CZ33755U1 - Sandwich collagen foam with low porous core and highly porous edge layers for controlled release of active substances - Google Patents

Description

Collagen sandwich foam with low porous core and highly porous edge layers for controlled release of active substances

Field of technology

The subject of the technical solution is a sandwich collagen foam with a low porous core and highly porous edge layers with hemostatic effects, controlled degradation time and controlled local release of active substances, such as antibiotics, for use in wound dressings in surgery, orthopedics, traumatology and plastic surgery.

Prior art

Bleeding on larger areas during surgery is a relatively common and very serious problem and in extreme cases can be a threat to the patient's life. Another serious problem is the penetration of the infection into the body. During postoperative administration of antibiotics, there is a problem of systemic burden, often insufficient penetration into the surgical wound, and in some cases systemic toxicity can occur.

One solution is to use a locally antiseptic non-adhesive material. In addition to its essential local antiseptic function, this material can also have local hemostatic and anesthetic properties at the same time.

Collagens isolated from large mammals such as cow, pig or horse are widely used in biomaterial engineering. Their disadvantage is the potential allergic reactions that affect 3 to 4% of the population. The solution is offered in the use of fish collagen, which shows excellent biocompatibility. In addition, the isolation of collagen from fish skin does not pose such a risk of transmitting various diseases as in the case of extraction from pig or bovine skin (BSE, PrPSc). Fish collagen shows lower reproducibility in terms of its structural properties compared to collagens isolated from large mammals. This deficiency can be overcome by chemically crosslinking it with carboimide-based compounds commonly used in collagen chemistry. The crosslinking conditions affect the resulting degree of crosslinking of the collagen material, which in turn has a great influence on its absorbency and aggregation properties in the physiological environment. Cross-linked collagen resists ionizing radiation well, which allows it to be sterilized with commonly used doses of 25 kGy. Using a lyophilization process, it is possible to further create a three-dimensional material with a given porosity.

The materials thus prepared have generally proved very useful as controlled elution drug carriers. The drug can be incorporated into the collagen directly into the solution before the given processing processes or by additional impregnation of the finished material with a solvent, which on the one hand does not degrade the structure of the collagen and at the same time is able to dissolve the desired drug. Additional impregnation has proven to be the most effective method, as there is no premature release of the drug during the processing of the collagen material.

The ability to process collagen into various final forms (layers, foams, etc.), its easy and economical availability (waste material in the food industry) together with its biocompatible and hemocoagulating properties make it an optimal candidate for use in hemostatic foams to cover surgical and postoperative wounds.

The most commonly used antibiotic in collagen dosage forms is gentamicin. In clinical practice, these products have found use primarily in dentistry, abdominal surgery and traumatology. Recently, clinical studies in the field of cardiac surgery have also appeared, which confirm the effectiveness of this approach in the prevention of postoperative infections. There are also studies on the use of collagen matrices with tetracycline and metronidazole in dental surgery. Collagen matrices releasing chlorhexidine in the oral cavity are used to treat periodontitis.

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In the vast majority of studies and clinically used products, the basic matrix is mammalian collagen (bovine or equine). In addition to mammalian collagen, marine fish collagen is rarely used for this purpose - only for the application of chlorhexidine in dentistry. In vitro and animal experiment data for ciprofloxacin are also available.

It follows that fish collagen, namely collagen from marine, not freshwater fish, is clinically used as a drug release matrix only marginally for the treatment of periodontitis with chlorhexidine. It is not used to treat antibiotics. Another interesting option that is not currently available would be the use of vancomycin in collagen foam.

In clinical practice, vancomycin is used mainly in the local treatment of fractures - vancomycin-impregnated beads and bone allografts have been used in combination with cement containing aminoglycosides to replace the hip joint. Vancomycin-impregnated collagen foams have not been studied.

Due to the fact that vancomycin, as well as aminoglycosides, insufficiently penetrates into tissues, systemic application for the treatment of postoperative wound infections is problematic. Topical release topical application would be particularly suitable for this antibiotic because, unlike aminoglycosides, its efficacy depends not only on the concentration achieved, but also on the time when the concentration exceeds the MIC. The value best correlated with the clinical response in systemic therapy of Staphylococcus aureus infections is AUC / MIC. If collagen dosage forms ensured long-term adequate local concentrations of vancomycin in the wound, it would be possible in this way to abandon the systemic use of other backup antibiotics (ceftaroline, linezolid) and their investigation for more serious infections.

