WO2005051448A1

WO2005051448A1 - Surgical implants for controlled release of medicaments

Info

Publication number: WO2005051448A1
Application number: PCT/IB2004/004196
Authority: WO
Inventors: Christoph Walther
Original assignee: Ethicon Gmbh
Priority date: 2003-11-26
Filing date: 2004-11-25
Publication date: 2005-06-09
Also published as: DE10355189A1; DE10355189B4

Abstract

A surgical implant has a first component which is able to swell in a given solvent, and a second component which is not able to swell in this solvent. The first component is not designed as a covering. An active substance soluble in a solvent is introduced into the first component by means of a swelling process. A covering can be provided as a third component.

Description

SURGICAL IMPLANTS FOR CONTROLLED RELEASE OF MEDICAMENTS

The invention relates to a surgical implant containing an .active substance, for example an antimicrobial active substance.

Medical implants, in particular surgical implants, can be provided with active substances (active agents) . The matrices used in this connection are non-absorbable polymers and absorbable polymers, or else partially absorbable polymer materials. The implants can have an areal or a three-dimensional configuration. Methods for providing medical implants with active substances include coating with the active agent, incorporation of the active agent into a coating, incorporation of the active agent into the polymer composition, or swelling of the polymer with subsequent penetration of the active agent into the polymer composition.

Active substances may originate from the areas of antimicrobial substances (here in particular organic components or metals and their corresponding compounds/salts), but can also be antiproliferative agents, antibiotics, analgesics, etc.

EP 0 748 634 A2 discloses a vascular prosthesis which has an absorbable coating with an active substance. The active substance is released throughout the period of absorption of the coating.

EP 1 273 313 A2 describes providing a catheter of polyurethane with the antimicrobial substance chlorhexidine, the catheter being placed in a solution with chlorhexidine and thus swelling, so that the catheter material takes up the substance.

Similarly, EP 0 550 875 Bl describes incorporating an active substance into an implantable device made of non-absorbable polymer material, by means of the device being treated with an organic solvent which contains the active substance.

US 4 024 871 discloses a multifilament suture material impregnated with an antimicrobial active substance; the surface is afterwards coated with polyurethane.

US 6 528 107 describes introducing an antimicrobial active substance into a medical device made of non- absorbable material, by exposing the device to a solution with the active substance.

US 2001 0055622 Al reveals the use of metals in crystalline form as antimicrobial coatings or powders on absorbable materials.

EP 1 157 708 A2 discloses surgical suture materials and meshes extruded from a starting material to which an antimicrobial active substance has been added -

EP 0 772 468 Al describes an abdominal wall implant whose non-absorbable base material is surrounded by gelatin. Before surgical intervention, an antimicrobial active substance can be incorporated therein.

US 5 902 283 reveals the impregnation of a non- absorbable medical implant with an antimicrobial active substance using a solution with an alkalizing agent.

The known implants and methods are associated with disadvantages. For example, simply coating the implant with the active substance leads to a very rapid release of the active agent after implantation (initial burst) ; active substance release over a longer, controlled time period is not achieved. Moreover, when coating a non- absorbable, absorbable or also partially absorbable implant with the active substance or with a coating composition containing the active agent, all parts of the implant are provided with the active substance, which is not always desirable. Metals used as active agents (antimicrobial active substance) remain in the body after implantation and are not metabolized. Mixing the active substance into the polymer composition can result in phase incompatibilities, so that the active substance blooms out over a prolonged time period; the implant is not stable on storage. It is also possible that mixing the active substance into the polymer composition will lead to a greatly reduced release because of substantial interactions between agent and polymer. Moreover, mixing the active agent into the polymer composition constitutes a thermoplastic process which subjects the active substance to considerable thermal stress and/or destroys it.

The object of the invention is to provide a possibility in which an active substance is introduced gently into an implant and which in principle permits a controlled release of the active substance from the implant after implantation.

This object is achieved by a surgical implant having the features of Claim 1, and by a method for producing a surgical implant having the features of Claim 15. Advantageous embodiments of the invention are set out in the dependent claims.

