Transdermals and Transdermal Drug Delivery Systems

• Transdermal Drug Delivery Systems (TDDSs)


  Facilitate the passage of therapeutic quantities of drug substances through the skin and into the general circulation for their systemic effects

  
• Percutaneous absorption


  The skin is just a medium but the drug will enter the circulation

  
• Transderm Scop (Baxter) was the first transdermal system approved by the U.S. Food and Drug Administration (FDA) in 1979 for prevention of nausea and vomiting associated with travel, particularly at sea

  
• Evidence of percutaneous drug absorption

  • Measurable blood levels of the drug, detectable excretion of the drug and/ or its metabolites in the urine, and clinical response of the patient to the therapy
• For transdermal drug delivery, it is considered ideal for the drug to migrate through the skin to the underlying blood supply without buildup in the dermal layers

  
• Stratum corneum


  The outer layer of the skin, composed of approximately 40% protein (mainly keratin) and 40% water, with the balance being lipid, principally as triglycerides, free fatty acids, cholesterol, and phospholipids
• Stratum corneum


  • The major rate limiting barrier to transdermal drug transport
  • 15 to 25 layers of flattened corneocytes with an overall thickness of about 10 mm
  • The rate of drug movement across this layer depends on its concentration in the vehicle, its aqueous solubility, and the oil-water partition coefficient between the stratum corneum and the vehicle
• Factors affecting percutaneous absorption

  • Drug concentration
  • Area of application
  • Drug physicochemical attraction
  • Solubility
  • Partition coefficient
  • Molecular weight
  • Condition of the skin/ skin hydration
  • Occlusive properties
  • Thickness of horny layer
  • Length of time/duration of application
  • Choice of vehicle
  • Cosolvent use
  • Penetration enhancers
  • Skin condition
• Chemical skin penetration enhancers

  Increase skin permeability by reversibly damaging or altering the physicochemical nature of the stratum corneum to reduce its diffusional resistance
• Iontophoresis


  Delivery of a charged chemical compound across the skin membrane using an electrical field
• Sonophoresis/Phonophoresis


  Use of ultrasound to enhance transdermal drug delivery and penetration

  
• Drugs studied for iontophoresis

  • lidocaine
  • dexamethasone
  • amino acids, peptides, and insulin
  • verapamil
  • propranolol
• Sonophoresis/Phonophoresis


  A type of high-frequency ultrasound used to enhance transdermal drug delivery
• Agents examined for sonophoresis

  • hydrocortisone
  • lidocaine
  • salicylic acid
• Stratum corneum


  The outer layer of the skin that is the main barrier to transdermal drug delivery

  
• In vivo studies


  • Verify and quantify the cutaneous bioavailability of a topically applied drug
  • Verify and quantify the systemic bioavailability of a transdermal drug
  • Establish bioequivalence of different topical formulations
  • Determine the incidence and degree of systemic toxicologic risk
  • Relate resultant blood levels to systemic therapeutic effects
• Models and samples used in in vivo studies

  • Humans
  • Animal models (weanling pig, rhesus monkey, hairless mouse or rat)
  • Biological samples (skin sections, venous blood, systemic blood, excreta)
• In vitro studies


  • Make use of petri dish, test tube, culture media
  • Test skin permeation using various skin tissues (human or animal whole skin, dermis, or epidermis) in a diffusion cell
• Human skin in vitro

  Difficult to procure, store, and has variation in permeation
• Animal skin in vitro

  More permeable than human skin, but excised animal skins may vary in quality and permeation
• Shed snakeskin


  An effective alternative to human and animal skin, being nonliving, pure stratum corneum, hairless, and similar to human skin but slightly less permeable
• Living Skin Equivalent (TESKIN)


  An organotypic coculture of human dermal fibroblasts and human epidermal keratinocytes, used as an alternative for dermal absorption studies

