JPH0640900B2 - Medical devices that perform antimicrobial activity, methods for infusing antimicrobial agents therewith, and antimicrobial compositions - Google Patents

Description

[Detailed Description of the Invention] Background of the Invention This invention is a related application to Japanese Patent Application No. 62-500412.

Implantable medical devices, such as catheters, valves, molded components, etc., that must remain in the body, in whole or in part, for relatively long periods of time,
Historically, the risk of infection has been a drawback. Examples of this type of device include hydrocephalus shunts and central venous catheters.

Bacterial colonization and proliferation on the interior surfaces of catheters or other portions of devices can create significant problems for the patient, including the need for removal or replacement of the implanted device and the condition of secondary infections.

Much thought and research has gone into attempting to prevent such colonization and growth through the use of antimicrobial agents, e.g., antibiotics, bound to the surfaces of materials used in such devices, with the goal of producing sufficient bacteriostatic or bactericidal activity to prevent colonization and growth.

These previous attempts have included a wide variety of antimicrobial agents and
It has been used to coat and adhere to a wide variety of substrate materials, including silicone elastomers, polytetrafluoromethane, polyester, polyethylene, and latex rubber.

Examples of the extensive approach researchers have taken to this problem are found in the following publications, which are helpful in understanding the present invention:

R. BAYSTON and R. D. G. MILNER: "Antibacterial activity of silicone rubber used in hydrocephalus shunts after antibacterial impregnation"
imicrobial Activity of Silicone Rubber Used in Hyd
rocephalus Shunts,after Impregnation with Antimicrobial
"Biological Substances," Journal of Clinical
J.Clin.Pathol., Vol. 134 (1981) 1,057-
1,062 pages.

Journal of Clinical Pathology (J.Clin.Patho
l.), Vol. 134 (1981), pp. 1,057-1,062.

Earl Bayston: "Effect of Antibiotic Impregnation on the Function of Slit Valves Used to Control Hydrocephalus"
ntibiotic Impregnation on the Function of Slit Val
ves Usedto Control Hydrocephalus), Zeitschrift fur Kinderchirgie (Z.Kinderchir.),
Volume 31, No. 4 (December 1980), pages 353-359.

R.A. Harvey and R.
RSGRECO: "The noncovalent bonding of antibiotics to a polytetrafluoroethylene-benzalkonium implant"
polyterafluoroethylene benzalkonium graft),” Annals of Surgery, Vol. 194 (19
1981) pages 642-7.

Stanley A. Truskin
N, Anthony P. Donetz, Richard A. Harvey, and Ralph S. Greco: Prevention of catarrheal sepsis by antibiotic combinations.
(heter sepsis by antibiotic boning),” Surgery
(Surgery), 1984, pp. 547-551.

AP Donets, R.A. Herbway, and R.S. Greco: "Stability of antibiotics bound to polytetrafluoroethylene using cationic surfactants"
"Polyethylene with cationic surfactants," Journal of Clinical Microbiology (J. Clin.
Microbiol., Vol. 19 (1984), pp. 1-3.

Unfortunately, these previous attempts have yielded less than optimal results, with a major drawback remaining that the antimicrobial activity achieved by certain surface treatments is relatively short-lived, the rationale being that the agents and methods used only temporarily bind the selected agent to the device surface.

In addition, the surface-treated equipment can be treated with antibacterial agents or
It has not been demonstrated that known methods can be successfully sterilized without adversely affecting the bond with the material from which the device is made: subsequent sterilization of surface-bound agents tends to shorten the duration of antimicrobial activity and may also result in the formation of by-products that are harmful to body tissue.

It is therefore an object of the present invention to provide a method by which antimicrobial agents can be attached to a wide range of conventional elastomers, or the like, thereby providing relatively long-term protection against bacterial establishment and proliferation on the surfaces of these materials without adverse side effects.

It is a further object of the present invention to provide an article having the above advantages that can be sterilized before use and still retain these advantages.

