Transdermal Drug Delivery systems

1. TransdermalDrug Delivery systems R. Dinarvand, PhD Professor of Pharmaceutics

2. Transdermal Drug Delivery Systems (TDDS) • Diffusion of the drug through skin into the systemic circulation for distribution and therapeutic effect • Most TDD systems use passive delivery • Note the difference with topical dosage forms

3. Advantages of TDDS • Reduces first-pass metabolism effect and GI incompatibility • Sustains therapeutic drug levels • Permits self-administration • Non-invasive (no needles or injections) • Improves patient compliance • Reduces side effects • Allows removal of drug source • Long acting drug delivery

4. Limitations of TDDS • Poor diffusion of large molecules • Skin irritation • Only suitable for very potent drugs • Skin is not for drug delivery! • More expensive than oral drugs

5. TDDS market

6. Skin structure Dermis width: 1-4 mm

7. Epidermis structure Epidermis width: 0.07-0.15 mm

8. Epidermis structure • basal layer: • single layer; columnar; keratin 5/14; only skin cells that can divide Þ stem cells Þ transient amplifying cells (50% of basal cells) Þ divide several times Þ differentiate • stratum spinosum: • 3-10 cells thick (largest layer); keratin 1/10 migrate towards surface Þ lose water, form desmosomes, become larger and flatter • stratum granulosum: • 2-3 cells thick; organelles begin degrading keratinocytes with keratohyaline granules: contain proflaggrin Þ flaggrin (component of stratum corneum) • stratum corneum (cornified layer): • 15 cells thick; flat, polyhedral cells (corneocytes); no organelles or nuclei cytosol: mostly keratin filaments and flaggrin; encased in protein shell (involucrin, loricrin) • lipid enriched membranes make up the extracellular space • ‘mortar’ between keratinocytes; provides water barrier

9. Skin functions Body appearance and shape Protection from mechanical impact (i.e. pressure, stroke) thermic impact (i.e. heat, cold) chemical impact (i.e. acids) microorganisms (bacteria, viruses, fungi) UV-radiation water loss Immune functionBesides providing a biological barrier against microorganisms through its acidic pH-value, the skin is immunologically active through defense mechanisms in epidermis and dermis. Temperature regulationThrough sweat-producing glands and the evaporation of sweat and water, the body temperature is controlled. Another mechanism for rapid cooling is vasodilation (widening of blood vessels). Through vasoconstriction (narrowing of blood vessels), heat loss is prevented. SensationThrough nerve endings and receptors in the skin, sensations such as touch, pain, heat or cold are processes Vitamin productionThe skin produces Vitamin D through exposure to ultraviolet radiation in sunlight. Social-interactiveThrough paling, blushing and other expressions regulated by the autonomic nervous system, the skin serves as a communication system.

10. Drug transport mechanism • Through skin pores, hair follicle, glands • Through cells • Intercellular • Intracellular (transcellular)

12. Therapies That Use Transdermal Delivery of Drugs

13. Permeability Coefficient Is the Critical Predictor of Transdermal Delivery Transport = Flux = (mg/cm2/sec) = P x A x (Cd – Cr) Permeability Coefficient = P = D x K (cm/sec) h Where A = Surface area of patch D = Diffusivity of drug in membrane (skin) K = Partition coefficient (patch/skin) C = Concentration in donor or receptor (patch or skin) h = Thickness of membrane (skin)

14. Attributes of a Passive TDD Drug Candidate • Daily dose (< 20 mg/day) • Half-life (10 hours or less) • Molecular weight (< 500 daltons) • Melting point (< 200 oC) • Skin permeability • Lipid solubility [partition coefficient (Log P) between –1.0 and 4] • Toxicology profile (non-irritating and non-sensitizing to skin)

15. TDD System Design Factors • Therapeutic indication • Desired drug delivery profile - Dose level, duration, etc. • Skin adhesion profile • Application site • Ease of application • Patch size, shape, appearance, comfort • Wear period • Packaging • Patch disposal • Patch cost

16. TDDS designs • Membrane control systems • Skin control systems

17. TDD Patches: A System of Components • Components must be chemically and physically compatible • Drug formulation may or may not include excipients • Backing: provides protection from external factors during application period • Membrane: moderates rate of drug release • Adhesive: maintains contact with patient’s skin; incorporates drug and excipients in drug-in-adhesive TDD systems • Liner: protects patch during storage; is removed prior to application

