Therapeutic systems lecture 5 b

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Therapeutic systems lecture 5 b

  1. 1. TRANSDERMAL THERAPEUTIC SYSTEMS (TTS) Prepared by: Sereta Campbell-Elliott B. Pharm; M Pharm. Sc
  2. 2. WHY USE A TRANSDERMAL THERAPEUTIC DEVICE? <ul><li>Topical drug application was previously used for local action; little or no systemic effects </li></ul><ul><li>Workers in an arms factory complained of headaches; drug absorption across the skin was observed </li></ul><ul><li>Aim of transdermal permeation is to deliver active drug/prodrug via a suitable vehicle to target sites in a controlled manner </li></ul><ul><li>Area of concern/barrier to drug movement is the skin </li></ul>
  3. 3. Transdermal Permeation: Structure of the skin <ul><li>Serves to protect from noxious agents; limits drug entry, stabilizes BP and temp </li></ul><ul><li>Vulnerable to damage </li></ul><ul><li>Has 3 distinct layers : </li></ul><ul><li>Epidermis : ≈ 0.1mm thick; multilayered; consists of dense layer of dead cells (‘brick’) with lipid-rich intercellular matrix (mortar) called stratum corneum or horny layer; lipoid in nature. This is relatively impermeable and is the principal barrier to percutaneous permeation; swells many folds when hydrated. </li></ul><ul><li>Dermis: 3-5 mm thick; has connective tissue pervaded with fibrous protein (elastin, collagen) embedded in a mucopolysaccharide. It has nerves, blood vessels, lymphatics and various glands; transport nutrients, waste, controls temp and BP, has defense cells and target site for systemic uptake </li></ul>
  4. 4. Transdermal Permeation: Structure of the skin cont’d <ul><li>Subcutaneous Tissue: contains fat and provides mechanical barrier to trauma and heat; synthesizes and stores high energy molecules </li></ul><ul><li>Routes of Penetration/ Permeation </li></ul><ul><li>- Stratum Corneum (through lipoid matrix); major route </li></ul><ul><li>- Skin appendages: sweat duct and hair follicle; due to small surface area (0.1% of skin) they are small contributors to percutaneous absorption; useful route for polar compounds, large compounds or colloidal preps </li></ul>
  5. 5. Transdermal Permeation: Structure of skin and routes of permeation
  6. 6. Advantages of TTS <ul><li>Provides constant drug levels </li></ul><ul><li>Useful for drugs with short biological t 1/2 </li></ul><ul><li>Dosing frequency is reduced; improved compliance </li></ul><ul><li>Reduced risk of GI irritation or chemical/pH-dependent degradation of susceptible drugs </li></ul><ul><li>Avoids pre-systemic and first-pass metabolism in the liver </li></ul><ul><li>Relative ease in termination of drug input with patch removal </li></ul>
  7. 7. Disadvantages of TTS <ul><li>Due to effective barrier to permeation systems are limited to potent drugs (5-10 mg/day may be effectively given) </li></ul><ul><li>May have a ‘lag time’ – due to delay in accumulation and onset of action; not suitable for rapid alleviation of symptoms </li></ul><ul><li>Limited to drugs with short biological t 1/2 and small volume of distribution (V D ) </li></ul><ul><li>LogP values of 2.5 – 3.5 needed for maximal penetration through skin </li></ul><ul><li>Allergic responses and irritation at site (drug or patch components) </li></ul><ul><li>Cost </li></ul>
  8. 8. TTS Design <ul><li>Modern design introduced in 1970’s </li></ul><ul><li>Basic design includes: </li></ul><ul><li>- Impermeable backing </li></ul><ul><li>- Drug reservoir </li></ul><ul><li>- Release mechanism </li></ul><ul><li>- Adhesive </li></ul><ul><li>Three types of TT device design: Reservoir-controlled, Matrix-controlled and Drug-in-Adhesive matrix </li></ul>
  9. 9. TTS Design cont’d Reservoir/Membrane-Controlled Release <ul><li>- Device has lag time in order to establish equilibrium between drug layer, membrane and adhesive; minimized with storage and produces a ‘burst effect upon use </li></ul><ul><li> - e.g. Transiderm-Nitro ®, Estraderm ®, Nicorette ®, </li></ul><ul><li>Androderm ®, Transderm-Scop® </li></ul><ul><li> Duragesic ® </li></ul>
  10. 10. TTS Design cont’d Matrix-Controlled Release <ul><li>Drug is dispersed in matrix or suspension </li></ul><ul><li>Adhesive layer has drug in equilibrium with matrix </li></ul><ul><li>e.g. Nitro-Dur ®, Nicotinell ® </li></ul>
  11. 11. TTS Design cont’d Drug-in-Adhesive Matrix <ul><li>Drug is dispersed in the adhesive matrix </li></ul><ul><li>Dispersed drug may be in various formulation e.g. crystals </li></ul><ul><li>e.g. Climara ® , Estraderm ® Mx, Minitran ®, Nicoderm CQ ® </li></ul>