Topical application is especially suitable for antibiotics with low tissue distribution, which correspond to aminoglycosides, vancoymcin and nitrofurantoin. We are newly placing these substances in the collagen matrix of freshwater fish collagen, which is an easily available material with lower immunogenicity than collagen obtained from mammals. We achieve different levels of retardation depending on the nature of the antibiotic, eg rapid release and high concentrations of gentamicin, or slow release of vancomycin - these characteristics correspond to different mechanisms of antibiotics and different target pharmacokinetic parameters (concentration x time-dependent antibiotics).

Other disadvantages of existing collagen-based materials are difficult to handle, as these materials lose contact with the body and tend to tear and disintegrate when handled.

The essence of the technical solution

The disadvantages of the prior art hemostatic cover materials are largely overcome by a sandwich collagen foam with a low porous core and highly porous edge layers, with controlled disintegration and controlled release of active substances, containing type I collagen, which is preferably impregnated with one or more active substances. , for example, selected from the group consisting of antibiotic, anesthetic, antiplatelet agent, antiviral agent, or a mixture thereof. Preferably, the collagen sandwich foam is impregnated with an antibiotic or mixture of antibiotics selected from the group consisting of vancomycin, gentamicin, rifampicin, nitrofurantoin. The ratio of collagen to the total amount of active substances in the collagen foam can be 40 to 70% by weight of collagen to 30 to 60% by weight of active substances. The sandwich collagen foam for controlled release of active substances according to the technical solution contains type I collagen and its structure consists of a low porous core and highly porous edge layers, the low porous core having an open porosity in the range of 70 to 90% and a mean pore size of 20 to 80 pm, where at least 50% of the pore volume is formed by pores below 50 pm, and the highly porous edge layer has an open porosity in the range of 70 to 90% and a mean pore size of 50 to 200 μm, where at least 50% of the pore volume is formed by pores about size

-2CZ 33755 U1 over 80 pm. Preferably, the collagen is derived from the skin of freshwater fish, which represents a great advantage over collagen isolated from large mammalian tissues, which has hitherto been used, in terms of eliminating possible potential allergic reactions. The volume of the core in a preferred embodiment is 40 to 60% and the volume of the edge layers is 40 to 60%. The whole sandwich preferably has a thickness in the range of 0.5 to 5 cm, for example 1 cm.

The sandwich foam is designed to show a sustainable local release of active substances, for example antibiotics, the total amount of which is 30 to 60% by weight. Controlled release of antibiotics and controlled breakdown of collagen foam is achieved by forming optimal amounts of cross-links in the collagen molecule, either physically, eg by irradiation, or chemically, preferably by applying N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDC) and N - hydroxysuccinimide (NHS) in its preparation.

The disintegration time of the sandwich foam is mainly controlled by the stabilization time (temperature). The controlled disintegration time, which can be selected on the basis of the desired foam application time, also affects the controlled release time of active substances, for example antibiotics, with rapid release from the peripheral layers while longer release from the core.

The basic benefit of this technical solution is the fact that the used collagen isolated from the skin of freshwater fish has hemostatic effects and its application is not associated with the risk of an allergic reaction or other adverse immune response of the organism. Another significant benefit of this technical solution is the fact that it allows to deposit into a microstructured surface with a large specific surface and sufficient open porosity of biologically active substance according to the expected extent of injury or damage before surgery, but also at the discretion of the surgeon and during the impregnation of collagen foam, e.g. into the antibiotic solution.

At the same time, the resorbable material enables its gradual safe absorption into the surrounding tissue and thus the gradual effective release of biologically active substances deposited in it.

Foams prepared from 1% by weight of collagen dispersions can hold a liquid weighing up to 30 times their weight in the first week. Full soaking occurs after only four hours. The ability to soak decreases with time due to the degradation in progress. A solid core prepared from 5% by weight of a collagen dispersion can hold a liquid weighing up to 15 times its weight in the first week.

The desired porosity is achieved both by the concentration of the collagen dispersion from which the foam is prepared and by the freezing point of the resulting foam before lyophilization and subsequent impregnation with the active substance. The more concentrated the collagen dispersion, the smaller the pores, and the lower the freezing temperature, the smaller the pores.

