materials
    • A61L31/06Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/08Materials for coatings

Abstract

A surgical implant has a basic structure with an at least partial coating. The implant comprises alpha-hydroxycarboxylic acid oligomers (preferably lactic acid oligomers) and/or provides these ase decomposition product after implantation. The coating includes polyol fatty acid monoester, preferably glycerol fatty acid monester. The implant has an antimicrobial action.

Description

SURGICAL IMPLANT COATED WITH A COMPOSITION COMPRISING A POLYOL FATTY ACID MONOESTER

The invention relates to surgical implants (including surgical suturing threads) having antimicrobial properties.

There are many possible ways of providing surgical implants and medical products with bactericidal or antimi- crobial properties, in particular coatings with the active substance triclosan, or triclosan as a constituent, of a resorbable coating, and further the addition of - silver

(see, for example, US' 2001/0010016 Al: medical products with triclosan and silver compound; US 2001/0055622 Al : antimicrobial bioabsorbable materials, silver in a bioab- sorbable substrate), the addition of antibiotics, of bactericidal substances of plant origin or of other substances such as quaternary ammonium compounds or cyanoac- rylates, iodine and iodine-containing compounds. Examples of antimicrobial active substances are to be found, for instance, in K.H. Wallhauser: Praxis der Sterilisation De- sinfektion Konservierung [Practice of sterilization disinfection preservation], 5th edition, 1995.

In DE 195 21 642 Al, an implant is described which consists of resorbable material on surface areas protected against infection and which contains an antimicrobial active substance. In this case, the solubility of the antimicrobial active substance is chosen so that it is re- leased substantially throughout the entire period of degradation of the material.

US 4 024 871 discloses surgical suture material in which a multifilament strand is impregnated with an antimicrobial agent and is coated on the surface with a segmented polyu- rethane polymer. This coated suture material . retains its antmicrobial action over an extended period of time. Surgical suture material with a long-lasting antimicrobial action is also known from US 3 987 797. The suture material contains an elastomeric ionically bonded block co- polymer of polyquaternary polyurethane.

A disadvantage is that often the active substances are not positionally stable on the implants, for example because they dissolve too readily in body fluids; the action in si tu on the implant is then too short because the effec- tive dose is available only for a short time. Conversely, however, an antimicrobial action over too long a period of time can also be undesirable.

A further disadvantage is that the implants in many cases cannot be sterilized by conventional methods, for example ethylene oxide gas, because the process conditions necessary for this (temperature, pressure and time) lead to changes in the concentration of the active substance (sublimation, evaporation, etc.; for example in the case of triclosan or lactic acid) or the active substances react or lose their efficacy, for example, through oxidation with ethylene oxide (for example antibiotics which are sensitive to oxidation) . The use of gamma rays (cobalt sterilization) can lead to difficulties because chlorine- containing substances, for example triclosan or chlorhex- idine, cannot easily be sterilized by radiation (formation of chlorine-containing aromatic reaction products) .

Some active substances have a sensitizing action and can- not therefore be considered for use or implantation in humans. Silver does not break down in the body.

WO 00/71789 Al discloses hydrophilic polypropylene fibres with antimicrobial activity which are suitable for absorb- ent layers and wound dressings. Glycerol monolaurate is added to the polypropylene in the melt, optionally with a further additive for enhancing the hydrophilicity. The antimicrobial properties of the glycerol monolaurate are im- proved if lactic acid is applied to the surface of the fibres, this lactic acid being sprayed on in aqueous solution during production.

US 5,208,257 and EP 0 530 861 A2 describe topical antimicrobial pharmaceutical compositions which contain glycerol fatty acid ester (in particular glycerol monolaurate) , a mixture of fatty acids, and a carrier. Lactic acid can be added as chelating agent to the carrier.

The document JP 20024852 A discloses an 'antimicrobial non- woven textile structure in which polylactide fibres are used.

US 4 002 775 discloses the preservation of foodstuffs with 1- or 2-glycerol monolaurate.

The object of the invention is to develop an effective and biocompatible way of providing surgical implants with an- timicrobial properties, without having to greatly modify existing production and sterilization techniques.

This object is achieved by a surgical implant having the features of Claim 1 and by methods of manufacturing such an implant in accordance with Claims 13 to 18. Advanta-- geous embodiments of the invention are set out in the dependent claims .

The surgical implant according to the invention has a ba- sic structure and an at least partial coating. The coating includes polyol fatty acid monoester. The implant also comprises alpha-hydroxycarboxylic acid oligomers and/or provides alpha-hydroxycarboxylic acid oligomers as decomposition product after implantation.

By means of the active substance combination of polyol fatty acid monoesters (preferably glycerol fatty acid monoester) and alpha-hydroxycarboxylic acid oligomers (preferably dimers of lactic acid or oligomers of lactic acid with more than two units) , a temporary antimicrobial action is obtained for the implant. These active substances are biocompatible and can be. broken down in the body. The decomposition products are inert and/or are excreted, they are physiologically safe and, after implantation, they act for a defined period of time which can be set..

The duration of the antimicrobial action can be controlled via the degree of decomposition of the oligomeric lactic acid in the implant. Monomeric lactic acid or oligomers of lactic acid are antibacterial and strengthen the antibacterial action of the glycerol fatty acid monoesters, so that, as a result of the decomposition of the oligomeric lactic acid, a sufficiently high level of lactic acid and of low-molecular-weight oligolactic acid is obtained over the period of resorption.