SUMMARY OF THE INVENTION The present invention provides a medical device made of a polymeric material, such as a silicone elastomer or the like, that can be implanted into living tissue, wherein the material has been treated to exhibit sustained antimicrobial activity during use of the device, and is capable of swelling by infiltration of a swelling agent, the swelling agent containing at least one or more antimicrobial agents as a solute, in complete solution, and the surface of the material is exposed to the swelling agent for a time sufficient to promote the swelling of the matrix of the material body, thereby allowing the material to be in contact with the swelling agent for a time sufficient to promote the swelling of the matrix of the material body, thereby allowing the material to be in contact with the solution containing the selected antimicrobial agent as a solute.
The present invention provides a medical device that allows the antimicrobial agent to diffuse and migrate into intermolecular spaces within the body of material due to the action of a swelling agent in the body of material, and further, the solvent can be removed from the solute within the body of material by evaporation, and after removal of the solvent, the body of material can substantially return to its original size and shape while the antimicrobial agent is substantially uniformly deposited therein and continues to migrate toward and diffuse through the surface.

The present invention also provides a method for infusing an antimicrobial agent into the body of an implantable medical device comprising a body of silicone elastomer material, comprising the steps of: thoroughly contacting the surface of the device with a solution comprising a swelling agent and at least one antimicrobial agent dissolved therein; maintaining contact between the solution and the surface for a time sufficient for the solution to completely swell the body of polymeric material and to diffuse into the intermolecular spaces of the expanded matrix; evaporating the solvent from the solution;
This also provides a method for substantially uniformly depositing an antimicrobial agent within the body of a polymeric material while substantially restoring the material to its original physical shape and condition, cleaning the treated surface, and sterilizing the treated body of material prior to use.

The present invention (1) is capable of increasing the intermolecular spacing of silicone elastomers or other polymeric materials or latex, and (2) is capable of infusing a selected antimicrobial agent into the swollen material under conditions and in a manner that allows the selected antimicrobial agent to be substantially uniformly dissolved without substantially changing its chemistry in an amount sufficient to maintain significant levels of antimicrobial activity for an extended period of time when the material is subsequently implanted in the body.

In vitro testing has shown that the present invention provides effective protection against excessive bacterial challenge in silicone elastomer tubing for at least 28 days when a nutrient solution is infused through the central lumen of the tubing at 37°C.
Silicone elastomers treated using the method of the present invention have also been shown to retain antimicrobial activity after at least 20 months of shelf life.

DETAILED DESCRIPTION OF THE INVENTION Generally, the medical devices of the present invention comprise a body of a substantially homogeneous polymeric material, such as a silicone elastomer or the like, having one or more antimicrobial agents dispersed substantially uniformly throughout the body of the polymeric material, providing a substantially uniform polymeric dispersion of the antimicrobial agents within the intermolecular spaces of the body of the polymeric material.

The polymeric body and the antibacterial agent therein effectively form a solid solution of the polymeric material molecules and the antibacterial agent molecules;
The antimicrobial molecules diffuse towards and through the sides of the polymeric body in a concentration sufficient to provide effective protection against bacterial colonization and proliferation after implantation in the human body for a sufficient period of time in use.

Suitable antibacterial agents for use in the methods of the present invention are as follows: (1) rifampin, a semisynthetic antibiotic derivative of rifamycin B [specifically, rifampin is a derivative of the hydrazone 3-(4-methyl-1-perezinyliminomethyl)-
Rifamycin SV].

(2) Clindamycin hydrochloride.

These preferred agents, preferably used in combination as solutes, provide broad-spectrum, excellent penetrating and sustained antibacterial activity in medical devices, such as those treated with the present invention, covering most strains of Gram-positive bacteria that account for the majority of infections occurring in hydrocephalus shunts. These agents may also be used as colloidal suspensions or emulsions.

The method for manufacturing the medical device comprises applying a suitable swelling agent (solvent), such as hexane, toluene, xylene, or preferably chloroform, and an antimicrobial agent (solvent) to the entire surface of the polymeric body for a sufficient time to allow total penetration and swelling of the polymeric body and substantially uniform dispersion of the antimicrobial agent throughout the polymeric body within its enlarged intermolecular spaces.

