Anti-infective Coatings

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Anti-infective Coatings
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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

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• 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.

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Combining Local Drug Delivery and Implantable
Medical Devices
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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.

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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.

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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

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Endotracheal Tubes from ICU at 4, 8 , 12 hrs.
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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 oxidesensitive
  antibiotics need to be tested carefully for
  efficacy after sterilization.

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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.

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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 surfactantssuch 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.

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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.

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Controlled Release Mechanisms
diffusion controlled

• matrices (monoliths)
• reservoirs (membranes)

chemically controlled

• Bioerosion
• degradation

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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.

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

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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
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Drawbacks and other considerations

• The major drawback is the extensive RD effort
  necessary to determine commercial viability and
  the potential cost of the final product
• Significant experimental work is required to
  qualify polymers appropriate for devicesresins
  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.

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The Ideal Surface Treatment

• BiocompatibilityThe 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 AvailabilityThe 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.
• AdhesionThe 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.

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The Ideal Surface Treatment-continued

• DurabilityThe surface treatment must be able to
  withstand the rigors of the insertion process and
  any subsequent device manipulation after
  placement.
• FlexibilityAny 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.
• CoverageThe 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.

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-continued

• SterilizabilityThe 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.
• StabilityThe 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
  treatmentsfor example, exposure to UVmay 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.

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-Continued

• Ease of UseTo 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.
• CostAn obvious consideration in all product
  development decisions. Do the benefits generated
  justify the costs?

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Emerging Technologies

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

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Coating Companies

• Polymer Technology GroupSurModicsCarmedaHydrom
  er Inc.AST Products Inc.STS BiopolymersBiocoat
  Richard James Inc.Biocompatibles
  Ltd.BioChromSurface Solutions
  LaboratoriesSpire Corp.Implant Sciences
  Corp.Advanced Polymer Systems Inc.