The implant according to the invention can already contain the alpha-hydroxycarboxylic acid oligomers when supplied. However, as an alternative, or in addition to this, alpha- hydroxycarboxylic acid oligomers can also develop, after implantation, as decomposition product from implant sub- stance. Thus, resorbable polymers of polyhydroxy acids (e.g. a copolymer of glycolide and lactide in a ratio of 90:10 sold by Ethicon under the name "Vicryl") form oligomeric hydroxy acids during resorption, for example oligolactic acid. Low-molecular-weight oligomers are to be expected to be present at fairly high concentrations only after a considerable degree of decomposition (for example, in the case of Vicryl, only after more than 30 days, or, in the case of the predegraded "Vicryl" material sold by Ethicon under the name "Vicryl. Rapid", only after more than ca. 5 days) . If so desired, however, the implant or suture material according to the invention can already be provided with alpha-hydroxycarboxylic acid oligomers when supplied, so that, after just a short time -of implantation (for example after a few hours, or later, for example up to 3 weeks after implantation) it provides and releases a sufficiently high concentration of oligomeric hydroxy acids .

A further advantage is that products with the implant according to the' invention can be produced, in a form which is stable .during storage, by means of customary sterilization methods (for example gas sterilization with ethylene oxide or sterilization with cobalt gamma rays) . Problems of the kind which are to be expected in the case of im- pregnation with monomers . of lactic acid, namely an initially strong and unwanted reaction of the body tissue or a possible change in concentration upon ethylene oxide sterilization as a result of evaporation of the lactic acid under the prevailing pressure and temperature conditions, do not arise.

The coating preferably comprises a resorbable matrix. In this way, it is possible to control the timing of the release of the polyol fatty acid monoester and if appropriate of the alpha-hydroxycarboxylic acid oligomers (if these are included in the coating) . A resorbable matrix can for example be made" up of polymers and copolymers which are soluble in organic solvents (for example polylactides or polycaprolactones, or, for example, compounds composed of polytetramethylene adipates or the like) .

The coating can also be non-resorbable. If a coating with a non-resorbable matrix is present, the matrix is prefera- bly porous so that the polyol fatty acid monoester or monoesters and if appropriate the alpha-hydroxycarboxylic acid oligomers included in the coating have access to the surrounding body tissue or tissue fluids so as to be able to deploy their antimicrobial action. With the' aid of the resorbable or non-resorbable matrix, the readily water- soluble decomposition products (in particular lactic acid or low- olecular-weight oligolactic acid) can temporarily bind to the implant in a stable position. Non-resorbable coatings can be produced, for example, on the basis of silicones or polyvinyl acetates. The access to the antimi- crobial active substances can also take place through swelling of the coating, by which means the coating takes up tissue fluids, which thus come into contact with polyol fatty acid monoester or alpha-hydroxycarboxylic acid oligomers .

As has already been indicated, the coating can include alpha-hydroxycarboxylic acid oligomers and/or can provide alpha-hydroxycarboxylic acid oligomers as decomposition product after 'implantation. Alternatively, or in addition to this, it is conceivable for the basic structure to provide alpha-hydroxycarboxylic acid oligomers as decomposition product after implantation.

Examples of preferred alpha-hydroxycarboxylic acid oli- gomers are dimers of L-lactic acid, higher oligomers of L- lactic acid, dimers of D-lactic acid, higher oligomers of D-lactic acid, dimers of DL-lactic acid, higher oligomers of DL-lactic acid, oligomeric copolymers of glycolide and lactides, and mixtures of the abovementioned substances. "Higher" oligomers are to be understood here as oligomers with more than two structural units.

The production of oligomeric lactic acid is described, for example, in the document GB 2 135 320 A, the disclosure of which is taken up in the present application. Oligomeric lactic acid is also obtainable as a commercial product. The inherent viscosity, which is a measure of the degree of polymerization, . serves for characterization. Thus, for example, Alkermes supplies what are called "Medisorb Poly- mers" with inherent viscosities in the range of 0.08 dl/g to 0.80 dl/g (type 5050 DL 1A with an inherent viscosity of 0.08 dl/g to 0.012 dl/g, and type 5050 Dl 4A with an inherent viscosity of 0.38 dl/g to 0.48 dl/g). Polyscience supplies poly (DL-lactic acid) with an inherent viscosity of 0.15 dl/g to 0.30 dl/g and with an inherent viscosity of 0.35 to 0.45 dl/g and poly (L-lactic. acid) of different degrees of polymerization and also poly(DL- lactide/glycolide) and pol (L-lactide/glycolide) of different degrees of polymerization. The inherent viscosity preferably lies in the range of 0.01 dl/g to 0.8 dl/g. Oligomeric copolymers of, for example, glycolide and lac- tides are also described in GB 2 135 320 A; here the molar mass is indicated instead of the inherent viscosity, because the inherent viscosity cannot be measured in standard solvents.

As hydroxycarboxylic acid derivatives or lactic acid de- rivatives, it is also possible, for example, to use so- called "monomer residues" from the processing or production of resorbable polymers.

Examples of polyol fatty acid onoesters are 1-glycerol fatty acid monoester having a fatty acid residue of a saturated fatty acid with 6 to 18 carbon atoms, preferably with 6, with 12 or with 18 carbon atoms, 2-glycerol fatty acid monoester having a fatty acid residue of a saturated fatty acid with 6 to 18 carbon atoms, preferably with 6, with 12 or with 18 carbon atoms, 1-glycerol fatty acid monoester with a fatty acid residue of an unsaturated fatty acid, 2-glycerol fatty acid monoester with a fatty acid residue of an unsaturated fatty acid, and mixtures of the abovementioned substances.

