Transdermal therapeutic systems (TTS) deliver drugs through the skin for systemic effects. The skin, especially the stratum corneum layer, acts as a barrier to drug permeation. TTS designs include reservoir, matrix, and drug-in-adhesive systems. Factors like drug properties, skin conditions, and permeation enhancers influence the rate and amount of drug delivery across the skin. Novel approaches can enhance permeation through methods like iontophoresis, phonophoresis, and electroporation.

1. TRANSDERMAL THERAPEUTIC SYSTEMS (TTS) Prepared by: Sereta Campbell-Elliott B. Pharm; M Pharm. Sc

2. WHY USE A TRANSDERMAL THERAPEUTIC DEVICE? Topical drug application was previously used for local action; little or no systemic effects Workers in an arms factory complained of headaches; drug absorption across the skin was observed Aim of transdermal permeation is to deliver active drug/prodrug via a suitable vehicle to target sites in a controlled manner Area of concern/barrier to drug movement is the skin

3. Transdermal Permeation: Structure of the skin Serves to protect from noxious agents; limits drug entry, stabilizes BP and temp Vulnerable to damage Has 3 distinct layers : 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. 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

4. Transdermal Permeation: Structure of the skin cont’d Subcutaneous Tissue: contains fat and provides mechanical barrier to trauma and heat; synthesizes and stores high energy molecules Routes of Penetration/ Permeation - Stratum Corneum (through lipoid matrix); major route - 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

5. Transdermal Permeation: Structure of skin and routes of permeation

6. Advantages of TTS Provides constant drug levels Useful for drugs with short biological t 1/2 Dosing frequency is reduced; improved compliance Reduced risk of GI irritation or chemical/pH-dependent degradation of susceptible drugs Avoids pre-systemic and first-pass metabolism in the liver Relative ease in termination of drug input with patch removal

7. Disadvantages of TTS Due to effective barrier to permeation systems are limited to potent drugs (5-10 mg/day may be effectively given) May have a ‘lag time’ – due to delay in accumulation and onset of action; not suitable for rapid alleviation of symptoms Limited to drugs with short biological t 1/2 and small volume of distribution (V D ) LogP values of 2.5 – 3.5 needed for maximal penetration through skin Allergic responses and irritation at site (drug or patch components) Cost

8. TTS Design Modern design introduced in 1970’s Basic design includes: - Impermeable backing - Drug reservoir - Release mechanism - Adhesive Three types of TT device design: Reservoir-controlled, Matrix-controlled and Drug-in-Adhesive matrix

9. TTS Design cont’d Reservoir/Membrane-Controlled Release - 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 - e.g. Transiderm-Nitro ®, Estraderm ®, Nicorette ®, Androderm ®, Transderm-Scop® Duragesic ®

10. TTS Design cont’d Matrix-Controlled Release Drug is dispersed in matrix or suspension Adhesive layer has drug in equilibrium with matrix e.g. Nitro-Dur ®, Nicotinell ®

11. TTS Design cont’d Drug-in-Adhesive Matrix Drug is dispersed in the adhesive matrix Dispersed drug may be in various formulation e.g. crystals e.g. Climara ® , Estraderm ® Mx, Minitran ®, Nicoderm CQ ®

12. Drug Release from TTS Drug permeation into the stratum corneum obeys Ficks’ Law where: dm = J = DCP dm/dt (J) – flux; amt of drug that dt h crosses stratum corneum D – Diffusion Coeffient of the drug C – drug conc. in patch/surface P – partition coeff. between patch and stratum corneum h – diffusional path/ membrane thickness

13. LAB ASSESSMENT PERCUTANEOUS DRUG DELIVERY Studies are designed to determine: Drug flux Permeation route Partitioning characteristics Rate-limiting step : ?diffusion, ?partitioning, ?skin structures, ?removal by vasculature How skin conditions affect delivery Nature of the vehicle : ? Modify drug release,? Affect permeation

14. LAB ASSESSMENT PERCUTANEOUS DRUG DELIVERY cont’d In vitro methods: 1 . Involves the use of excised skin (rats, mice, guinea pigs, human skin) to measure passage of drug in a fluid bath 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 3. May use technique that releases drug in an immiscible phase and measure; only assesses drug/patch factors that affect release

15. LAB ASSESSMENT PERCUTANEOUS DRUG DELIVERY cont’d In vivo methods: 1. Analysis of various compartments of the body 2. Monitoring for pharmacological or physiological response/reactions (allergic rxn, BP changes, gland activity, de/pigmentation, systemic changes) 3. Monitor physical changes in stratum corneum (histological damage, surface loss)

16. FACTORS INFLUENCING PERMEATION Biological Factors - Condition of skin : healthy skin is impermeable but compromising skin interigty increases permeation. Inflammatory diseases may increase permeation while callouses/thickening may decrease permeation - Age : Little difference seen except in children and premies - Blood Flow : Not clinically significant - Variation in skin sites : affected by thickness and nature of stratum corneum, density of skin appendages - 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

17. FACTORS INFLUENCING PERMEATION cont’d Physicochemical Factors - State of skin hydration : Hydrated skin facilitates permeation; degree of occlusion is TTS > lipophilic oint > creams - 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 - 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 - Drug Conc .: Permeation ↑with large concentration gradient - LogP value : Determines partitioning from patch to skin and from stratum corneum to dermal layer - Molecular size/shape : Small molecules penetrate faster; size and shape affect diffusion and partitioning rates

18. NOVEL APPROACH TO ENHANCE PERMEATION 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. E.g. Chemical enhancers like surfactants, alcohols, fatty acids, azone. Use of Prodrugs : may be used to improve a drugs’ LogP value and increase permeation; later hydrolysed to release active drug

19. NOVEL APPROACH TO ENHANCE PERMEATION cont’d Physical Enhancers - 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 - Phonophoresis : use of ultrasound to drive drug molecules across skin - Electroporation : application of a high-voltage pulse to increase permeation by opening aqueous pores in horny layer