  
• Diffusion cell systems


  • Employed in vitro to quantify the release rates of drugs from topical preparations
  • Skin membranes or synthetic membranes may be used as barriers to simulate the biologic system
  • Typical diffusion cell has two chambers, one with a temperature-controlled drug solution and the other with a receptor solution
• The USP describes the apparatus and procedure to determine dissolution (release) of medication from a transdermal delivery system and provides an acceptance table
• Commercial systems use transdermal diffusion cells and automatic sampling systems to determine the release rates of drugs from transdermal systems

  
• In USP 35/NF 30, there were two official transdermal systems: clonidine and nicotine
• Monolithic TDDS


  Incorporate a drug matrix layer between the backing and the frontal layers, with the polymer matrix controlling the drug release rate

  
• Membrane-controlled TDDS


  Contain a drug reservoir or pouch, usually in liquid or gel form, with a rate-controlling membrane and backing, adhesive and protecting layers
• The device is the controlling factor

  If the drug is delivered to the stratum corneum at a rate less than the absorption capacity
• The skin is the controlling factor


  If the drug is delivered to the skin area to saturation
• Design objectives of TDDS

  • Deliver the drug to the skin for percutaneous absorption at therapeutic levels
  • Contain drugs with the necessary physicochemical characteristics to release from the system and partition into the stratum corneum
  • Occlude the skin to promote one-way into the stratum corneum
  • Have therapeutic advantages over other dosage forms
  • Not irritate or sensitize the skin
  • Adhere well to the patient's skin and have size, appearance, and site placement that promote patient acceptance

  
• Advantages of TDDS


  • Avoid gastrointestinal drug absorption difficulties
  • Avoid first-pass hepatic metabolism
  • Provide a controlled, continuous drug input
  • Improve patient compliance
  • Terminate drug delivery by simply removing the system
  • Provide site-specific drug delivery
  • Reduce side effects
• Rate of drug transport

  Controlled by either artificial or natural skin membranes in all transdermal drug delivery systems, monolithic and membrane

  
• Design objectives of a transdermal drug delivery system

  • Deliver the drug to the skin for percutaneous absorption at therapeutic levels at an optimal rate
  • Contain medicinal agents/drugs having the necessary physicochemical characteristics to release from the system and partition into the stratum corneum
  • Occlude the skin to promote one-way into the stratum corneum
  • Have therapeutic advantages over other dosage forms and drug delivery systems
  • Not irritate or sensitize the skin
  • Adhere well to the patient's skin and have size, appearance, and site placement that promote patient acceptance

  
• Transdermal scopolamine


  • First TDDS to receive FDA approval
  • Scopolamine - a belladonna alkaloid used to prevent travel-related motion sickness as well as nausea and vomiting due to anesthetics and analgesics in surgery
• Transderm Scop Systems


  • A circular flat patch (0.2mm thick and 2.5 cm2 in area) and a 4-layer system
  • Contains 1.5mg of scopolamine and is designed to deliver approximately 1mg of scopolamine at an approximately constant rate to the systemic circulation over the 3-day lifetime of the system
  • Initial priming dose of 200 microgram of scopolamine in the adhesive layer of the system saturates the skin binding sites and rapidly brings the plasma concentration to the required steady-state level
  • The continuous release of scopolamine through the rate-controlling microporous membrane maintains the plasma level constant
  • The rate of release is less than the skin's capability for absorption so the membrane, not the skin controls the delivery of the drug into circulation
  • The patch is placed/worn in a hairless area behind the ear
  • Due to the small size of the patch the system is unobtrusive, convenient and well-accepted by patients
  • The TDDS is applied at least 4 hours before the anti nausea effect is required
  • Only one disk/patch should be worn at a time and may be kept in place for up to 3 days
  • If continued treatment is required, a fresh disk is placed behind the other ear, and the other is removed
  • Common side effects include dryness of mouth and drowsiness
  • Geriatric population use may also interfere with orientation, cognition, and memory
  • TDDS is not intended for use in children and should be used with caution during pregnancy