The coating can, for example, comprise copolymers of glycolide and lactides, preferably of 35 wt-% glycolide and 65 wt-% L-lactide, predegraded copolymers of glycolide and lactides, copolymers of caprolactone and glycolide, co- polymers of caprolactone and lactides, copolymers of caprolactone, glycolide. and lactides, polytetramethylene adipate, copolymers of aliphatic diols and aliphatic di- carboxylic acids, or soluble polyurethanes but also, for example, silicones or polyvinyl acetates.

Resorbable . coatings of L-lactides/glycolides in different mixing ratios are particularly preferred. Such coatings can at the same time -be a 'source of' alpha- hydroxycarboxylic acid oligomers (lactic acid deriva- tives/hydroxycarboxylic acid derivatives) which are re-, leased during resorption and have an antimicrobial action (see above) . The molar mass of the coating is preferably chosen such that a wax-like covering is obtained.

Resorbable coatings with polytetramethylene adipate are particularly suitable for polyester (e.g. for polyethylene terephthalate PET) , for example in the case of non- resorbable suture material made of PET, like the suture material sold by Ethicon under the name "Ethibond". Copolymers of caprolactone and glycolide/lactides are known as suture material coatings .

The surgical implant according to the invention can be configured for numerous different applications. Generally, the nature of the application is determined by the form of the basic structure. Examples of implants and their basic forms are: suturing threads, surgical sutures, cord-like implants, tape-like implants, areal implants, films, meshlike implants, mesh-like implants with small pores, meshlike implants with large pores, three-dimensional implants (i.e. implants with a relatively large extent in all three spatial directions), textile structures of every kind, voluminous fleece-like implants, implants for dura replacement, suture-bearing implants, constructs for tissue formation, constructs for cell colonizing, tubes, wires, stents, drainages, catheters, vessel prostheses.

The basic structure can be resorbable, non-resorbable or partially resorbable. Examples of materials of or in the basic' structure are: bioco patible metals, steel, tita- niu , nitinol, metal alloys, ceramics, glasses, silicones, natural polymers, synthetic polymers resorbable, polymers, polypropylene, polyvinylidene fluoride, fluorinated polyolefins, polyesters, polyethylene terephthalate, poly- mers and copolymers of lactides, glycolides, caprolactone and/or trimethylene carbonate, predegraded copolymers of glycolide and L-lactide, poly-p-dioxanone, polyurethanes .

In the case of predegraded material, a resorbable material undergoes preliminary treatment leading to more rapid resorption after implantation. In particular, copolymers of glycolide and L-lactide can - be predegraded by treating them in a hydrolysis buffer or by -irradiation. An example of such a material is "Vicryl Rapid" (see above) : It is also conceivable to predegrade the resorbable portion of a finished basic structure (e.g. in partially resorbable implants or suture material) . As has already been mentioned above, this permits more rapid provision of alpha- hydroxycarboxylic acid oligomers .

In advantageous embodiments of the invention, the coating includes (in addition to polyol fatty acid onoesters and if appropriate alpha-hydroxycarboxylic acid oligomers) at least one biologically active substance, for example natu- ral ingredients, synthetic ingredients, antibiotics, che- motherapeutics, cytostatics, metastasis inhibitors, anti- diabetics, antimycotics, gynaecological agents, urological agents, anti-allergic agents, analgetics, neuroleptics, antirheu atics, anti-inflammatory agents, antimicrobial agents, sexual hormones, sexual hormone inhibitors, haemo- styptics, hormones, peptide hormones, antidepressants, an- tihistamines, naked DNA, plasmid DNA, cationic DNA complexes, RNA, cell constituents, vaccines, cells occurring naturally in the body, genetically modified cells. In ad- dition to the stated antimicrobial properties' (which can also have an antiproliferative character, as is shown in Example 9 below) , the implant can be given further fea- tures, for example extended antimicrobial and/or antipro- liferative properties.

In preferred embodments, the coating amounts to 0.1% to 20% of the total weight of the implant.

There are many possible methods of manufacturing an implant according to the invention. In a preferred embodiment, the coating is applied to the basic structure as a solution or dispersion. The solution or dispersion contains a matrix material, alpha-hydroxycarboxylic acid oligomers, polyol fatty acid monoester and a solvent or dispersing agent. The solvent or dispersing agent is subsequently evaporated. . The solution or dispersion preferably includes 1 wt-% to 30 wt-% .of matrix material (for example the basic materials mentioned above for the coating), 0.1 wt-% to 10 wt-% of alpha-hydroxycarboxylic acid oligomers, 0.1 wt-% to 10 wt-% of polyol fatty acid monoester, optionally up to 30 wt-% of additional substances, and sol- vent or dispersing agent, preferably an organic solvent or dispersing agent, as balance.

If the solution or dispersion includes copolymers of glycolide and lactides or predegraded copolymers of glycolide and lactides as matrix material (and in addition to these also polyol fatty acid monoester and a solvent or dispersing agent) , addition of alpha-hydroxycarboxylic acid oligomers can be dispensed with, even if the basic structure contains no alpha-hydroxycarboxylic acid oligomers or does not provide them as decomposition product.

To create a two-stage coating, a solution or • dispersion with alpha-hydroxycarboxylic acid oligomers and polyol fatty acid monoester in • a solvent or dispersing agent (without matrix material or binder or only with a slight addition thereof) is first applied to the basic structure.. After evaporation of the solvent or dispersing agent," a further layer is applied. Dipping or spraying methods, for example, are suitable for applying the solution or dispersion.