The preparation of the sandwich collagen foam is carried out by mixing a weighed amount of collagen with deionized water in a concentration of 4 to 8% by weight of collagen. The resulting dispersion is then frozen and lyophilized to constant weight. This solid, non-porous core is further impregnated with 0.1 to 3% by weight of a collagen dispersion and thus left for 1 to 3 hours at 15 to 25 ° C, frozen at -60 to -90 ° C for 3 to 8 hours, and lyophilized to constant weight. In this way, a sandwich collagen foam is prepared, the inner part of which consists of a low-porous core and the edges consist of highly porous layers. The final volume amount of the low porous core in the sandwich foam is 10 to 90%, preferably 30 to 70%, most preferably 40 to 60%. The stability of the sandwich collagen foam is increased physically or chemically after lyophilization, preferably by chemical crosslinking with EDC and NHS. Further, the foam may be impregnated with an alcohol-based solution containing a weighed amount of active ingredients, wherein the active ingredients may be an antibiotic, anesthetic, antiaggregant, antiviral, or a mixture thereof, preferably an antibiotic selected from the group consisting of vancomycin, gentamicin, rifampicin, nitrofurantoin, or combinations thereof. , so that their final amount is 30 to 60% by weight. The impregnated foam can then be frozen and lyophilized.

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Impregnation with selected antibiotics can be carried out only before its application, for which an aqueous solution of antibiotics is used or the antibiotics are mixed with physiological solution and the foam is applied after their evaporation, i.e. after reaching a constant weight of foam. In this way, a foam is obtained with a final amount of collagen of 40 to 70% by weight. And 30 to 60% by weight, antibiotics.

The foam according to the technical solution has the following advantages:

programmable (controlled) disintegration of foam programmable (controlled) release of active substances elastic memory, bending stiffness easier handling of foam, possibility of reduction (does not tear, does not disintegrate) reduced risk of allergic reaction or other unwanted immune response of the organism.

Thanks to the method of preparation of sandwich collagen foam, the individual layers do not separate, the layers remain connected even when handled in the body environment and do not separate from each other. At the same time, the sandwich foam according to the technical solution is characterized by elastic memory and flexural rigidity, easy handling (does not tear) and the possibility of reduction.

Explanation of drawings

Giant. 1 shows a sandwich collagen foam with a low porous core prepared from a 5% by weight collagen dispersion and with highly porous edges prepared from a 1% by weight collagen dispersion, prepared according to Example 2. On the far right is an image of the transition interface between the core and the edge.

Giant. 2 shows a graph of the dependence of the contracted stress on the deformation for the porous foam alone, the rigid core alone and for the sandwich foam (preparation according to Example 2). The graph shows a several times increased resistance to deformation of the sandwich foam compared to the foam itself.

Example of implementing a technical solution

Definition

Collagen foam in the context of this technical solution is synonymous with the term "collagen sponge, ie a porous collagen-based material.

Under the term "open porosity, resp. "Open pores" means the space that communicates with the surface of the product, ie with the external environment. These can be individual pores connected to the surface, but also interconnected pores, at least one of which also communicates with the surface of the product.

Under the term "closed porosity, resp. "Closed pores" are so-called solitary pores or pores which are not connected to the outer surface of the product.

The term "highly porous" in the context of this technical solution is those foams which have an open porosity in the range of 70% to 90%, preferably 80% to 90%, and a pore size in the range of 50 to 200 μm, at least 50% of the pore volume being formed by pores with a size above 80 μm, preferably above 100 μm.

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The term low porosity in the context of this technical solution is those foams which have an open porosity in the range of 70% to 90% and a pore size in the range of 20 to 80 [mu] m, with at least 50% of the pore volume being pore sizes below 50 gm.