The swelling agent is then removed by evaporation, reversing the swelling and retaining the antimicrobial agent as a substantially uniform dispersed phase within the intermolecular spaces throughout the entire body of the polymeric material.

As a result, the molecules of the antimicrobial agent essentially become a solid solution with the molecules of the polymeric body and then migrate toward and through the surface of the polymeric body solely by molecular diffusion.

After removal of the swelling agent, the device is suitably sterilized using either ethylene oxide, gamma irradiation, or low-temperature steam autoclave. In the autoclave, a temperature of about 121°C (250°F) and atmospheric pressure are maintained at about 100°C.
Steam is applied to the device at a pressure of more than 1.08 kg/ ^cm² (15 psi)
This is preferred to achieve advantageous results as described below.

One objective is that a sufficient amount of antimicrobial agent must be present to maintain the desired strength of activity for the desired period of time.

Another objective is that the antimicrobial agent must be present in an amount insufficient to cause toxic or other deleterious effects on the implant or its function, or on the recipient. Overall, the length of time during which there is risk of infection resulting from the surgery to implant the device can vary from the time of implantation to all time during the life of the device after surgery. Therefore, it is advantageous to be able to control the amount and degree of dispersion of the antimicrobial agent within the elastomeric matrix.

To achieve the desired results, the materials from which the device is constructed must be designed to retain the antimicrobial agent on the surface of the device for a sufficient length of time to provide a continuous and effective supply of the agent while preventing excessive drug release.

The effective amount of antimicrobial agent used (e.g., 0.1-1.0% by weight to volume of each of the agents relative to the solvent) will depend on the size and shape of the particular medical device and the type and wall thickness of the polymeric material selected. In a preferred embodiment of the invention, for devices such as shunts or catheters, the amount of antimicrobial agent is about 0.1-1.0% by weight of each agent to volume of the solvent.
0.2% is preferred.

It has been unexpectedly discovered that the polymeric material body can be heated to about 121°C (250°F), preferably in an autoclave.
sterilization of the device under steam heat at a temperature of 100°F ( ⁴⁰⁰ °C) and a pressure of about 15 psi above atmospheric pressure for about 30 minutes without adversely affecting the activity of the antimicrobial agent.
A sufficient amount of antimicrobial agent can be retained, and this sterilization method in particular has a favorable effect on the diffusion characteristics.
Temperature, pressure, and time can be varied to achieve complete sterilization depending on the size, shape, and other characteristics of the device.

The impregnation process used in the present invention is carried out in custom glass impregnation vessels that are made to fit the maximum swelling shape of the device selected for the impregnation process. These vessels are designed to fit the device to be impregnated. The solution is poured into the vessel so that contact with all surfaces of the device is achieved.
Use a sufficient amount.

The clean, dry device to be impregnated with the antimicrobial agent is submerged in the solution of the antimicrobial agent, thoroughly immersing the device in contact with the solution on both the interior and exterior surfaces and removing any air bubbles. The silicone rubber device is secured within the bath, as it will protrude from the loading bath if not properly secured when it swells in the solution to be loaded.

The treatment time begins when the tube is fully submerged.
The bath is covered to minimize evaporation of solvent from the loading solution during processing. The swelling itself can be substantially complete in approximately 10 minutes, but the duration of the treatment in contact with the solution is approximately 30 minutes to 1 hour. The loading bath is inspected visually throughout the treatment to ensure that the device remains submerged.

After the treatment period has elapsed, carefully remove the device from the bath and
The liquid inside the device is allowed to flow down into the tank. The swollen silicone rubber is mechanically fragile at this stage and easily breaks, so it must be handled gently.

After removal from the loading bath, the treated devices are immediately submerged in an ethyl alcohol bath to prevent the antimicrobial agent from drying out and leaving a patchy residue on the exterior of the device, without significantly reducing the level of antimicrobial activity.

The device is then suspended in a vertical position and allowed to air dry at room temperature (21°C). It is then left in this position overnight to allow the device to outgas. At room temperature, the device typically recovers to its original size and shape within 10 minutes of removal from the loading chamber.

