Anti-infective Coatings

1. Anti-infective Coatings

2. General strategies to Prevent Device-related Infections • Minimize contact- Clean Room Conditions • Kill every thing in contact-Sterilization • Minimize binding at contact-Surface coating • Kill after contact-Anti-infective coatings

3. Medical Device A device implanted permanently or temporarily in the body for a mechanical/structural purpose. Usually manufactured by extrusion or injection-molding (polymeric devices) Drug Delivery Device A device intended to deliver a drug for prophylactic or therapeutic purposes. Usually, such devices control the rate at which the drug is made available to the body (controlled release devices) Hybrid device A medical device with a primary mechanical/structural function and a secondary drug delivery function, either for device protection or targeted drug delivery.

4. Combining Local Drug Delivery and Implantable Medical Devices

5. Anti-infective Coatings • In recent years, there have been numerous efforts to sequester antimicrobials and antibiotics on the surface of or within devices that are then placed in the vasculature or urinary tract as a means of reducing the incidence of device-related infections; • The presence of active anti-infective agents in or on the device is secondary to the device's primary therapeutic or diagnostic function; • We are not talking about the use of devices as a means of drug delivery to treat preexisting conditions but rather as a deterrent to device associated infections after implantation.

6. The Central Concept • Site-specific delivery-Locating active agents or drugs only at the surface of or in the vicinity of the device to reduce the incidence of device-related infections, which is preferable to administering the same drugs systemically; • Systemic administration requires maintaining dose levels throughout the body, whereas local administration from the device surface concentrates the drug at the precise site where it is needed; • There are increasing concerns about bacterial resistance due to chronic systemic antibiotic administration.

7. Effective Delivery • In order for local administration to be effective there must be sufficient amounts of the agent released from the device, and the duration of release must be appropriate for the condition. If there is good elution of drug from the device, drug concentration will be high at and near its surface, but will diminish with distance;

8. Endotracheal Tubes from ICU at 4, 8 , 12 hrs.

9. Other Considerations • To be effective, device-based drugs must be available at and near the surface in sufficiently high concentration to preclude bacterial propagation; • In other words, the device surface must serve as a reservoir for a large amount of drug and be capable of releasing it over time in appropriate quantities; and, • It is also critical that the drug remain potent after sterilization. • For this reason, devices incorporating heat-, radiation-, or ethylene oxide—sensitive antibiotics need to be tested carefully for efficacy after sterilization.

10. METHODS OF DRUG ATTACHMENT AND ENTRAPMENT • Much of the early work in the field focused on surface adsorption. • The simplest surface-adsorption technique is the immersion of the device in a solution of the drug. • This approach is limited by the short time the drug remains on the surface of the device: because it is not bound to the surface or sequestered in any way, it washes away from the surface very quickly, generally less than a few hours; • In addition, only a thin film is deposited on the surface, typically yielding, at best, only moderate release levels of drug.

11. Adding Positive Charges • It has long been recognized that many antibiotics have negative charges analogous to that of heparin. • This finding has led to a method of binding antibiotic molecules to the surface of prosthetic materials through the adsorption of positively charged surfactants—such as benzalkonium or tridodecylmethylammonium chloride (TDMAC). • The bound surfactant acts as an anchor for subsequent binding of negatively charged antibiotic molecules, which include, for example, the penicillin and cephalosporin families of drugs.

12. Electrostatic interaction with positively charged adsorbed species • The pharmacological agents are not irreversibly bound to the prosthesis, however, and after exposure to blood or body fluid are slowly released, resulting in a local environment of high drug concentration at the surface of the prosthesis, far in excess of what could be achieved by systemic administration. • This high concentration of antibiotic causes localized inhibition of bacterial growth.