Example 1

In preparing a sandwich collagen foam, a weighed amount of collagen, preferably isolated from the skin of freshwater fish, such as common carp, is mixed with deionized water after the collagen has swelled at 5 to 15 ° C for 1 to 3 hours. the mixture is homogenized twice for 1 to 20 minutes at 5 to 15,000 rpm with a 20 minute delay at 15 to 25 ° C. The concentration of the collagen dispersion for the preparation of the core is 4 to 8% by weight. The concentration for the preparation of the edge portions is 0.1 to 3% by weight, preferably 0.1 to% by weight. In the first step, the resulting 4 to 8% mass, the dispersion is dosed into molds, frozen at -60 to -90 ° C for 3 to 8 hours and lyophilized until a constant weight is reached. In the second step, the solid core is impregnated with 0.1 to 3% by weight, dispersed in a mold and thus left for 1 to 3 hours at 15 to 25 ° C, frozen at -60 to -90 ° C for 3 to 8 hours and lyophilized to constant weight, to obtain a sandwich collagen foam with a porous core and highly porous edge layers. The stability of the collagen sandwich foam is increased after lyophilization by dipping in a solution of 95% by weight, ethanol and water with EDC and NHS at 25 to 40 ° C, preferably 30 to 40 ° C, most preferably at 37 ° C for 2 to 4 hours. 1 g of collagen contains 0.51.5 g of EDC and 0.125 to 0.750 g of NHS mixed with 140 to 160 ml of 95% by weight. Ethanol solution with water. After collagen crosslinking, the foam is washed with 0.5 to 1.5 M disodium hydrogen phosphate for at least 30 minutes and further washed for at least 20 minutes in distilled water, frozen at -15 to -30 ° C for 5 to 7 hours and lyophilized. The final volume amount of the low porous core in the sandwich foam is 40 to 60%. The final preparation step according to a preferred embodiment is to impregnate the sandwich foam with 95% by weight, a solution of ethanol with water containing a weighed amount of active substances, for example antibiotics selected from the group consisting of vancomycin, gentamicin, rifampicin, nitrofurantoin, or a combination thereof. 60% by weight. The impregnated foam can then be frozen and lyophilized. The sandwich foam can also be impregnated with selected antibiotics only before its application, for which an aqueous solution of antibiotics is used or the antibiotics are mixed with physiological saline and the foam is applied after their evaporation, i.e. after reaching a constant weight of foam. In this way, a foam is obtained with a final amount of collagen of 40 to 60% by weight, and 40 to 60% by weight, of antibiotics.

Example 2

To prepare a sandwich collagen foam, a weighed amount of collagen is mixed with deionized water at a concentration of 5% by weight of collagen, and after the collagen has swelled at 10 ° C for 2 hours, the mixture is homogenized twice for 10 minutes at 10,000 rpm. / min with a 20 minute delay at 20 ° C. The resulting 5% by weight dispersion is dosed into molds, frozen at -80 ° C for 6 hours and lyophilized until constant weight, to give a solid, slightly porous core. In the second step, the solid core is impregnated with 1% by weight of the dispersion in a mold, the volume ratio of the two dispersions (dispersion for core preparation and dispersion for edge preparation) being 1: 1, and thus left for 2 hours at 20 ° C. at -80 ° C for 6 hours and lyophilized to constant weight to obtain a sandwich foam consisting of a low porous core and highly porous edge layers. The stability of the collagen sandwich foam is increased after lyophilization by dipping in a solution of 95% by weight, ethanol and water with EDC and NHS at 37 ° C for hours. 1 g of EDC and 0.250 g of NHS mixed with 150 ml of 95% by weight, ethanol-water solution were used per 1 g of collagen. After collagen crosslinking, the foam is washed with 1 M disodium hydrogen phosphate for at least 30 minutes and further washed for at least 20 minutes in distilled water, frozen at -20 ° C for 6 hours and lyophilized. The final volume amount of the low porous core in the sandwich foam is 50%. The last step of the preparation is the impregnation of the sandwich foam with 95% by weight, a solution of ethanol with water containing weighed

The amount of antibiotics selected from the group consisting of vancomycin, gentamicin, rifampicin, nitrofurantoin, or a combination thereof so that the final amount is 45% by weight. The impregnated foam can then be frozen and lyophilized. In this way, a foam is obtained with a final amount of collagen of 55% by weight, and 45% by weight, of antibiotics.

Example 3

The procedure is the same as in Example 2, but the crosslinking time is 3 hours.

Example 4

The procedure is the same as in Example 2, but the crosslinking time is 4 hours.

Example 5

The procedure is as in Example 2, except for the last preparation step, i.e. the impregnation of the foam with a solution containing the active substance. The foam is frozen at -70 ° C, lyophilized and cut to size. In this way, a sandwich foam consisting of pure collagen is obtained.

