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Overview

  • Topical and transdermal administration
  • Factors affecting topical and transdermal drug uptake
  • Topical treatment of infections
  • Advantages and disadvantages of transdermal application
  • Design of delivery systems

By the end of this lecture you should be able to

  • Understand the terms “topical” and “transdermal” drug administration.
  • Identify factors which affect bioavailability, pharmacokinetics and toxicity of topically applied drugs.
  • Provide and discuss examples of topical antimicrobial agents.
  • Discuss the advantages and disadvantages of transdermal drug administration.

Topical Administration of Drugs

  • Definition: Application of drugs to epithelial surfaces for local effects
    • skin
    • eye
    • ear
    • intranasal
    • inhalation
    • vaginal

Cutaneous Drug Delivery

  • Vehicle: applied formulation
  • Stratum corneum: main barrier, but also reservoir (long-lasting, slow-release of a drug through the skin)
  • After absorption: binding to targets in epidermis or dermis OR diffusion into vasculature, leading to systemic distribution
  • Normally we want a drug to bind in the epidermis or dermis, and not to permeate into the vasculature (we're aiming for local effects)

Regional Differences in Absorption

  1. mucous membrane
  2. scrotum
  3. eyelids
  4. face
  5. chest and back
  6. upper arms and legs
  7. lower arms and legs
  8. dorsa of hands and feet
  9. palmar and plantar skin
  10. nails
  • Major reason: variable stratum corneum thickness affects penetration

Factors that influence absorption

  • Occlusion- eg airtight dressings, penetration enhancers, greasy ointments: increases hydration (opens up stratum corneum) and temperature, limits rub-off/wash-off
  • Contact time
  • Vigorous rubbing: increases surface area and blood supply, may exfoliate
  • Hair follicles: enhance penetration, scalp and beard areas present less of a barrier
  • Diseased, abraded or eczematised skin

Therapeutic Efficacy of Topical Drugs

  • Dependant on potency and absorption
  • Very slow rate of absorption
  • Peak concentrations reached slowly
  • Stratum corneum can act as a reservoir

Systemic Toxicity of Topical Drugs

  • Generally safer than other routes of administration
  • However:
    • No first pass metabolism
      • increased levels of administered compound
    • Stratum corneum acts a reservoir
      • long diffusion period (many days)
    • Young children at greater risk due to increased surface area to volume ratio

Accidental Poisoning through Skin Uptake

  • Most drugs/chemicals are absorbed very poorly through unbroken skin
  • Some organophosphate insecticides:
    • need to penetrate the insect cuticle
    • are absorbed through skin
    • accidental poisonings in farm workers through skin uptake

Topical Antimicrobial Agents

  • Antibiotics
    • most commonly used in acne vulgaris
    • treatment of other superficial cutaneous bacterial infections
    • treatment of non-infectious diseases, such as acne rosacea
    • topical agents can be very effective
    • often employed prophylactically (wounds, injuries)
    • systemic antibiotics are required for deeper/established bacterial infections and are commonly used for acne v.
  • Antifungal agents
    • fungal infections among the most common causes of skin diseases
    • examples include tinea pedis, onychomycosis (nail infections)
    • systemic therapy necessary for tinea capitis, follicular-based fungal infections
  • Antiviral agents
    • viral infections of the skin are very common
    • examples include human papillomavirus, herpes simplex virus, chicken pox
  • Infestations with ectoparasites
    • common examples include lice and scabies

Topical Antibiotics

  • Acne: clindamycin, erythromycin, benzoyl peroxide and antibiotic/benzoyl peroxide combinations
  • Other skin infections
    • gram-positive organisms mostly responsible
    • topical treatment useful in impetigo (superficial bacterial skin infection) (S. aureus, S. pyogenes)
    • mupirocin (impetigo): inhibits protein synthesis; highly active against staphylococci and most streptococci; inactive against normal skin flora; activity enhanced by acid pH; available as a 2% ointment or cream; applied 3 x daily

Topical Antifungal Agents

  • Tinea pedis: azoles, allylamines
  • Onychomycosis:
    • often due to psoriasis or other conditions
    • histological examination or culture required before initiating therapy
    • azoles, if localised and caused by candida
    • systemic therapy usually necessary

Other Topical Agents

  • Acyclovir (zovirax) available for mucocutaneous herpes simplex virus infection
  • Permethrin for scabies and lice; approved for infants from 2 months of age; creams, cream rinse, topical solution
  • Lindane: several cases of neurotoxicity (in other words systemic toxicity); only as a second-line drug in pediculosis, scabies; only to be prescribed for a single application
  • Various agents for lice and head lice; some, less effective agents may be used during pregnancy or on nursing mothers, ie sulfur in petrolatum

Transdermal Administration of Drugs

  • Definition: Application of drugs to the skin for systemic effects
    • Very different to topical (where we only want local effects)

Transdermal Administration of Drugs

  • Advantages of transdermal delivery
    • avoids first pass metabolism
    • reduced peak plasma levels
      • = decreased side effects
    • reductions in fluctuations of plasma levels
    • reduced frequency of dosing
      • better compliance
  • Notes
    • Frequency of dosing with IV has to be high to keep conc in therapeutic range; excreted + metabolised
      • If you want a fast-acting drug, you don't want transdermal
      • Repeated oral take >1 dose to get therapeutic levels, and then concentration varies widely
    • E.g. scopolamine: giving transdermally has low enough concentrations to avoid side effects, and has long-lasting actions
  • Disadvantages:
    • Relatively expensive
    • Properties drugs need for successful transdermal delivery
      • effective at low concentrations (potent) due to low skin permeability of most drugs and small area covered
      • molecular mass of drug <500 Da
      • soluble in oil and water
      • low melting point

Anatomy of transdermal patch

  • Plastic backing
  • Adhesive
  • Rate-controlling membrane
  • Drug reservoir

Examples of transdermal patch

See table

All have low MW

Transdermal Delivery Systems

  • Transdermal patch


  • Systems to overcome unfavourable drug properties
    • Ultrasound
    • Ionotophoresis
    • Electroporation
    • Microneedles

Ultrasound

  • No limit to molecular weight (large molecules eg insulin)
  • < 20 mg/ day daily dose
  • Low frequency ultrasound (20-100 KHz) most effective (ultrasound used for muscles 1-16MHz)
  • Mechanism of action
    • disruption of lipid packing of stratum corneum

Ionotophoresis

Uses electrical current

  • No limit to molecular weight
  • < 20 mg/ day daily dose; need a potent drug
  • Small electrical current (0.5 mA/cm2)
  • Mechanism of action
    • charged species repulsed by electrode of same charge
    • increased permeability of skin
    • electroosmosis: water enters stratum corneum, carrying dissolved drug with it

Basically use the skin as a salt bridge

Electroporation

  • Electrical pulses μs-ms 100-1000V
  • Increases absorption of charged molecules <40kDa 10-10000 fold
  • Mechanism of action
    • creates transient aqueous pores in lipid bilayers; to let charged molecules go through (only charged)

Microneedles

  • Needle length 10-900 μm
  • Stratum corneum 10-20 μm thick
  • No pain: probably due to small needle size, missing nerves or too small to activate nerves
  • No limit to molecular weight
  • < 30 mg/ day daily dose

Mechanism of action

  • needles cross stratum corneum