  12. 12. Drug Release from TTS <ul><li>Drug permeation into the stratum corneum obeys Ficks’ Law where: </li></ul><ul><li>dm = J = DCP dm/dt (J) – flux; amt of drug that </li></ul><ul><li>dt h crosses stratum corneum </li></ul><ul><li>D – Diffusion Coeffient of the drug C – drug conc. in patch/surface </li></ul><ul><li>P – partition coeff. between patch and stratum corneum </li></ul><ul><li>h – diffusional path/ membrane thickness </li></ul>
  13. 13. LAB ASSESSMENT PERCUTANEOUS DRUG DELIVERY <ul><li>Studies are designed to determine: </li></ul><ul><li>Drug flux </li></ul><ul><li>Permeation route </li></ul><ul><li>Partitioning characteristics </li></ul><ul><li>Rate-limiting step : ?diffusion, ?partitioning, ?skin structures, ?removal by vasculature </li></ul><ul><li>How skin conditions affect delivery </li></ul><ul><li>Nature of the vehicle : ? Modify drug release,? Affect permeation </li></ul>
  14. 14. LAB ASSESSMENT PERCUTANEOUS DRUG DELIVERY cont’d <ul><li>In vitro methods: </li></ul><ul><li>1 . Involves the use of excised skin (rats, mice, guinea pigs, human skin) to measure passage of drug in a fluid bath </li></ul><ul><li>2. Use of artificial membranes (cellulose acetate, silicone rubber or systems designed to imitate lipoid stratum corneum; do not accurately represent complex nature of human skin </li></ul><ul><li>3. May use technique that releases drug in an immiscible phase and measure; only assesses drug/patch factors that affect release </li></ul>
  15. 15. LAB ASSESSMENT PERCUTANEOUS DRUG DELIVERY cont’d <ul><li>In vivo methods: </li></ul><ul><li>1. Analysis of various compartments of the body </li></ul><ul><li>2. Monitoring for pharmacological or physiological </li></ul><ul><li>response/reactions (allergic rxn, BP changes, gland activity, </li></ul><ul><li>de/pigmentation, systemic changes) </li></ul><ul><li>3. Monitor physical changes in stratum corneum (histological damage, surface loss) </li></ul>
  16. 16. FACTORS INFLUENCING PERMEATION <ul><li>Biological Factors </li></ul><ul><li>- Condition of skin : healthy skin is impermeable but compromising skin interigty increases permeation. Inflammatory diseases may increase permeation while callouses/thickening may decrease permeation </li></ul><ul><li>- Age : Little difference seen except in children and premies </li></ul><ul><li>- Blood Flow : Not clinically significant </li></ul><ul><li>- Variation in skin sites : affected by thickness and nature of stratum corneum, density of skin appendages </li></ul><ul><li>- Metabolic activity of the skin : presence of enzyme systems may reduce amount of drug available for systemic action; true for about 5% topically applied drugs; process is useful for prodrug activation </li></ul>
  17. 17. FACTORS INFLUENCING PERMEATION cont’d <ul><li>Physicochemical Factors </li></ul><ul><li>- State of skin hydration : Hydrated skin facilitates permeation; degree of occlusion is TTS > lipophilic oint > creams </li></ul><ul><li>- Temp/pH : ↑ temp increases permeation; pH will affect ionization of weak acids/bases and affect permeation based on prevalence of unionized species; however balance must exist to maximize permeation to and out of dermal layer </li></ul><ul><li>- Value of D: influenced by properties of drug and diffusion medium; drug must be able to diffuse betwn layers in patch, from patch to skin and across skin to vasculature; measures penetration rate </li></ul><ul><li>- Drug Conc .: Permeation ↑with large concentration gradient </li></ul><ul><li>- LogP value : Determines partitioning from patch to skin and from stratum corneum to dermal layer </li></ul><ul><li>- Molecular size/shape : Small molecules penetrate faster; size and shape affect diffusion and partitioning rates </li></ul>
  18. 18. NOVEL APPROACH TO ENHANCE PERMEATION <ul><li>Penetration Enhancers : temporarily reduces permeability of skin; should be non-toxic, non-irritating, non-allergenic, immediate and predictable action, immediate skin recovery upon removal, compatible with drug/excipients, good solvent, aesthetic, inexpensive. </li></ul><ul><li>E.g. Chemical enhancers like surfactants, alcohols, fatty acids, azone. </li></ul><ul><li>Use of Prodrugs : may be used to improve a drugs’ LogP value and increase permeation; later hydrolysed to release active drug </li></ul>
  19. 19. NOVEL APPROACH TO ENHANCE PERMEATION cont’d <ul><li>Physical Enhancers </li></ul><ul><li>- Iontophoresis :use of electrical potential gradient to increase permeation; current is applied and the ionized drug is repelled by electrode with like polarity; used for proteins/peptides </li></ul><ul><li>- Phonophoresis : use of ultrasound to drive drug molecules across skin </li></ul><ul><li>- Electroporation : application of a high-voltage pulse to increase permeation by opening aqueous pores in horny layer </li></ul>

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