18. Component/Composition • Matrix devices • Active agent in polymeric membrane, adhesive, solvent, penetration enhancer, backing, • Reservoir devices • Active agent, gelling agent or excipient, solvent, penetration enhancer, adhesive, membrane, backing, release liner

19. TDD Patch Construction Reservoir Matrix

21. TDD Patch Construction Comparison

22. Additional Development Stages • Clinical evaluation • Formulation and manufacturing scale-up • Stability studies • Analytical evaluation • Regulatory submission and approval

23. Transdermal System Design: What’s Ahead? • Delivery of larger molecules using enhanced passive and active delivery systems • Materials and formulations to reduce skin irritation, enhance the adhesion profile, and improve comfort and wear • Patch designs with specialized drug delivery profiles • Patches with features that aid in application and use • User and environmentally-friendly packaging designs

24. Iontophoresis Non-invasive, needle-free Rapid onset and cessation kinetics Controlled, programmable and titratable drug delivery capabilities Ability to provide smooth, variable or bolus plasma levels, singly or in combination, all in a single delivery system Enhanced transdermal delivery for a broad range of compounds, including large drug molecules such as peptides and oligonucleotides Minimal variability in the delivery profiles among patients and body sites Potential for enhanced patient compliance and control

25. Iontophoresis • Non-invasive, needle-free • Rapid onset and cessation kinetics • Controlled, programmable and titratable drug delivery capabilities • Ability to provide smooth, variable or bolus plasma levels, singly or in combination, all in a single delivery system • Enhanced transdermal delivery for a broad range of compounds, including large drug molecules such as peptides and oligonucleotides • Minimal variability in the delivery profiles among patients and body sites • Potential for enhanced patient compliance and control

26. SCIENTIFIC BASIS OF IONTOPHORESIS The Nernst-Planck equation, seen below, is the traditional relationship accepted for describing transport of an ionic species across a membrane: J = DzVFC/kT+ Cu - D(dC/dx) where J = molar flux D = diffusivity coefficient C = the concentration (molar) u = the convective flow of water T = temperature k = Boltzman's constant z = charge on the species V = electric field F = Faraday's constant

27. Phonophresis • Phonophoresis is the introduction of substances into the body by ultrasonic energy. Unlike iontophoresis which involves the transfer of ions into the tissue, phonophoresis transmits molecules - a different process although similar in concept. • Some of the common chemicals compounded for phonophoresis include: • Betamethasone Dipropionate • Dexamethasone • Dexamethasone / Lidocaine • Fluocinonide • Hydrocortisone • Hydrocortisone /Lidocaine • Ketoprofen / Naproxen • Piroxicam / Sodium Salicylate

28. How it works

29. Sonophoresis facts: • Sonophoresis has been shown to be effective in the formation of microscopic aqueous channels (Lacunae) through the bilayers of the epidermis. • The optimum frequency range of the “sonic” waveform to achieve this is in the region of 20-25Khz with power outputs of less than 125mW/cm2. This waveform is pulsed for very short periods (typically 100ms) usually once per second. • Sonophoresis has been shown to be even more effective when combined with iontophoresis, with further spectacular increases in the efficiency (up to 4000%) of active ingredient absorption in to the lower levels of the epidermis

31. overview • A cataplasm (TDDS) containing biphenylacetic acid as the antirheumatic pain deadener is marketed in Japan as SelTouch by Teikoku and has an area of 10 cm by 14 cm. It utilizes an aqueous gel which acts both as the adhesive and reservoir for the active.  This is a popular dosage form in China and Japan, and this size is typical of their commercial cataplasm patches. •  Patents can be found by searching the key words "Patch" and "Plaster" at USPTO. •  The general (ideal) criteria for selecting drugs for transdermal delivery as follows: • Molecular weight should be less than 500 da • Dose shoule be less than 10 mg • Log P should be between 1-3 • Even if the the log P is less than 1 and the dose is potent , still it may be possible to delivery transdermally by manipulating the • patch size. • The selection of drugs for transdermal delivery is more often than not dictated by the clinical need and particularly drugs having short half life and which undergo First pass elimination may be suitable candidates •  The dose of the drug depend upon many variables, • solubility, kind of TDDS, Pka, Partition coeff...etc..