Chapter 11 Transdermal Drug Delivery Systems 1. o o 2.

. Define Transdermal Drug Delivery System (TDDS) Facilitates passage of drug substances through the skin and into the general circulation for their systemic effects 1965 Stoughton conceived the word percutaneous absorption 1979 - First transdermal system: Transderm Scop Nausea and vomiting

Give evidences of percutaneous drug absorption 1. Measurable blood levels of drug 2. Detectable excretion of drug or its metabolites in urine 3. Clinical response of patient to therapy Blood concentration needed to achieve the therapeutic efficacy may be determined by comparative analysis of patients response to drug blood levels Ideal for drug to mitigate through the skin to the underlying blood supply without build up in the dermal layers, unlike ointments and creams What is the major late limiting barrier of TDDS? Describe it Percutaneous absorption of drug results from direct penetration of the drug through the stratum corneum

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Stratum Corneum a. 40% protein, 40% water b. Semi-permeable membrane penetrated by passive diffusion c. 10-15um thick with 15-25 layers of flat, partially desiccated nonliving tissue d. Lipid component important determinant in first step of absorption Stratum Corneum -> Epidermis -> Dermis

4. How can drug penetrate this barrier? 1. Rate of drug movement across Stratum Corneum depends on: a. Concentration in vehicle b. Aqueous solubility c. Oil-water partition coefficient between stratum corneum and vehicle 2. Aqueous and lipid soluble drugs are good candidates 5. What factors affect percutaneous absorption? 1. Drug concentration - more drug is available to be absorbed 2. Larger area of application more place for drug to be absorbed 3. Drug should have a greater physiochemical attraction to skin than vehicle leave the vehicle in favour of the skin a. Partition coefficient influences rate b. Drugs penetrate skin better in unionized form c. Nonpolar drugs tend to cross cell barrier through lipid-rich regions d. Polar drugs favour transport between cells (intrercellular) 4. Drugs with molecular weights of 100 800 and adequate lipid and aqueous solubility can permeate skin a. Ideal mol. Wt : 400 or less 5. Hydration of skin favors percutaneous absorption a. TDDS acts as occlusive moisture barrier through which sweat cannot pass, increasing skin hydration 6. Absorption is greater when TDDS is applied to a site with thin horny layer 7. The longer the medicated application is placed, the greater is the total drug absorption 6. 1. Explain these different skin penetration enhancers. Give examples Chemical increases skin permeability by reversibly damaging physiochemical nature of stratum corneum to reduce its resistance i. Increase in hydration ii. Change in structure of lipids and lipoproteins in intercellular channels through solvent action or denaturation iii. Acetone, azone, dimethyl acetamide, dimethyl foramide, dimethyl sulfoxide, ethanol,oleic acid, PEG, propylene glycol, sodium lauryl sulphate iv. Selection based on efficacy, dermal toxicity and physiochemical ad biologic compatibility with the system Ionophoresis delivery of charged chemical compound using an electrical field i. Drugs using ionophoresis: Lidocaine, dexamethasone, amino acids, peptides and insulin, verapamil, propranolol Sonophoresis high frequency ultrasound can influence integrity of stratum corneum and affect its penetrability i. Hydrocortisone, lidocaine, salicylic acid What are the different purposes for in vivo skin penetration studies Verify and quantify cutaneous bioavailability of topically applied drug Verify and quantify systemic bioavailability of transdermal drug

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Establish bioequivalence of different topical formulations of the same drug substance Determine incidence and degree of systemic toxicologic risk following topical application of drug Relate resultant blood levels of drug in human to systemic therapeutic effects Animal models Weanling pig Rhesus monkey Hairless mouse or rat Biological samples Skin sections Venous blood from application site Blood from systemic circulation Excreta (urine, feces and expired air)

8. What materials are used in vitro skin penetration studies 1. Skin tissues Human skin Difficult to get, storage, expense and variation in permeation Animal skin Vary quality and permeation (more permeable) Use shed snakeskin (elaphe obsolete, black rat snake) similar to human, less permeable