The implant can finally be sterilized with ethylene oxide. This is because the antimicrobial active substances are not impaired, or are not impaired to any appreciable extent, as explained above, under the conditions which then prevail. Sterilization with gamma rays, for example cobalt radiation, is likewise possible.

The invention is explained in more detail , below on the basis of examples.

Example 1

Surgical suture material of "Vicryl" (Ethicon; copolymer of glycolide and lactide in a ratio of 90:10) can be pro- vided with an antimicrobial coating in analogy to . standard methods for thread coating of suture material.

A suitable coating mixture for "Vicryl" threads (thread strengths according to USP of between 9-0 and 6) is a mix- ture with a coating copolymer of glycolide/L-lactide as matrix material (4.5 wt-% to 7.5 wt-%), calcium stearate

(manufactured by Malinckrodt Chemical Inc;

4.5 wt-% to 7.5 wt-%), L-oligolactic acid (Polyscience)

(0.1 wt-% to 5 wt-%), glycerol monostearate (Albimono 90 V manufactured by AB Technologies Ltd; content of monoglyc- erides more than 90%, according' to USP 23; 0.1 wt-% to 5 wt-%) and ethyl acetate as solvent and dispersing agent (remaining wt-%) .

The coating is carried out in a one-stage method with subsequent "pliabilization". To do this, a bath with the above mixture is first set up. An uncoated thread is guided via rollers throuαh this bath and subsequently dried in a channel at ca. 50 °C to 55 °C. The coil material is then dried in vacuo for 16 hours at ca. 50°C. A "pli- abilization" is then carried out; i.e. the wax-like coating is broken open by reeling it between pairs of rollers in order to enlarge the active surface and improve the handling of the thread; the thread ι is thus made softer. The thread contains ca. 0.5 to 20 weight percent (wt-%) of the coating components. The thread is finally finished, packed and sterilized.

In a concrete example, a "Vicryl" thread of strength 1 was passed through a bath made up as follows:

5 wt-% of G/L copolymer (35 wt-% of glycolide, 65 wt-% of lactide, inherent viscosity 0.4 dl/g to 0.8 dl/g),

5 wt-% of calcium stearate,

1 wt-% of oligolactic acid (poly (L-lactic acid), Polyscience; inherent viscosity 0.10 dl/g to 0.20 dl/g; molecular weight 1600 to 2400),

1 wt-% of glycerol monostearate,

dispersed in ethyl acetate (remaining wt-%)

The coating was carried out in the way described above; thereafter, the thread was packed and sterilized. The thread contained ca. 2 wt-% of the coating components.

The antimicrobial activity of the described sterile thread was determined using AATCC Test Method 100-1999 ("Assess¬ ment of antibacterial finishes on textile materials") , specifically with Staphylococcus aureus. Compared to an uncoated thread, there was a marked reduction of colony- forming units after an incubation period of 24 hours. Example 2

In a coating according to example 1, glycerol monolaurate was used instead of glycerol monostearate. A plant-based glycerol monolaurate with the trade name "Monomuls", type 90-L-12 was used (produced by Grϋnau Illertissen; sold by Cognis Deutschland GmbH, Care Chemicals) . This product is molecularly distilled and has a monoester content of at least 90%; the starting materials are coconut oil and glycerol.

Example 3

In a two-stage method, a mixture with oligolactic acid and glycerol fatty acid derivative in ethyl acetate or another suitable solvent or dispersing agent is first applied to the basic structure. After drying, a further coating with, for example, copolymers of lactide and glycolide or co- polymers of glycolide and caprolactones is applied in a second' stage. For this further coating, it is also possible to use a standard coating, as is employed for example in suture material.

Example 4

Threads of polyester (polyethylene terephthalate PET; sold by Ethicon under the name "Mersilene" or, coated, as "Ethibond") can be coated as in example 1. The coating bath contains glycerol monostearate, oligolactic acid, 3 wt-% to 15 wt-% of polytetramethylene adipate (produced by Ethicon; molar mass ca. 1100 to 3200 g/mol) as .matrix material and, for example, toluene as solvent. The amount of solid applied to the thread is then ca. 0.5 wt-% to 15 wt- %. Thread strengths of between # 7-0 to strength 7 (USP) are suitable, but also, for example, cords with a diameter of 1 mm or more. Example 5

In order to ' investigate the antimicrobial activity, a coating bath was first set up in accordance with the concrete recipe in example 1 (but without calcium stearate) , and using glycerol monolaurate ' instead of glycerol monostearate. A sample of a section of "Vypro II" mesh (composite mesh of "Vicryl" and polypropylene yarns; Ethi- con) was coated by dipping . it into this coating bath and then drying it.

This mesh sample, provided with a coating containing glycerol monolaurate and an oligomeric lactic acid in a coat- ing copolymer, was dipped for 5 seconds into a solution of Staphylococcus aureus with 10,000 CFU/ l (CFU: colony- forming units) . The number of microbes on the mesh was determined immediately and after 1 hour, after 6 hours and after 24 hours (surface-sampling with Rodac plates) .

For comparison purposes, an uncoated mesh was subjected to the same treatment.

Compared to the uncoated mesh, there was a marked reduc- tion in the number of microbes after just 6 hours.

The test was repeated with Escherichia coli. Again, compared to an uncoated mesh, there was a marked reduction in the number of microbes after just one hour.