Example 6

A weighed amount of collagen is mixed with deionized water at a concentration of 4% by weight. After swelling the collagen at 15 ° C for 1 hour, the mixture is homogenized twice for 15 minutes at 8,000 rpm with a 20 minute delay at 15 ° C. In the first step, the resulting 4% mass is dispersed, the dispersion is dosed into molds, frozen at -75 ° C for 4 hours and lyophilized to constant weight, to obtain a solid core. In the second step, the solid core is impregnated with 0.6% by weight of the dispersion in the mold, the ratio of the core preparation dispersion to the edge layer dispersion being 2: 3, and thus left for 1 hour at 25 ° C, frozen at -75 ° C for 4 hours and lyophilized to constant weight to obtain a sandwich foam consisting of a low porous core and highly porous edge layers. The stability of the collagen sandwich foam is increased after lyophilization by soaking in a solution of 95% by weight, ethanol and water with EDC and NHS at 37 ° C for 3 hours. 0.7 g of EDC and 0.2 g of NHS mixed with 140 ml of 95% by weight, ethanol-water solution were used per 1 g of collagen. After collagen crosslinking, the foam is washed with 0.8 M disodium hydrogen phosphate for at least 30 minutes and further washed for at least 20 minutes in distilled water, frozen at 30 ° C for 5 hours and lyophilized. The final volume amount of the low porous core in the sandwich foam is 40%. The final step in the preparation is to impregnate the sandwich foam with 95% by weight, an ethanol-water solution containing a weighed amount of antibiotics selected from the group consisting of vancomycin, gentamicin, rifampicin, nitrofurantoin, or a combination thereof so that the final amount is 30% by weight. The impregnated foam can then be frozen and lyophilized. In this way, a foam is obtained with a final amount of collagen of 70% by weight, and 30% by weight, of antibiotics.

Example 7

A weighed amount of collagen is mixed with deionized water at a concentration of 7% by weight. After swelling the collagen at 12 ° C for 2.5 hours, the mixture is homogenized twice for 20 minutes at 15,000 rpm with a 20 minute delay at 25 ° C. C. In the first step, the resulting 7% by weight dispersion is dosed into molds, frozen at -85 ° C for 3 hours and lyophilized to constant weight, to obtain a solid core. In the second step, the solid core is impregnated with 1% by weight, dispersion in the mold (ratio of dispersion for preparation of the core to dispersion for preparation of the edge layers is 3: 2) and thus left for 2.5 hours at 25 ° C, frozen at -85 ° C for 3 hours and lyophilized to constant weight to obtain a sandwich foam consisting of a low porous core and highly porous edge layers. The stability of the collagen sandwich foam is increased after dipping by dipping

-6GB 33755 Ul in a solution of 95% w / w, ethanol and water with EDC and NHS at 37 ° C for 3 hours. 1.4 g of EDC and 0.7 g of NHS mixed with 160 ml of 95% by weight, ethanol-water solution were used per 1 g of collagen. After crosslinking the collagen, the foam is washed with 1.5 M disodium hydrogen phosphate for at least 30 minutes and further washed for at least 20 minutes in distilled water, frozen at 30 ° C for 5 hours and lyophilized. The final volume amount of the low porous core in the sandwich foam is 60%. The final step in the preparation is to impregnate the sandwich foam with 95% by weight, an ethanol-water solution containing a weighed amount of antibiotics selected from the group consisting of vancomycin, gentamicin, rifampicin, nitrofurantoin, or a combination thereof so that the final amount is 30% by weight. The impregnated foam can then be frozen and lyophilized. In this way, a foam is obtained with a final amount of collagen of 70% by weight, and 30% by weight, of antibiotics.