  
• Transdermal nitroglycerin


  • A number of nitroglycerin-containing TDDS have been developed including: Minitran (3 M Pharmaceuticals), Nitro-Dur (Key), Transderm-Nitro (Summit), Nitrodisc (Roberts)
  • Each of these products maintains nitroglycerin drug delivery for 24 hours after application
  • Tolerance, however, is a major factor limiting the effectiveness of these systems when used continuously for more than 12 hours per day
  • An appropriate dosing schedule would include a daily "patch-on" period of 12 to 14 hours and a "patch off" period of 10 to 12 hours
  • Nitroglycerin is widely used as a prophylactic treatment of angina
  • Contains a relatively low dose, short plasma half-life, high peak plasma levels and inherent side effects when taken sublingually
  • It is rapidly metabolized by the liver when taken orally; this first-pass effect is bypassed by transdermal route
  • The various nitroglycerin TDDSs control the rate of drug delivery through a membrane and/or controlled release from the matrix or reservoir
  • Upon application of TDDS, nitroglycerin is absorbed continuously, resulting in an active drug reaching the target organs (heart, extremities) before inactivation by the liver
  • Only a portion of the total glycerin in the system is delivered over the usual 24-hour use period; the remainder serves as the thermodynamic energy source to release the drug and remains in the system
• Transderm-Nitro Systems


  • The rate of drug release depends on this system. In this system, Nitroglycerin 0.02mg is delivered per hour for every square centimeter of patch
  • In DEPONIT SYSTEM, each square centimeter delivers approximately 0.013mg of nitroglycerin per hour
  • Nitro-Dur Matrix is in a highly kinetic equilibrium state, acts as saturated reservoir for diffusive drug input through the skin
  • Dissolved nitroglycerin molecules are constantly exchanging with adsorbed nitroglycerin molecules bound to the surfaces of the suspended lactose crystals
  • These TDDS are applied on the chest, back, upper arms or shoulders. The site should be free of hair, clean and dry so the patch adheres without difficulty

  
• Transdermal clonidine


  • The first transdermal system for hypertension, Catapres-TTS (clonidine transdermal therapeutic system, Boehringer Ingelheim), was marketed in 1985
  • Clonidine lends itself to transdermal delivery because of its lipid solubility, high volume of distribution and therapeutic effectiveness in low plasma concentrations
  • The TDDS provides a controlled release of clonidine for 7 days
  • The product is a four-layer patch
  • Clonidine flows in the direction of lower concentration at a constant rate controlled by a membrane
  • The system is applied to a hairless area of intact skin on the upper outer arm or chest. After application, clonidine in the adhesive layer saturates the skin site. Then clonidine from the reservoir begins to flow through the rate-controlling membrane and the skin to the systemic circulation
  • Therapeutic plasma clonidine levels are achieved 2 to 3 days after initial application
  • Application of new system to a fresh skin site at weekly intervals maintains therapeutic plasma concentration
  • If the patch is removed and not replaced with a new system, therapeutic plasma clonidine levels will persist for about 8 hours and then decline slowly for several days

  
• Transdermal nicotine


  • Used as adjuncts along with counseling in smoking cessation programs
  • Example products: Nicoderm CQ (GlaxoSmithKlein), Nicotrol (Pharmacia), Prostep (Wyeth)
  • Provides sustained blood levels of nicotine replacement therapy to help patient establish and sustain remission from smoking
  • The commercially available patches contain 7 to 12mg of nicotine for daily application during the course of treatment ranging from about 6 to 12 weeks
  • A nicotine TDDS is usually applied to the upper arm or upper front torso with patients advised not to smoke when wearing the system
  • The TDDS is replaced daily with sites alternated
  • Some nicotine replacement programs provide a gradual reduction in nicotine dosage during the treatment
  • Used TDDS should be discarded properly because the retained nicotine is poisonous to children and pets