Example 6

In the manner already explained, and also described in ex- ample 5, areal implants and three-dimensional implants

(for example fleeces) can likewise be made bactericidal or antimicrobial with alpha-hydroxycarboxylic acid oligomers and polyol fatty acid monoester. Examples of basic structures which may be mentioned here are:

meshes made of "Vicryl" (copolymer of glycolide and lac- tide in the ratio of 90:10, Ethicon),

mesh pouches made of "Vicryl" (Ethicon) ,

"Vypro" meshes (composite meshes made of "Vicryl" and polypropylene, Ethicon) ,

"Mersilene" meshes (meshes made of polyester, Ethicon) ,

"Vypro II" meshes (composite meshes made of "Vicryl" and polypropylene yarns; Ethicon),

"Monocryl"-containing meshes (Ethicon; "Monocryl": copolymer of glycolide and epsilon-caprolactone) ,

other non-resorbable meshes, for example of "Pronova", a mixture of polyvinylidene fluoride and a copolymer of vi- nylidene fluoride and hexafluoropropene (Ethicon) , or other composite meshes made up of resorbable and non- resorbable proportions, or tapes, e.g. a woven tape of polyester yarns (such as that sold by Ethicon under the name "Mersilene tape") ,

cords, for example of polyesters or of resorbable materials,

fleeces, for example of "Vicryl" and poly-p-dioxanone yarns (trade name "Ethisorb" from Ethicon) , but also, for example, needlefelts of "Vicryl" yarns,

drainages or catheters,

vessel prostheses, implants of stainless steel, for example stents.

The coating can be applied to the basic structure in one stage, for example analogously to examples 1 and 4, or in two stages (e.g. analogously to example 3). Moreover, the coating can additionally be provided with further active substances .

A dipping method for applying the coating takes place for example analogously top example 1 (dipping, drying, packing and sterilization with ethylene oxide) . Instead of using a dipping bath, a solution/dispersion of the coating agents can also be sprayed onto the basic structure.

In a further embodiment, the basic structure is dipped into a bath with a solution/dispersion of the coating agents and is then removed from the bath. The temperature is then increased so that the coating melts and penetrates into the basic structure. After drying and packing, ster- ilization is carried out with ethylene oxide.

Example 7

In the case of a "Vypro" mesh (Ethicon, see example 6) , the "Vicryl" proportion can be predegraded by hydrolysis (e.g. at pH 7.26 in a phosphate buffer solution at ca. 50°C for two days, followed by brief washing and drying), so that an addition of oligolactic acid is not required since this is already provided by the hydrolysis. This is followed by impregnation with glycerol fatty acid monoes- ters and, optionally, additional coating.

An analogous method can be carried out with "Vicryl" meshes or with meshes containing "Monocryl" (see example 6) . In the latter case, the hydrolysis is done, for example, for 5 days at 41°C in a phosphate buffer, with oli- go eric structural units arising from the glycolide proportion.

Example 8

Non-resorbable coatings can be produced for example on, the basis of silicones.

Thus, for example, metal implants or medical products, as are described in DE 197 22 880 Cl for surgical needles, can be coated with different silicone oils in a plurality of stages, and the coating solutions can contain the antimicrobial active substances or also additional active sub- stances. This method is also suitable, for example, for coating catheters made of silicones.

Other non-resorbable coatings can, for example, contain a matrix of polyvinyl acetates. Examples of suitable coating methods are dipping or spraying methods in which a solution of polyvinyl acetates and active substances in a suitable solvent is used.

Example 9

The therapeutic efficacy of a medical-quality stainless steel probe coated with a mixture containing oligolactic acid and glycerol monostearate was demonstrated in the following way:

1) LS174T cells (tumour cells) were cultured in a standard Petri dish (DMEM medium with 10% foetal bovine serum; 37° Celsius; 5% carbon dioxide) . This preparation served as a control for a coated and an uncoated stainless steel probe. 2) A stainless steel probe measuring 3 cm in length was dipped several times into a 1:1 mixture of oligolactide and glycerol monostearate (Albimono 90 produced by AB Technologies Ltd) in THF (ca. 5% strength) and was dried with evaporation of the solvent THF. The coating had a thickness, viewable by microscope, of less than 50 micrometres. The probe was fixed on the bottom of a Petri dish by means of a magnet mounted on the outside of the Petri dish. The cultured LS174T cells were then transferred to this Petri dish.

3) Analogously to 2), an uncoated stainless steel probe was introduced into a Petri dish and fixed therein by a magnet. The cultured LS174T cells were then also trans- ferred to this Peri dish. This preparation served as a control for the behaviour of a stainless steel probe not provided with a coating.

The status of the cells in preparations 1) to 3) was checked after 24 hours, 48 hours and 72 hours. The criterion used for evaluating the status of the cell cultures was the formation of a homogeneous cell lawn on the bottom of the culture dishes.

The findings were as follows: In the preparation described under 1), the cells multiplied normally and formed an almost homogeneous cell lawn. In the preparation .described under 2) , the status of the cell culture was markedly poorer after 24 hours. No almost homogeneous cell lawn had formed. After 48 hours and 72 hours too, no cells had grown on. In the preparation described under 3) , the status of the cell culture was as in the control described under 1) .

This investigation shows clearly that the coating of the stainless steel probe prevents the growth of the cells.