13. Controlled Release Mechanisms diffusion controlled • matrices (monoliths) • reservoirs (membranes) chemically controlled • Bioerosion • degradation

14. Incorporation into the Polymer • The concept is that the device substrate can be a reservoir that allows the drug to elute, providing antimicrobial activity at and adjacent to the surface; • A significant amount of drug can be entrapped within the device substrate by compounding the agent into the plastic prior to injection molding or extrusion, in the same manner that pigments, stabilizers, and strengtheners are added to the resin; • There have been reports of good experimental results using this technique, with antimicrobial activity demonstrated up to 3 or 4 weeks.

15. Q Q √t t Matrix (monolithic) -drug uniformly distributed through polymer matrix -no danger of drug dumping -first-order kinetics

16. Sequestering Drugs into Device Coatings • the surface treatments can be applied without changing the basic properties of the device, and a sufficient quantity of drug can be incorporated; • The several commercially available systems are generally prepared by one of two methods: surface treating devices by cross-linking polymers that contain drugs, or coating devices with polymer solutions that contain antimicrobial agents.

19. Q t Reservoirs system -drug core surrounded by biodegradable polymer -properties of drug and polymer govern diffusion rate -‘drug-dumping’ if membrane ruptures or degrades to quickly -zero-order kinetics from ‘constant activity’ source

20. Drawbacks and other considerations • The major drawback is the extensive R&D effort necessary to determine commercial viability and the potential cost of the final product; • Significant experimental work is required to qualify polymers appropriate for devices—resins whose molding integrity is not compromised by the addition of the drug; • One must also determine appropriate drug-plastic combinations that will allow for controlled release at a sufficient level over the requisite time period; • Because of the iterative nature of the testing and the complexity of the molding setups, the time and costs required to achieve adequate results may be daunting.

21. The Ideal Surface Treatment • Biocompatibility—The full complement of biocompatibility tests should be considered for all devices that contact body fluids and tissues. (For general testing requirements, see the ISO 10993/EN 30993 standard and the FDA Blue Book Memorandum G95-1.) • Drug Availability—The amount of drug available is obviously critical. Any surface-modification system that cannot provide drug in sufficient quantities over the needed time period allows for unnecessary exposure to infection. • Adhesion—The selected surface treatment cannot shed or peel. Loss of large particles from the surface could create emboli or distribute the drug to nontargeted areas of the body.

22. The Ideal Surface Treatment-continued • Durability—The surface treatment must be able to withstand the rigors of the insertion process and any subsequent device manipulation after placement. • Flexibility—Any surface treatment that measurably adds to the diameter of the device can be expected to add some stiffness. Minimizing this added stiffness can be crucial for devices such as small-diameter catheters and guidewires that rely on very flexible tips to minimize the risk of perforation. • Coverage—The selected treatment should entirely cover whatever surfaces of the device are exposed to body fluids, so as to reduce the risk of exposure to bacteria.

23. -continued • Sterilizability—The device must be presented sterile. For commercial products, this means that it must be packaged and sterilized without diminishing the efficacy of the antibiotic, antimicrobial, or antithrombogenic agent. • Stability—The surface treatment and drug must remain stable under normal storage and use conditions and must have a reasonable shelf life. Radiation sterilization and some types of surface treatments—for example, exposure to UV—may cause cross-linking. In many polymers, cross-linking reactions will continue even after the exposure to radiation or UV has been terminated. Products that rely on cross-linking as a surface treatment or that are radiation sterilized should be tested for this continuation of the cross-linking process, which can cause embrittlement.

24. -Continued • Ease of Use—To be clinically viable, the treated device must be relatively easy to use. This presents a drawback for devices to which the drug must be added during the clinical procedure. • Cost—An obvious consideration in all product development decisions. Do the benefits generated justify the costs?

25. Emerging Technologies • Coatings for enhanced imaging • Cell coated grafts for tissue engineering • Coating to enhance regenerative processes • Coatings for drug delivery

26. Coating Companies Polymer Technology GroupSurModicsCarmedaHydromer Inc.AST Products Inc.STS BiopolymersBiocoatRichard James Inc.Biocompatibles Ltd.BioChromSurface Solutions LaboratoriesSpire Corp.Implant Sciences Corp.Advanced Polymer Systems Inc.