After degassing, the treated equipment is rinsed briefly with running tap water, followed by deionized water. It is again air dried briefly in a warm dry air oven at temperatures not exceeding 200°F. The treated equipment is then thoroughly sterilized in an autoclave as described above at 121°C and 1.08 kg/ ^cm² above atmospheric pressure for 30 minutes.

As part of the present invention, sterilization using an autoclave is
It has been discovered that this is not only satisfactory, but also provides novel and unexpected results in that the antimicrobial agent is better retained within the bulk of the polymeric material.

After sterilization, the treated device should be stored in the dark at room temperature.

Antimicrobial agents used to impregnate devices are best prepared as a solution immediately prior to use. Because the agents may be light-sensitive and the solutions are volatile, extreme care must be taken not to expose the solution to direct sunlight or store it in solution for any excessively long period before use. After use, the solution should be discarded immediately.

Antimicrobial agents are stored in dry form according to the manufacturer's recommendations. Immediately prior to use, they are weighed using an analytical balance and the respective concentrations are determined to be typically 0.1 wt. to vol.
% or more.

The solute is dissolved in a suitable solvent, such as chloroform.
Use only glass beakers and glass volumetric flasks to handle this solvent-based solution.

Summary of Advantages and Results In summary, the device is fabricated using a silicone elastomer of a size and shape that is expandable to temporarily widen the normal intermolecular spaces to allow penetration of a removable dilator and treatment solution such as an antimicrobial agent, and then contracts to a substantially normal size and shape and a substantially normal molecular structure upon removal of the dilator, while retaining a substantial amount of chemically unaltered antimicrobial agent within the substantially normal molecular structure.

In use, it is believed that the antimicrobial agents within the bulk of the polymeric material are released by solid-state diffusion to and through the surface. Given the molecular structure of the polymer and the intimate molecular association of the antimicrobial agents therewith, the diffusion of these agents occurs at a rate that provides antimicrobial efficacy at the surface of the device for a significant period of time.

Silicone elastomers of varying consistency or molecular configuration, when processed according to the present invention, exhibit the ability to: (1) absorb antimicrobial agents within their intermolecular spaces and retain the antimicrobial agents chemically intact within their intermolecular spaces;

(2) Constant diffusion of the antimicrobial agent towards and through the surface releases the antimicrobial agent over an extended period of time.

(3) It retains antibacterial activity even after sterilization.

(4) Sterilization can be performed using an autoclave without losing antibacterial activity and while increasing the retention of the antibacterial agent.

(5) Retains antimicrobial activity over extended storage times.

(6) It provides effective protection even against overly powerful bacterial attacks.

(7) When processed according to the present invention and transplanted into living tissue,
There are no harmful side effects on surrounding tissues or organs.

As noted above, when fabricated in accordance with the present invention, surgically implanted silicone elastomer devices, such as hydrocephalus shunts, are protected from bacterial contamination introduced during surgery, which can lead to bacterial colonization and proliferation in the implant and its eventual failure, removal, and replacement;
Furthermore, the constant diffusion of the antibacterial agent onto the surface of the device is believed to provide long-term protection against the establishment and proliferation of introduced bacteria.

The inventive concepts described herein may be embodied in a variety of different forms, and therefore, the invention as defined by the appended claims is intended to encompass alternative embodiments other than those limited by the prior art.

Claims (10)