Claims

Claims
1. Surgical implant,, having a basic structure and an at least partial coating, the implant comprising alpha- hydroxycarboxylic acid oligomers and/or providing alpha-' hydroxycarboxylic acid oligomers as decomposition product after implantation, and the coating including polyol fatty acid monoester.
2. Implant according to Claim 1, characterized in that the coating comprises a resorbable matrix.
3. Implant according to Claim 1, characterized in that the coating is non-resorbable or comprises a non-resorbable matrix.
4. Implant according to one of Claims 1 to 3, characterized in that the coating includes alpha-hydroxycarboxylic acid oligomers and/or provides alpha-hydroxycarboxylic acid oligomers as decomposition product after implantation.
5. Implant according to one of Claims 1 to 4, characterized in that the basic structure provides alpha- hydroxycarboxylic acid oligomers as decomposition product after implantation.
6. Implant according to one of Claims 1 to 5, characterized in that the alpha-hydroxycarboxylic acid oligomers comprise at least one of the substances selected from the following group: dimers of L-la"ctic acid, higher oligomers of L-lactic acid, dimers of D-lactic acid, higher oligomers of D-lactic acid, dimers of DL-lactic acid, higher oligomers of DL-lactic acid, oligomeric copolymers of glycolide and lactides, mixtures of the above- mentioned substances .
7. Implant according to one of Claims 1 to 6, characterized in that the polyol fatty acid monoester comprises at least one of the substances selected from the following group: 1-glycerol fatty acid monoester having a fatty acid residue of a saturated fatty acid with 6 to 18 carbon atoms, preferably with 6, with 12 or with 18 carbon atoms, 2-glycerol fatty acid monoester having a fatty acid residue of a saturated fatty acid with 6 to 18 carbon atoms, preferably with 6, with 12 or with 18 carbon atoms, 1-glycerol fatty acid monoester with a fatty' acid residue of an unsaturated fatty acid, 2-glycerol fatty acid monoester with a fatty acid residue of an unsaturated fatty acid,- mixtures of the abovementioned sub- stances.
8. Implant according to one of Claims 1 to 7, characterized in that the coating comprises at least one of the substances selected from the following group: copolymers of glycolide and lactides, preferably of 35 wt-% glycolide and 65 wt-% L-lactide, predegraded copolymers of glycolide and lactides, copolymers of caprolactone and glycolide, copolymers of caprolactone and lactides, copoly-- mers of caprolactone, glycolide and lactides, polytet- ramethylene adipate, copolymers of aliphatic diols and aliphatic dicarboxylic acids, soluble polyurethanes, silicones, polyvinyl 'acetates .
9. Implant according to one of Claims 1 to 8, characterized in that the basic structure has one of the forms selected from the following group: suturing threads, surgical sutures, cord-like implants, tape-like implants, areal implants, films, mesh-like implants, mesh-like implants with small pores, mesh-like implants with large pores, three-dimensional implants, textile structures, voluminous fleece-like implants, implants for dura replacement, suture bearing implants, constructs for tis- sue . formation, constructs for cell colonizing, tubes, wires, stents, drainages, catheters, vessel prostheses.
10. Implant according to one of Claims 1 to 9, characterized ' in that the basic structure comprises 'at least one of the substances selected from the following group: bio- compatible metals, steel, titanium, nitinol, metal alloys, ceramics, glasses, silicones, natural polymers, synthetic polymers, resorbable polymers, polypropylene, polyvinylidene fluoride, fluorinated polyolefins, polyesters, polyethylene terephthalate, polymers and copolymers of lactides, glycolides, caprolactone and/or tri- methylene carbonate, predegraded copolymers of glycolide and L-lactide, poly-p-dioxanone, polyurethanes .
11. Implant according to one of Claims 1 to 10, characterized in that the coating includes at least one biologically active agent, which preferably comprises at least one of the substances selected from the following group: natural ingredients, synthetic ingredients, antibiotics, chemotherapeutics, cytostatics, metastasis inhibitors, antidiabetics, antimycotics, gynaecological agents, uro- logical agents, anti-allergic agents, analgetics, neuro- leptics, antirheu atics, anti-inflammatory agents, anti- microbial agents, sexual hormones, sexual hormone in¬ hibitors, haemostyptics, hormones, peptide hormones, an- tidepressants, anti istamines, naked DNA, plasmid DNA, cationic DNA complexes, RNA, cell constituents,- vaccines, cells occurring naturally in the body, geneti- cally modified cells.
12. Implant according to one of Claims 1 to 11, characterized in that the coating amounts to 0.1% to 20% of the total weight of the implant.
13. Method of manufacturing an implant according to one of Claims 1 to 12, characterized in that the coating is ap¬ plied to the basic structure as solution. or dispersion, the solution or dispersion containing a matrix material, alpha-hydroxycarboxylic acid oligomers, polyol fatty acid monoester and a solvent or dispersing agent, and in that the solvent or dispersing agent is subsequently evaporated.
14. Method according to Claim 13, characterized in that the solution or dispersion includes 1 wt-% to 30 wt-% of matrix material, preferably at least one of the substances according to Claim 8, 0.1 wt-% to 10 wt-% of alpha- hydroxycarboxylic acid oligomers, 0.1 wt-% to 10 wt-% of polyol fatty acid monoester, optionally up to 30 wt-% of additional substances, and solvent or dispersing agent, preferably an organic solvent or dispersing agent, as balance.
15. Method of manufacturing an implant according to one of Claims 1 to 12, characterized in that the coating is applied to the basic structure as solution or dispersion, the solution or dispersion including copolymers of glycolide and lactides or predegraded copolymers of glycolide and lactides as matrix material, polyol fatty acid monoester and a solvent or dispersing agent, and in that the solvent or dispersing agent is evaporated after- wards.
16. Method of manufacturing an implant according to one of Claims 1 to 12, characterized in that a solution or dispersion with alpha-hydroxycarboxylic acid oligomers and polyol fatty acid monoester in a solvent or dispersing agent is applied to the basic structure and in that, after evaporation of the solvent or dispersing agent, a further layer is applied.
17. Method according to one of Claims 12 to 16, characterized in that, finally, the implant is sterilized with ethylene oxide.
8. Method according to one of Claims 12 to 16, characterized in that, finally, the implant is sterilized with gamma rays, preferably cobalt radiation.
PCT/EP2003/012760 2002-11-20 2003-11-14 Surgical implant coated with a composition comprising a polyol fatty acid monoester WO2004045663A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE10254215.5 2002-11-20
DE2002154215 DE10254215B4 (en) 2002-11-20 2002-11-20 A surgical implant