Example 8

A weighed amount of collagen is mixed with deionized water at a concentration of 8% by weight. After swelling the collagen at 20 ° C for 3 hours, the mixture is homogenized twice for 20 minutes at 6,000 rpm with a 20 minute delay at 25 ° C. In the first step, the resulting 8% by weight dispersion is dosed into molds, frozen at -80 ° C for 3 hours and lyophilized to constant weight, to obtain a solid core. In the second step, the solid core is impregnated with 1.5% by weight, dispersion in the mold (ratio of dispersion for preparation of the core to dispersion for preparation of the edge layers is 7: 3) and thus left for 2 hours at 25 ° C, frozen at -80 ° C for 3 hours and lyophilized to constant weight to obtain a sandwich foam consisting of a low porous core and highly porous edge layers. The stability of the collagen sandwich foam is increased after lyophilization by soaking in a solution of 95% by weight, ethanol and water with EDC and NHS at 37 ° C for 2 hours. 1.4 g of EDC and 0.35 g of NHS mixed with 160 ml of 95% by weight, ethanol-water solution were used per 1 g of collagen. After crosslinking the collagen, the foam is washed with 1.5 M disodium hydrogen phosphate for at least 30 minutes and further washed for at least 20 minutes in distilled water, frozen at -30 ° C for 5 hours and lyophilized. The final volume amount of the low porous core in the sandwich foam is 70%. The final step in the preparation is to impregnate the sandwich foam with 95% by weight, an ethanol-water solution containing a weighed amount of antibiotics selected from the group consisting of vancomycin, gentamicin, rifampicin, nitrofurantoin, or a combination thereof so that the final amount is 30% by weight. The impregnated foam can then be frozen and lyophilized. In this way, a foam is obtained with a final amount of collagen of 70% by weight, and 30% by weight, of antibiotics.

Example 9

In Table 1, the maximum disintegration times of the sandwich collagen foam and the maximum antibiotic release times, crosslinking time and temperature are obtained, the preparation of the sandwich foam being performed according to Example 2 with variable final volumes of low porous core in the sandwich foam 40%, 50%, 60% , i.e. with variable dispersion ratios (2: 3, 1: 1, 3: 2).

Tab. 1

Core volume fraction crosslinking time at 15 - 25 ° C crosslinking time at 30-40 ° C Achieved maximum degradation time Maximum antibiotic release time 40% 6 hours 2 hours 4 weeks 21 days 9 hours 3 hours 6 weeks 25 days 12 hours 4 o'clock 8 weeks 30 days 50% 6 hours 2 hours 5 weeks 31 days 9 hours 3 hours 7 weeks 35 days

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12 hours 4 o'clock 9 weeks 40 days 60% 6 hours 2 hours 6 weeks 41 days 9 hours 3 hours 8 weeks 45 days 12 hours 4 o'clock 10 weeks 50 days

Industrial applicability

Collagen sandwich foams with a low porous core and highly porous edge layers with hemostatic effects, with a controlled degradation time and with controlled local release of antibiotics according to this utility model can be used in human and veterinary medicine, especially in surgery, orthopedics, wound dressings, leg ulcers, traumatology and plastic surgery. It is particularly suitable for less extensive inflammation or in potentially infectious terrain, ie where a rapid release of the optimal dose of active substance is required first, followed by a longer-lasting effect of the active substance, which prevents the recurrence of inflammation.

Claims (7)

CLAIMS FOR PROTECTION A sandwich collagen foam for controlled release of active substances, characterized in that it contains type I collagen and its structure consists of a low-porous core and highly porous edge layers, the low-porous core having an open porosity in the range of 70 to 90% and a mean size. pore size 20 to 80 μm, where 50 to 100% of the pore volume consists of pores below 50 μm, and the highly porous edge layer has an open porosity in the range of 70 to 90% and a mean pore size of 50 to 200 μm, where at least 50 to 100% of the pore volume consists of pores larger than 80 μm. Collagen foam according to Claim 1, characterized in that the highly porous edge layer has an open porosity in the range from 80 to 90%. Collagen foam according to claim 1 or 2, characterized in that the type I collagen is collagen isolated from the skin of freshwater fish. Collagen foam according to any one of the preceding claims, characterized in that the core volume is 10 to 90%, preferably 30 to 70%, most preferably 40 to 60%. Collagen foam according to any one of claims 1 to 4, characterized in that it is impregnated with at least one active substance and that the ratio of collagen to the total amount of active substances in the collagen foam is 40 to 70% by weight, collagen to 30 to 60% by weight. active substances. Collagen foam according to claim 5, characterized in that the active substance is selected from the group consisting of an antibiotic, an anesthetic, an antiplatelet agent, an antiviral agent, or a mixture thereof. Collagen foam according to claim 6, characterized in that the active substance is an antibiotic selected from the group consisting of vancomycin, gentamicin, rifampicin, nitrofurantoin, or a mixture thereof.