The surgical implant according to the invention has a first component which is able to swell in a given solvent, and a second component which is not able to swell in this solvent. An active substance soluble in a solvent is introduced into the first component; the first component is not designed as a covering.

The first component can be absorbable and for example have a copolymer of glycolide and L-lactide, preferably in the weight ratio 10:90 ("Panacryl", Ethicon) , or a copolymer of glycolide and ε-caprolactone ("Monocryl", Ethicon) . However, the first component may also be non- absorbable. Examples of this are polyamides or mixtures of polyvinylidene fluoride and copolymers of vinylidene fluoride and hexafluoropropylene (in particular "Pronova", tradename used by Ethicon for monofilaments made of a mixture of polyvinylidene fluoride (PVDF) and a copolymer of 95% by weight vinylidene fluoride and 5% by weight hexafluoropropylene) .

To produce a surgical implant of this kind, a composite with a first component, which is able to swell in a given solvent, and a second component, which is not able to swell in this solvent, is exposed for a predetermined time to this solvent and to the active substance dissolved in a solvent, and the solvent is then removed. The relative weight increase after swelling and subsequent drying amounts to preferably 0.1% to 5%.

To equip composite implants with an active agent, the incorporation of the active substance is thus achieved by selective swelling of the polymer fraction of the first component and subsequent penetration of the active substance into this area. For this purpose, a solution of the active substance is preferably prepared in a solvent which readily dissolves the active substance and selectively swells the first component of the implant. By fixing the parameters of the swelling process (choice of solvent, temperature on swelling, duration of swelling) , it is possible to control the active substance uptake and the subsequent active substance release. The swelling is in principle a reversible procedure which generally does not lead to changes in the material properties.

After implantation, the active substances are released in the patient' s body by diffusion or, if appropriate, by absorption of the first component. If the first component is absorbable, the fact that the incorporation of active substance is limited to the absorbable part of the implant means that no residues of the active substance remain in the implant after complete degradation of this implant part. The active agent can therefore be completely metabolized in the body.

The selective swelling of the first component of the implant in a suitable solvent with simultaneous active substance uptake from the solvent represents a very simple method for equipping implants with an active agent. This method is preferably carried out under moderate conditions (room temperature to ca. 50°C) . After the swelling process, the drying of the implant can be carried out in vacuum and/or at temperatures of up to 40°C or 50°C. The result is that the active agent is not subjected to thermal stresses, as is the case when incorporating the active substance into the polymer by thermoplastic methods or during polymerization, for example bulk polymerization or polycondensation. Furthermore, the method of swelling a polymer fraction of the implant affords the advantage that this processing step on the implant can be carried out at a very advanced production stage (semi-finished article, directly before sterilization) .

The second component of the implant contains, for example, polypropylene or a copolymer of glycolide and

L-lactide, preferably in the weight ratio of 90:10 ("Vicryl", Ethicon) .

The release of the active substance can additionally be influenced by coating with an (absorbable) polymer after the swelling process and the penetration of the active substance, specifically with a view to delaying release. For this purpose, the implant, in a preferred embodiment, contains a covering consisting of a third component, for example a copolymer of glycolide and lactide, preferably in the weight ratio 35:65. With the aid of a further covering, for example containing polyacrylamides, it is possible to further influence the time course of the active substance release.

The active substance is preferably soluble in the given solvent in which the first component is able to swell. In this case, the method can be carried out in the manner already explained, by dissolving the active substance in a solvent in which the first component is able to swell and the second component is not able to swell, and exposing the composite from the outset and for a predetermined time to the solution of the active substance in this solvent. The swelling of the first component and the uptake of the active substance then take place in one operation. However, it is also conceivable for the composite first to be exposed for a predetermined time to a solvent in which the first component is able to swell and the second component is not able to swell, and for the composite then to be exposed for a predetermined time to the solution of the active substance in a solvent (which is preferably the same solvent as the first-mentioned solvent) . In this case, therefore, the structure of the first component is expanded by the swelling process in a first step, so that it is accessible to the active substance, but the active substance is introduced only in a second step.

