Presentation Transcript

1. Topical & Transdermal Drug Delivery an introduction and overviewDr Chris AllenderWelsh School of PharmacyCardiff
2. Contents Fundamentals Benefits Limitations Current practice Research and the future
3. Fundamentals –role of the skin Two way barrier keeping things in Water – controlled loss keeping things out environmental chemicals cosmetics therapeutics excellent barrier function
4. Fundamentals –structure of the skin Epidermis Stratum corneum Viable epidermis Dermis
5. Fundamentals –structure of the skin Stratum corneum ‘Dead’ layer Evolved barrier function 98% of skin barrier No active transport processes Little metabolism Dense 1.3 g /ml
6. Fundamentals –structure of the skin Two routes across the SC Shunt route Hair follicles and sweat glands Trans-epidermal route Across stratum corneum, viable epidermis and dermis Shunt route Shorter lag-time, significant early after dose is applied and for certain molecular species e.g. ions, large polar molecules Trans-epidermal route In general considered the main route of delivery
7. Fundamentals –structure of the skin
8. Fundamentals –what sort of barrier is SC? The intracellular route is lipophilic and is main route across the SC. Therefore… Only relatively lipophilic, uncharged molecules, will passively diffusemost effectively across the SC
9. Fundamentals Oral route vs topical route Fundamental difference Large proportion of GI tract designed as a gateway to absorption Skin designed as a barrier Unsurprising that industries targets oral route Pulmonary, topical, buccal, rectal, ocular, vaginal Further reading: Physicochemical Principles of Pharmacy; Florence and Attwood (5th Ed) Transdermal Drug Delivery; Adrian Williams
10. So why develop topical delivery systems? Avoids first pass intestinal and hepatic metabolism Easily turned on and off Can avoid some side effects Prolonged, controlled delivery possible
11. So why both with any other route? Or perhaps too good to be true?
12. Skin structure
13. And the consequences of this? Only moderately lipophilic molecules can be delivered by the transdermal route 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 Consequences for local delivery / systemic delivery? Greatly limits the range of drugs that can be effectively delivered
14. So what drives delivery / passive diffusion? Formulation? Drug physicochemical properties? Barrier properties?
15. From Fick’s First Law of Diffusion J  ∆C J is flux ∆C is concentration gradient
16. From Fick’s First Law of Diffusion J  ∆C Therefore for a given drug in solvent system (commonly termed ‘vehicle’) is there a J max?
17. From Fick’s First Law of Diffusion In practice, in a given drug/vehicle system: J  % Saturation When the drug is saturated in the vehicle flux will be at a maximum
18. From Fick’s First Law of Diffusion What about different vehicles? Solubility of drug in different vehicles will be vary?
19. From Fick’s First Law of Diffusion 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?
20. Formulation design . In general aiming to bring about max. flux. Why? Therefore aiming to increase % saturation or change the barrier function of the skin
21. Formulation design: increasing % saturation . By changing the solubility of the drug in the formulation by: pH effects Solvent effects
22. Formulation design: increasing % saturation pH effects and pKa What is pKa? Why is it so important? pH at which 50% of an ionisable group is ionised
23. e.g. 2. 1. Acid or base pKa? Ionisation? Aq solubility? Solubility in EtOH? % Saturation in aq and ethanol? Best topical formulation?
24. Formulation design: decreasing barrier effect of the SC Permeation enhancers topically applied must permeat into SC Enhancers work by either : increasing the solubility of the active in SC increasing the diffusion coefficient of the active in the SC or both
25. From Fick’s First Law of Diffusion 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) But what is steady state?
26. From Fick’s First Law of Diffusion Kp is a commonly used to descibe the efficiency of a (trans)dermal delivery system: Kp= J/∆C HIGH Kp = EFFICIENT SYSTEM LOW Kp = INEFFICIENT SYSTEM Also Kp is useful in that it negates need to report ∆C as would be necessary to compare values of J
27. Idealised permeation profile Steady state flux when J  C (Fick’s First Law is obeyed) Total permeated (ug/cm2) Lag phase Saturation/depletion phase Steady state flux Time (hours)
28. Kp -1 2 5 LogP oct/water LogP vs Kp
29. Molecular weight vs Kp Kp 20 400 Molecular Weight
30. In vitro experimental design Topical vs oral models Physicochemical predications Oral can be very misleading Active processes in and out Significant paracellular migration Topical Dead layer Simpler predictive modelling
31. Physicochemical parameters Lipinski ‘rule of five’ for oral absorption Hydrogen bonding Molecular weight Lipophilicity (logP) Similarly, can be applied to skin barrier
32. Potts and Guy equation log kp (cm/h) = -2.7 + 0.71 log Koct –0.0061 MW Kp is permeability coefficient LogK is logP octanol/water MW is molecular weight
33. Rate limiting barrier Stratum corneum Kp up to 10000x smaller than other layers within skin Therefore, in general, model systems and predictive systems need only consider the SC as the barrier
34. Skin models Complex multi-layered structure Model systems Silicone membrane Pig’s skin Hairless mouse skin Solid supported lipid membranes Cultured skin Heat separated epidermal membrane Stratum corneum
35. The Franz diffusion cell
36. Industrial set-up
37. Formulation Oral vs Topical Oral, limited possibilities Topical, many possibilities Gels, creams, powders, patches
38. Physical methods of permeation enhancement Ultrasonics Iontophoresis Microsneedles
39. Microneedles