Publications (1)

Publication Number Publication Date
WO2004045663A1 true true WO2004045663A1 (en) 2004-06-03

Family

ID=32308615

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/012760 WO2004045663A1 (en) 2002-11-20 2003-11-14 Surgical implant coated with a composition comprising a polyol fatty acid monoester

Country Status (2)

Country Link
DE (1) DE10254215B4 (en)
WO (1) WO2004045663A1 (en)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1743660A3 (en) * 2005-07-11 2007-11-07 Tyco Healthcare Group Lp Antimicrobial sutures and methods of making them
US20080142023A1 (en) * 2006-12-11 2008-06-19 3M Innovative Properties Company Biocompatible antimicrobial compositions
US7901705B2 (en) 2006-02-28 2011-03-08 Tyco Healthcare Group Lp Antimicrobial releasing polymers
US8075612B2 (en) 2006-11-13 2011-12-13 Aesculap Ag Textile vascular prosthesis with a coating
US8092824B2 (en) 2005-01-19 2012-01-10 Heraeus Kulzer Gmbh Antibiotic coating of implants
US8273105B2 (en) 2008-02-20 2012-09-25 Tyco Healthcare Group Lp Compound barb medical device and method
US8353931B2 (en) 2006-11-02 2013-01-15 Covidien Lp Long term bioabsorbable barbed sutures
US8414612B2 (en) 2010-11-08 2013-04-09 Covidien Lp Multifilament barbed suture
EP2415488A3 (en) * 2010-08-06 2014-01-08 Aesculap AG Thread, especially surgical thread, an implant comprising the thread and also a process for producing the thread and the implant
US8661632B2 (en) 2011-09-22 2014-03-04 Ethicon, Inc. Method and apparatus for pliabilizing knitted or woven materials
US8888810B2 (en) 2008-02-20 2014-11-18 Covidien Lp Compound barb medical device and method
US8932329B2 (en) 2008-02-20 2015-01-13 Covidien Lp Compound barb medical device and method
US8932327B2 (en) 2008-04-01 2015-01-13 Covidien Lp Anchoring device
US9034011B2 (en) 2008-04-01 2015-05-19 Covidien Lp Anchoring device
US9044224B2 (en) 2010-04-12 2015-06-02 Covidien Lp Barbed medical device and method
US9107660B2 (en) 2012-02-01 2015-08-18 Covidien Lp Wound closure device
US9220492B2 (en) 2012-02-01 2015-12-29 Covidien Lp Wound closure device
US9307983B2 (en) 2006-09-06 2016-04-12 Covidien Lp Bioactive substance in a barbed suture
US9358002B2 (en) 2008-04-01 2016-06-07 Covidien Lp Anchoring device
US9487893B2 (en) 2009-03-31 2016-11-08 3M Innovative Properties Company Dimensionally stable nonwoven fibrous webs and methods of making and using the same

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10355189B4 (en) * 2003-11-26 2015-04-30 Johnson & Johnson Medical Gmbh A method of manufacturing a surgical implant and surgical implant
DE102004063794A1 (en) * 2004-12-30 2006-07-13 Universität Duisburg-Essen implant
DE102006039346A1 (en) * 2006-08-22 2008-03-13 Biotronik Vi Patent Ag Biocorrodible metallic implant with a coating or cavity filling of a PEG / PLGA copolymer
DE102007039871A1 (en) 2007-08-21 2009-02-26 Friedrich-Baur-Gmbh A soft tissue implant with antibacterial effect
DE102011107109A1 (en) * 2011-07-12 2013-01-17 Translumina Gmbh Implantable endoprosthesis

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4201216A (en) * 1976-12-15 1980-05-06 Ethicon, Inc. Absorbable coating composition for sutures
WO2000071789A1 (en) * 1999-05-21 2000-11-30 3M Innovative Properties Company Hydrophilic polypropylene fibers having antimicrobial activity
WO2000071183A1 (en) * 1999-05-21 2000-11-30 3M Innovative Properties Company Antimicrobial articles

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7030127B2 (en) * 2001-06-29 2006-04-18 Ethicon, Inc. Composition and medical devices utilizing bioabsorbable polymeric waxes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4201216A (en) * 1976-12-15 1980-05-06 Ethicon, Inc. Absorbable coating composition for sutures
WO2000071789A1 (en) * 1999-05-21 2000-11-30 3M Innovative Properties Company Hydrophilic polypropylene fibers having antimicrobial activity
WO2000071183A1 (en) * 1999-05-21 2000-11-30 3M Innovative Properties Company Antimicrobial articles