Examples of suitable solvents are ketones, for example acetone, methyl ethyl ketone, etc., esters, for example ethyl acetate, butyl acetate, etc., ethers, for example tetrahydrofuran, 1,4-dioxane, ethyl butyl ether, etc., alcohols, for example isopropanol, but also higher alcohols, or hydrocarbons, also higher hydrocarbons, or mixtures; preference is given to low-boiling solvents. In principle, the solvent should be tailored to the desired swelling behavior of the first component and second component and, if appropriate, to the properties of the active substance. If necessary, the composite can be pretreated in a pretreatment step with a pretreatment agent, preferably with a suitable solvent, in particular in order to extract dyes and residual monomers.

The active substance preferably has a molar mass of less than 2500, preferably less than 1000. In preferred embodiments, the active substance is antimicrobial and has, for example, triclosan. Other suitable antimicrobial active substances are phenol derivatives, quaternary ammonium compounds, guanidine derivatives (for example chlorhexidine) , fluoroquinolones, macrolides, ketolides, and silver compounds. For example, antiproliferative agents, antibiotics or analgesics are likewise conceivable as active substance.

For the implant according to the invention, a large number of configurations are possible, for example as surgical suture threads, cords, bands, areal implants, implant meshes or three-dimensionally structured implants. Applications are also conceivable in soft- tissue augmentation and as substrate for cells.

In a preferred embodiment, the implant is designed as an implant mesh with monofilaments of a copolymer of glycolide and ε-caprolactone as first component, and monofilaments of polypropylene as second component, the active substance having triclosan, and a covering being provided as third component.

The invention is described in more detail below with reference to illustrative embodiments. In the drawing:

Figure 1 shows a graph of the time course of the release of triclosan from differently treated implant meshes. Preliminary test

A preliminary test was performed to investigate the influence of the swelling on the mechanical properties of suture materials made of a copolymer of glycolide and L-lactide in the weight ratio 10:90 ( "Panacryl", Ethicon) , a copolymer of glycolide and ε-caprolactone ("Monocryl", Ethicon) _r and a mixture of polyvinylidene fluoride (PVDF) and a copolymer of vinylidene fluoride and hexafluoropropylene in the weight ratio 95:5 'Pronova' Ethicon] For this purpose, specimens of the respective materials were placed for several hours in acetone, which leads to swelling of these materials. After drying, the breaking force ("Force maximum") and elongation at break ("Elongation") were measured; the results are shown in Table 1, set against the values for untreated specimens (MV: mean value; SD: standard deviation) . Table 1: Determination of the breaking force of unswollen suture material and of suture material swollen in acetone

It will be seen that, within the scope of the measurement errors, at least for "Panacryl" and "Monocryl" the breaking force and elongation behaviour are not impaired by the swelling.

Polypropylene does not swell in acetone. Thus, selective swelling of the absorbable part is possible in composite implant meshes which contain polypropylene and "Panacryl" or polypropylene and "Monocryl" ("Ultrapro", Ethicon) . This is used in the following Examples 1 to 4.

Example 1

In a further preliminary test, an "Ultrapro" implant mesh (composite of polypropylene and "Monocryl", Ethicon) was swollen in acetone for 2 hours at room temperature. The solvent uptake was 2.5% by weight.

Preferred concentrations of the active agent (active substances) are between 1% by weight and 20% by weight in solution. The solutions of 5% by weight and 10% by weight of triclosan in acetone used in Examples 2 to 4 below give weight increases of between 3% by weight and 10% by weight, in partially absorbable implants made of polypropylene and "Panacryl" or of polypropylene and "Monocryl".

Example 2

In a pretreatment step, dyes and residual monomers were extracted with acetone from "Ultrapro" implant meshes (composite of polypropylene and "Monocryl", Ethicon) . After drying in vacuum, the pretreated implant meshes were placed in a solution of triclosan in acetone (2 g triclosan to 40 g solution) for 3 hours at room temperature, removed, and shaken off. The solvent was evaporated, and the implant meshes were then dried at 40°C in a drying cabinet to constant weight. The relative weight increase was 3.5%.