[Claims] [Claim 1] A medical device made of a material that can be implanted in living tissue and remain there for a long period of time, and that exhibits sustained antimicrobial activity upon use, comprising a body of polymeric material that can be swelled with a swelling agent comprising chloroform or its chemical analogues and that contains at least one or more antimicrobial agents completely dissolved therein as solutes, the body of material being exposed to the swelling agent for a time sufficient to promote swelling of the body and expand its normal dimensions and the intermolecular spaces therein;
This causes the solution containing rifampin, clindamycin hydrochloride, and the antibacterial agent selected from these compounds to diffuse and move into the expanded intermolecular space within the material body due to the action of the swelling agent within the material body, and further
a medical device that exhibits antibacterial activity, wherein the solvent is removed from the solute within the matrix of the body of material by evaporation, and the solute remains in the intermolecular spaces of the body of material, and after the removal of the solvent, the body of material substantially returns to its original size and shape and has substantially normal intermolecular spaces, and the antibacterial agent is substantially uniformly deposited thereon and continues to molecularly migrate toward and diffuse through the surface, thereby continuously exerting antibacterial activity on the surface during use in the human body, and the medical device is sterilized using an autoclave before use, and the polymeric material and the antibacterial agent are selected so that the rates of continuous molecular migration and molecular diffusion remain the same or are inhibited by the effects of sterilization using an autoclave. 2. The medical device of claim 1, wherein each of the selected antimicrobial agents is dissolved in the swelling agent in an amount that provides a weight to volume ratio of swelling agent of about 0.1 to 1.0%. Claim 3: Sterilization using an autoclave is performed at approximately 121°C.
(250°F) and atmospheric pressure of approximately 1.08 kg/cm ² (15 ps
3. A medical device according to claim 1 or 2, wherein i) the pressure exceeds 100 psi. [Claim 4] A method for infusing an antimicrobial agent into a body of a medical device comprising a body of material capable of being implanted in living tissue and remaining therein for an extended period of time, comprising the steps of: contacting the surface of the body made of said material thoroughly with a solution consisting of a swelling agent comprising chloroform or its chemical analogs as a solvent and at least one antimicrobial agent selected from the group consisting of rifampin, clindamycin hydrochloride, and mixtures thereof as a solute dissolved therein, said material and said at least one antimicrobial agent being selected so that the rate of diffusion of the antimicrobial agent from the medical device remains the same or is inhibited by the effects of sterilization using an autoclave; maintaining contact between the solution and the surface for a time sufficient to allow the solution to completely penetrate and swell and expand the normal intermolecular spaces of the body of material, thereby diffusing the solution into the expanded intermolecular spaces caused by the swelling; evaporating the solvent from the solution, thereby depositing and retaining the antimicrobial agent within the intermolecular spaces of the elastomeric body;
1. A method of infusing an antimicrobial agent into a body of a medical device, comprising the steps of: substantially restoring the body of material to its original physical shape and condition with substantially normal intermolecular spacing; and cleaning the surface of the treated body of material and sterilizing the treated body of material using an autoclave prior to use. Claim 5: Sterilization using an autoclave is performed at approximately 121°C.
(250°F) and atmospheric pressure of approximately 1.08 kg/cm ² (15 ps
The process of claim 4, wherein i) is carried out at a pressure greater than 0.1%. [Claim 6] An antibacterial composition that can be injected into the body of a medical device made using a silicone elastomer or its analogues, comprising a swelling agent for the silicone elastomer, a solvent, and a solute containing rifampin and clindamycin hydrochloride, wherein the swelling agent is chloroform or one of its homologues. [Claim 7] A medical device for use in the human body, comprising: a body of silicone elastomer having a matrix of highly polymerized molecules; and two antimicrobial agents dispersed substantially uniformly throughout the body of said polymeric material and dispersing the molecules of the antimicrobial agents substantially uniformly within the normal intermolecular spaces of the body of said silicone elastomer; wherein said body of silicone elastomer and said antimicrobial agents therein effectively form a solid solution of molecules of the polymeric material and molecules of the antimicrobial agents, and the concentration and concentration distribution of the antimicrobial agents are such that solid diffusion of molecules of the antimicrobial agents into and through the intermolecular spaces of the body of said polymeric material occurs for a period of time sufficient to provide effective protection against infection after implantation into the human body, and the rate of said solid diffusion remains the same or is inhibited by sterilization of the device using an autoclave. 8. The medical device of claim 7, wherein the swelling agent is chloroform or one of its chemical homologues. 9. The medical device of claim 7 or 8, wherein the antibacterial agent is selected from the group consisting of rifampin, clindamycin hydrochloride, and mixtures thereof. 10. The medical device of claim 9, wherein each of the antibacterial agents is dissolved in chloroform in an amount that provides a weight ratio of agent to volume ratio of chloroform of about 0.1 to 1.0%.