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8092824B2 (en) 2005-01-19 2012-01-10 Heraeus Kulzer Gmbh Antibiotic coating of implants
US8273104B2 (en) 2005-07-11 2012-09-25 Tyco Healthcare Group Lp Antimicrobial sutures and methods of making them
EP1743660A3 (en) * 2005-07-11 2007-11-07 Tyco Healthcare Group Lp Antimicrobial sutures and methods of making them
US20110129512A1 (en) * 2006-02-28 2011-06-02 Tyco Healthcare Group Lp Antimicrobial Releasing Polymers
US7901705B2 (en) 2006-02-28 2011-03-08 Tyco Healthcare Group Lp Antimicrobial releasing polymers
US9307983B2 (en) 2006-09-06 2016-04-12 Covidien Lp Bioactive substance in a barbed suture
US8353931B2 (en) 2006-11-02 2013-01-15 Covidien Lp Long term bioabsorbable barbed sutures
US8075612B2 (en) 2006-11-13 2011-12-13 Aesculap Ag Textile vascular prosthesis with a coating
US20080142023A1 (en) * 2006-12-11 2008-06-19 3M Innovative Properties Company Biocompatible antimicrobial compositions
US9555167B2 (en) 2006-12-11 2017-01-31 3M Innovative Properties Company Biocompatible antimicrobial compositions
US8273105B2 (en) 2008-02-20 2012-09-25 Tyco Healthcare Group Lp Compound barb medical device and method
US9713467B2 (en) 2008-02-20 2017-07-25 Covidien Lp Compound barb medical device and method
US8888810B2 (en) 2008-02-20 2014-11-18 Covidien Lp Compound barb medical device and method
US9050082B2 (en) 2008-02-20 2015-06-09 Covidien Lp Compound barb medical device and method
US8932329B2 (en) 2008-02-20 2015-01-13 Covidien Lp Compound barb medical device and method
US9788832B2 (en) 2008-02-20 2017-10-17 Covidien Lp Compound barb medical device and method
US9034011B2 (en) 2008-04-01 2015-05-19 Covidien Lp Anchoring device
US8932327B2 (en) 2008-04-01 2015-01-13 Covidien Lp Anchoring device
US9358002B2 (en) 2008-04-01 2016-06-07 Covidien Lp Anchoring device
US9487893B2 (en) 2009-03-31 2016-11-08 3M Innovative Properties Company Dimensionally stable nonwoven fibrous webs and methods of making and using the same
US9044224B2 (en) 2010-04-12 2015-06-02 Covidien Lp Barbed medical device and method
EP2415488A3 (en) * 2010-08-06 2014-01-08 Aesculap AG Thread, especially surgical thread, an implant comprising the thread and also a process for producing the thread and the implant
US8414612B2 (en) 2010-11-08 2013-04-09 Covidien Lp Multifilament barbed suture
US8661632B2 (en) 2011-09-22 2014-03-04 Ethicon, Inc. Method and apparatus for pliabilizing knitted or woven materials
US9107660B2 (en) 2012-02-01 2015-08-18 Covidien Lp Wound closure device
US9220492B2 (en) 2012-02-01 2015-12-29 Covidien Lp Wound closure device

Also Published As

Publication number Publication date Type
DE10254215B4 (en) 2014-10-09 grant
DE10254215A1 (en) 2004-06-09 application

Similar Documents

Publication Publication Date Title
US6093200A (en) Composite bioabsorbable materials and surgical articles made therefrom
US5152781A (en) Medical devices fabricated from homopolymers and copolymers having recurring carbonate units
US5037429A (en) Method for improving the storage stability of a polymeric braided suture susceptible to hydrolytic degradation and resulting article
US6485749B1 (en) Absorbable ε-Caprolactone polymers and medical devices
US5462162A (en) Packaged synthetic absorbable surgical elements
US5447966A (en) Treating bioabsorbable surgical articles by coating with glycerine, polalkyleneoxide block copolymer and gelatin
US6260699B1 (en) Packaged synthetic absorbable surgical elements
US6916483B2 (en) Bioabsorbable plugs containing drugs
US5110852A (en) Filament material polylactide mixtures
US5222978A (en) Packaged synthetic absorbable surgical elements
US20060147491A1 (en) Biodegradable coating compositions including multiple layers
US5061281A (en) Bioresorbable polymers and implantation devices thereof
US5578662A (en) Bioabsorbable branched polymers containing units derived from dioxanone and medical/surgical devices manufactured therefrom
US20050037047A1 (en) Medical devices comprising spray dried microparticles
EP1669093A1 (en) Polyoxyalkylene copolymer blends as biomaterial for drug delivery and surface modification
US6878757B2 (en) Antimicrobial suture coating
US20040185250A1 (en) Triclosan containing absorbable sutures with extended antimicrobial properties
US6339130B1 (en) Bioabsorbable branched polymers containing units derived from dioxanone and medical/surgical devices manufactured therefrom
US20060233852A1 (en) Prosthetic for tissue reinforcement
US20060198868A1 (en) Biodegradable coating compositions comprising blends
US5306289A (en) Braided suture of improved characteristics
US6315788B1 (en) Composite materials and surgical articles made therefrom
US5352515A (en) Coating for tissue drag reduction
US20060018948A1 (en) Biodegradable implantable medical devices, methods and systems
US20040171323A1 (en) Antimicrobial, synthetic, fibrous, and tubular medical divices

Legal Events

Date Code Title Description
AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct app. not ent. europ. phase
WWW Wipo information: withdrawn in national office

Country of ref document: JP

NENP Non-entry into the national phase in:

Ref country code: JP