An Introduction to Transdermal Drug Delivery Dr Chris Allender Welsh School of Pharmacy Cardiff

1. An Introduction to Transdermal Drug Delivery Dr Chris AllenderWelsh School of PharmacyCardiff

2. So why develop topical delivery systems?

3. So why develop topical delivery systems? • Avoid first pass intestinal and hepatic metabolism • Easily turned on and off • Can avoid some side effects • Prolonged, controlled delivery possible • Reduced dosage frequency • Improved patient acceptance and compliance • Sustained therapeutic action • More consistent delivery of drug • facilitates termination of dosing

4. “So why not patches for all drugs?”

5. Barrier function of the skin • Two way barrier • keeping things in • Water – controlled loss • keeping things out • environmental chemicals • cosmetics • therapeutics • excellent barrier function

6. Skin structure • Epidermis • Stratum corneum • Viable epidermis

7. Skin structure • Stratum corneum • ‘Dead’ layer • Evolved barrier function • 98% of skin barrier • No active transport processes • Little metabolism • Dense 1.3 g /ml

8. Stratum corneum barrier Two routes across the SC • Shunt route • Hair follicles and sweat glands • Shorter lag-time, significant early after dose is applied and for certain molecular species e.g. ions, large polar molecules • Trans-epidermal route • Across stratum corneum, viable epidermis and dermis • In general considered the main route of delivery

9. Stratum corneum barrier • Trans-epidermal route

10. Stratum corneum barrier The intracellular route is lipophilic and is main route across the SC. Therefore… Only relatively lipophilic, uncharged molecules, will passively diffuseacross the SC

11. Stratum corneum barrier • Greatly limits the range of drugs that can be effectively delivered • Even for drugs with optimal physicochemical properties diffusion across the SC is slow and only low therapeutic concentrations can be achieved • e.g nicotine, hormone replacement therapies, analgesics such as fentanyl

12. Optimal physicochemical properties for permeation

13. Total permeated -1 2 5 LogP oct/water Optimal physicochemical properties for permeation

14. Optimal physicochemical properties for permeation Total permeated 20 400 Molecular Weight

15. Permeation and formulation • Drug delivery - from a formulation - through (or into) the SC is diffusion controlled • Formulation aims (largely) to optimise drug delivery (flux) by encouraging the movement of drug from the formulation and into the SC

16. Obstacles to transdermal delivery

17. Permeation and formulation – in vitro studies

18. Fundamentals – permeation profile Total permeated (ug/cm2) Time (hours)

19. Fundamentals – permeation profile Lag phase Steady state Saturation / depletion phase Total permeated (ug/cm2) Time (hours)

20. Fundamentals – permeation profile Lag phase Steady state Saturation / depletion phase Total permeated (ug/cm2) Steady state slope = flux (J) Time (hours)

21. Total permeated Hours

22. Permeation and formulation • Fick’s First Law of Diffusion J  ∆C Where J (μg cm-2 hour-1) is flux and ∆C (μg cm-3) is concentration gradient

23. Permeation and formulation At steady state trans-epidermal flux can be estimated: J  ∆C J = ∆CKp Kp = PD / h P is partition coeffficient D is diffusion coefficient (cm2/hour) J is flux (ug/cm2/hour) ∆C is concentration gradient (ug/cm3) Kp is permeability coefficient (cm/hour) h is diffusional path length (cm)

24. Permeation and formulation Therefore might predict that flux can be indefinitely increased by increasing ∆C?

25. Permeation and formulation • This is clearly not the case • ∆C is limited by the solubility of the drug in the formulation therefore: J % Saturation of drug in formulation JMAX at 100% Saturation

26. Permeation and formulation What about the effect of formulation (vehicle)? Solubility of drug in different vehicles will vary?

27. Example: 3 saturated formulations of drug X In 1. Saturated solubility = 1g/ml In 2. Saturated solubilty = 1mg/ml In 3. Saturated solubility = 1g/ml Assuming that none of the formulations effect the barrier function of the skin what are the relative fluxes likely to be?

28. Example: answer • Since J  % Saturation of drug in formulation….. Steady state flux is the same (and maximal) for all formulations

29. Permeation and formulation By maximising drug saturation in the formulation flux can be increased • Controlling % drug saturation in formulations • Not simply increasing the amount of drug in given volume • Solubility and changing formulation pH • pKa • Solubility and co-solvents

30. e.g. 2. 1. • Acid or base • pKa? • Ionisation? • Aq solubility? • Solubility in EtOH? • % Saturation in aq and ethanol? • Best topical formulation?

31. Permeation and formulation • How else can flux be influenced by formulation design?

32. Permeation and formulation • Remember that J = ∆CKp (Fick’s first law) • Therefore for a given concentration gradient increasing Kp increases flux • Since Kp = PD / h increasing partition coefficient (P)or the diffusion coefficient (D) will increase flux.

33. Permeation enhancement • The partition coefficient (P) is a function of the solubility of the drug in the SC • Therefore by increasing the solubility of the drug in the SC, P and hence J are also increased

34. Permeation enhancement • Similarly diffusion coefficient (D) is a measure of the drugs ability to move once within the SC • Therefore if D increases then J will increase

35. Permeation enhancement • Penetration enhancers • Compunds that co-permeate with the drug and change the environment within the SC lipids.

36. Penetration enhancers • Ordered SC Lipid lamellae • Pathway for drug long and torturous

37. Penetration enhancers • Ordered SC Lipid lamellae • Pathway for drug long and torturous

38. Penetration enhancers • Permeation enhancers increase disorder in SC Lipid lamellae • Increase P or D (or both) for drug in SC

39. Permeat applied in different alcohols • % saturation constant

40. Permeation enhancement • Water and hydration • Occlusive formulations increase flux

41. Commercial nicotine delivery devices

42. Commercial nicotine delivery devices

43. Commercial nicotine delivery devices NiQuitinCQTM

44. Conclusions - perspective • Still few drugs routinely delivered transdermally across intact SC • Many new approaches aiming to increase J by compromising the SC barrier….

45. Conclusions – new developments • Ultrasonics • Iontophoresis • High velocity injection • Electroporation • Microneedles

46. Conclusions – future • New drug and therapies • Opportunities for controlled delivery • Monitoring and delivery and PoC devices

47. Acknowledgments • Keith Brain and colleagues at Welsh School of Pharmacy