Chapter 11 - Transdermal Drug Delivery System

CHAPTER 11 - TRANSDERMAL DRUG DELIVERY SYSTEMS TRANSDERMAL DRUG DELIVERY SYSTEMS -Facilitate the passage of therapeutic quantities of drug substance through the skin and into the general circulation for synthetic effects in underlying blood supply without build up in the dermal layers. PERCUTANEOUS DRUG ABSORPTION EVIDENCE 1.) Measurable blood levels of the drug 2.) Detectable excretion of the drug and its metabolites in the urine 3.) Clinical response of the patient to the therapy STRATUM CORNEUM - Skin’s barrier layers to penetration by external agents - Percutaneous absorption of a drug generally results from direct penetration of the drug through the stratum corneum, a 10- to 15 -µm thick layer of flat, partially desiccated non-living tissue. - Composed of 40% protein (keratin) and 40% water - Keratinized semi-permeable artificial membrane - Drug molecules penetrate by passive diffusion. FACTORS AFFECTING PERCUTANEOUS ABSORPTION 1.) Drug concentration concentration: The amount of drug percutaneously absorbed per unit of surface area per time interval increases with an increase in the concentration of the drug. 2.) The larger the area of application, the more drug is absorbed  3.) Should have a greater physiochemical  attraction to the skin rather than to the vehicle o Non-polar drugs: cross the cell barrier through the lipid-rich region o Polar Drugs: favor transport between cells (intercellular route: H2O) 4.) 100 to 800 drug molecular weights & adequate lipid and aqueous solubility can permeate skin. 5.) HYDRATION of the SKIN generally favors  percutaneous absorption. 6.) Percutaneous absorption appears to be grater  when the TDDS is applied to a site with a thin horny layer than with a thick one. 7.) The LONGER THE MEDICATED APPLICATION  is  permitted to remain in contact with the skin; the greater is the total drug absorption.

PERCUTANEOUS ABSORPTION ENHANCERS  CHEMICAL ENHANCERS - Skin penetration enchancer increases skin  permeability by reversibly damaging damaging or altering the  physiochemical nature of the stratum stratum corneum to reduce its diffusional resistance   Acetone   Azone  Dimethyl acetamide  Dimethyl formamide  Dimethyl sulfoxide  Ethanol   Oleic Acid   Polyethylene glycol   Propylene glycol   Sodium lauryl sulphate PHYSICAL ENHANCERS  o IONTOPHORESIS - is delivery of charged chemical compound  across the skin membrane using an electrical field. o SONOPHORESIS - High-frequency ultrasound  - Is also being studied as a means to enhance transdermal drug delivery. - Can influence the integrity of the stratum corneum and thus affect its penetrability.  Hydrocortisone  Lidocaine  Salicylic acid  PERCUTANEOUS ABSORPTION MODELS IN-VIVO STUDIES 1. To verify and quantify the cutaneous bioavailability of a topically applied drug. 2. To verify and quantify the systemic bioavailability of a transdermal drug. 3. To establish bioequivalence of different topical   formulations of the same drug substance. substance. 4. To determine the incidence and degree of  systemic toxicologic risk following topical  application of a specific drug or drug substance. 5. To relate resultant blood levels of drug to human to systemic therapeutic effects. humans. - MOST relevant studies are  performed in humans. -  Animal models may be used insofar as they may be effective as predictors of human response.

IN-VITRO STUDIES - Skin permeation may be tested in-vitro using various skin tissues (human or animal) in a diffusion cell. - Shed snakeskin (Elaphe obsolete; Black rat snake) > Non-living, pure stratum corneum, hair-less and similar to human skin but slightly less permeable.  LIVING SKIN EQUIVALENT TESTSKIN - An alternative for dermal absorption studies - The material is an organotypic co-culture of  human dermal fibroblasts in collagen-containing matrix and a stratified epidermis composed of  human epidermal keratinocytes.  DIFFUSION CELL SYSTEMS - Are employed in-vitro to quantify the release rates of drugs from topical preparations. - Skin membranes or synthetic membranes may be employed as barriers to the flow of drug and vehicle to stimulate the biologic system. DESIGN FEATURES OF TRANSDERMAL DRUG DELIVERY SYSTEMS TDDS or Transdermal Patches - are designed to support the passage of drug substances from the surface of the skin through its various layers and into the systemic circulation.  MONOLITHIC SYSTEMS - Incorporate a drug matrix layer between the backing and the frontal layers o Drug matrix layer  - is composed of a polymeric material in which the drug dispersed. o Polymer matrix  - Controls the rate at which the drug is released for percutaneous absorption - The matric may be of two types: with or  without an excess of drug MEMBRANE CONTROLLED SYSTEMS  - Are designed to contain a drug reservoir or pouch - Usually in liquid or gel form - A rate controlling membrane, and backing, adhesive and protecting layers   Advantage o As long as the drug solution in the reservoir remains saturated the release rate of the drug through the controlling membrane remains constant. o Device: Drug is delivered to the stratum corneum at a rate less than absorption capacity  o Skin: Drug is delivered to the skin area to saturation

LAYERS OF TDDS 1) An occlusive backing membrane 2) A drug reservoir or matrix system 3) A release liner 4) An adhesive layer to maintain contact with the skin after application o Peripheral adhesive – outer edge o Face adhesive – entire face BACKING LAYER  Occlusive  2 to 3mm thick   Low moisture vapor transmission rate  Transparent or pigmented films: polypropylene,  polyethylene, polyolefin ADHESIVE LAYER  Pressure sensitive  Tested for skin compatibility: test for irritation, sensitivity and cytotoxicity   Contains Polybutyl acrylate DESIGN OBJECTIVES 1) Deliver the drug to the skin for percutaneous absorption 2) Contain medicinal agents having the necessary   physicochemical characteristics 3) Occlude the skin to ensure one-way flux of the drug 4) Have a therapeutic advantage over other  dosage forms and drug delivery systems 5) Not irritate or sensitize the skin 6)  Adhere well to the patient’s skin and have size, appearance and site placement that encourage acceptance ADVANTAGE OF TDDS’s

1) They can avoid gastrointestinal drug absorption difficulties 2) They can substitute for oral administration of  medication when hat route is unsuitable 3) The avoid first-pass effect  4) They are non-invasive 5) They provide extended therapy with a single application DISADVANTAGES OF TDDS’s 1) Only relatively potent drugs are suitable candidates for TDDS because of the natural  limits of drug entry imposed by the skin’s impermeability. 2) Some patients develop dermatitis

TRANSDERMAL SCOPOLAMINE - First TDDS to receive FDA approval CLINICAL CONSIDERATONS IN THE USE OF TDDS’s

1) The patient should be advised of the importance of using the recommended site and rotating locations within the site. 2) Should be applied to clean, dry skin than is relatively free of hair and not oily, irritated, inflamed, broken, or callused. 3) Use of skin lotion should be avoided  4) TDDS should NOT be physically altered by  cutting 5) Should be removed from its protective package 6) Should be placed at a site that will NOT subject  it to being rubbed off by clothing or movement  7) Should be worn for the full period stated in the  product’s instructions 8) Should be instructed to cleanse hands thoroughly before and applying a TDDS 9) If the patient exhibits sensitivity of intolerance to a TDDS she/he must seek re-evaluation 10) Upon removal, the TDDS should be folded in half  with adhesive layer together so that it cannot  be reused.