Example 3

In a pretreatment step, dyes and residual monomers were extracted with acetone from "Ultrapro" implant meshes (composite of polypropylene and "Monocryl", Ethicon) . After drying in vacuum, the pretreated implant meshes were placed for 3 hours in a solution of triclosan in acetone (4 g triclosan to 40 g solution) at room temperature, removed, and shaken off. The solvent was evaporated, and the implant meshes were then dried at 40 °C in a drying cabinet to constant weight. The relative weight increase was 7.5%.

Example 4

"Ultrapro" implant meshes (composite of polypropylene and "Monocryl", Ethicon) were swollen at room temperature for 3 hours in a solution of triclosan in acetone (10 g triclosan to 200 g solution), and shaken off. After evaporation of the solvent, the implant meshes were dried to constant weight. The implant meshes were then coated by an immersion process with a 0.5% strength copolymer solution (copolymer of glycolide and lactide in the weight ratio 35 to 65 in ethyl acetate) and dried.

The release of triclosan from implant meshes produced according to Examples 2 and 4 was determined in a Franz diffusion cell. As Figure 1 shows, the release of the active substance by incorporation into the polymer in the implant mesh according to Example 2 is delayed compared to a conventional "Ultrapro" implant mesh containing triclosan in a copolymer coating. The release behaviour is modified by the additionally applied coating (Example 4). In the present example, there is a partial diffusion of the triclosan from the "Monocryl" material into the coating (covering) ; this results in a more rapid release than in pure incorporation into the "Monocryl" material, but still slower release than when the active substance is applied only via a coating.

The release of the active substance is further slowed down by a further covering of the impregnated implant with a polymer such a polyacrylamide applied from aqueous solution.

Example 5

Braided bands or cords, as are described for example in DE 198 33 796, with cores of monofilament "Monocryl" and a braided jacket of "Vicryl" multifilament yarns, were immersed in a solution with the active substance chlorhexidine and the solvent ethyl acetate. The "Monocryl" part was initially swollen with ethyl acetate and thus charged with the active substance, while the "Vicryl" part is able to swell only minimally in ethyl acetate under mild conditions and during a short reaction time.

Example 6

In the same way as in Example 5, braided bands or cords, as are described for example in DE 198 33 796, with cores of "Pronova" and a braided jacket of polypropylene multifilament yarns, were immersed in a solution with an active substance and the solvent acetone. The "Pronova" part was swollen and thus charged with the active substance, while the polypropylene part does not swell in acetone.

Example 7

Band-like implants, made as wovens or knits/crochet galloon knits, in which the wefts and warps each consist of different materials, can be differently equipped through the choice of swelling agent and active substance.

Example 8

Braided suture material with a core of "Monocryl" and a braided jacket of "Vicryl" was treated as described in Example 5.

Example 9

Three-dimensionally structured implants according to DE 100 19 605 (in particular Figures 5 a - d) with "Monocryl" as first component and polypropylene as second component were immersed in a solution of the active substance triclosan in acetone, in order to swell the absorbable "Monocryl" part and charge it with active substance.

Example 10

An "Ultrapro" mesh (Ethicon) with "Monocryl" as first component and monofilament polypropylene as second component was immersed for one hour in a solution consisting of a mixture of 20 ml of a 10% strength triclosan solution in acetone and 1 ml of a 0.5% strength silver lactate solution in water, and then dried. Examination by light microscope revealed a black silver layer which had spread uniformly across the mesh and had penetrated into the upper layers of the "Monocryl" yarn.

In a mesh made of pure polypropylene and treated in parallel, the silver predominantly lay at the node points and did not penetrate into the fibres.

If a mixture with a higher water content (for example 30%) was used, no penetration of the silver compound into the fibres was detectable by light microscopy after a reaction time of 10 minutes on an "Ultrapro" mesh. Only after considerably longer reaction times, the silver spread more uniformly across the mesh surface and was no longer located predominantly at the node points.

Example 11

Analogously to Example 10, a solution was used consisting of a mixture of 20 ml of a 5% strength triclosan solution in acetone and 2 ml of a 5% strength silver acetate solution in acetone. The reaction time of this mixture on an "Ultrapro" mesh was 2 hours at room temperature.

Claims

1. Surgical implant, with a first component which is able to swell in a given solvent, and a second component which is not able to swell in this solvent, an active substance soluble in a solvent being introduced into the first component, and the first component not being designed as a covering.

2. Implant according to Claim 1, characterized in that the first component is absorbable and preferably contains at least one of the substances selected from the following group: copolymers of glycolide and lactide, preferably in the weight ratio 10:90, copolymers of glycolide and ε- caprolactone .

3. Implant according to Claim 1, characterized in that the first component is not absorbable and preferably contains at least one of the substances selected from the following group: polyamides, mixtures of polyvinylidene fluoride and copolymers of vinylidene fluoride and hexafluoropropylene .

4. Implant according to one of Claims 1 to 3, characterized in that the second component contains at least one of the substances selected from the following group: polypropylene, copolymers of glycolide and lactide, preferably in the weight ratio 90:10.

5. Implant according to one of Claims 1 to 4, characterized by a covering consisting of a third component .

Implant according to Claim 5, characterized in that the covering contains at least one of the substances selected from the following group: copolymers of glycolide and lactide, preferably in the weight ratio 35:65.

7. Implant according to Claim 5 or 6, characterized by a further covering which preferably contains at least one of the substances selected from the following group: polyacrylamides .

8. Implant according to one of Claims 1 to 7, characterized in that the active substance is soluble in the given solvent in which the first component is able to swell.

9. Implant according to one of Claims 1 to 8, characterized in that the active substance has a molar mass of less than 2500, preferably less than 1000.

10. Implant according to one of Claims 1 to 9, characterized in that the active substance has at least one of the substances selected from the following group: antimicrobial active substances, triclosan, phenol derivatives, quaternary ammonium compounds, guanidine derivatives, chlorhexidine, fluoroquinolones, macrolides, ketolides, soluble silver salts; antiproliferative agents; antibiotics; analgesics.

11. Implant according to one of Claims 1 to 10, characterized in that the implant has one of the configurations selected from the following group: surgical suture threads, cords, bands, areal implants, implant meshes, three-dimensionally structured implants.

12. Implant according to one of Claims 1 to 11, characterized in that the implant is designed as an implant mesh with monofilaments of a copolymer of glycolide and ε-caprolactone as first component, and monofilaments of polypropylene as second component, the active substance having triclosan, and a covering preferably being provided as a third component.

13. Use of an implant according to one of Claims 1 to 12 for soft-tissue augmentation.

14. Use of an implant according to one of Claims 1 to 12 as substrate for cells.

15. Method for producing a surgical implant, in which a composite with a first component, which is able to swell in a given solvent, and a second component, which is not able to swell in this solvent, is exposed for a predetermined time to this solvent and to the active substance dissolved in a solvent, and the solvent is then removed.

16. Method according to Claim 15, characterized in that the active substance is dissolved in a solvent in which the first component is able to swell and the second component is not able to swell, and in that the composite is from the outset exposed for a predetermined time to the solution of the active substance in this solvent.

17. Method according to Claim 15, characterized in that the composite is first exposed for a predetermined time to a solvent in which the first component is able to swell and the second component is not able to swell, and in that the composite is thereafter exposed for a predetermined time to the solution of the active substance in a solvent, which is preferably the same solvent as the first-mentioned solvent.

18. Method according to one of Claims 15 to 17, characterized in that the solvent has at least one of the substances selected from the following group: ketones, acetone, methyl ethyl ketone; esters, ethyl acetate, butyl acetate; ethers, tetrahydrofuran, 1,4-dioxane, ethyl butyl ether; alcohols, isopropanol, higher alcohols; hydrocarbons .

19. Method according to one of Claims 15 to 18, characterized in that, in a pretreatment step, the composite is pretreated with a pretreatment agent, preferably a solvent, in particular to extract dyes and residual monomers .

20. Method according to one of Claims 15 to 19, characterized in that the solvent is removed by drying and/or reduced pressure, preferably at temperatures below 50°C.

21. Method according to one of Claims 15 to 20, characterized in that, after removal of the solvent, at least one coating is applied.