Transdermal Drug Delivery. Arto Urtti

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Olivia Juusonen
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1 Transdermal Drug Delivery Arto Urtti

Granular cell layer Epidermis Hair follicle Dermis Desmosomes

2 The major structures of the skin 1) Epidermis living epidermis, stratum corneum 2) Dermis 3) Subcutaneus tissue Stratum corneum Granular cell layer Epidermis Hair follicle Dermis Desmosomes Spinous cell layer Subcutaneus tissue Sweat gland Basal cell layer

3 SKIN BARRIER stratum corneum is the limiting barrier dead layer unique lipid composition corneocytes TER > 10 kohm cm 2 important factors solubility in the vehicle partitioning into the stratum corneum

4 Vehicle (skin surface) C d Drug permeation across the skin Stratum corneum C 1 Receiver (blood side) D = diffusion coefficient S = surface area K = partition coefficient (s.c./vehicle) C= concentration P = permeability coefficient (cm/sec) d = donor, r = receiver C 1 =concentration of drug in the s.c at the skin surface C 2 =concentration of drug in the s.c. at the other side C 2 C r amount h = thickness P = J/C d dm/dt=j = slope time

5 dm dt = D S K C h d P = D K h M/mg dm = dt P S C d P = J/C d dm/dt=j = kulmakerroin t

6 Ihoimeytymiseen vaikuttavia tekijöitä Ihon paksuus Valmiste Pinta-ala korvan takana ohut, kantapäässä paksu okluusio --> läpäisevyys kasvaa ihon vettyessä laaja ala --> nopeampi imeytyminen Imeytymisen edistäjät etanoli, propyleeniglykoli, pinta-aktiiviset aineet

7 Transdermaalinen lääkkeen anto Ihon kautta imeytyminen on hidasta Soveltuu pienille rasvaliukoisille yhdisteille (logp yleensä yli 2) Vrk-annos on oltava pieni (yleensä < 10 mg) Puhdistuma ei saa olla kovin suuri.

8 Vakaan tilan pitoisuus plasmassa transdermaalisessa lääkinnässä vrt. infuusiona lääkkeen anto C ss = J/CL (infuusio) C ss = (C s x P x A) / CL C s =lääkeaineen liukoisuus hikeen tai vehikkeliin P = permeabiliteetti stratum corneumissa CL = puhdistuma A = pinta-ala

9 Lääkelaastarien kinetiikasta * Vaihtelu Depot Nopeutta rajoittava tekijä Ihoalue

10 Iontoforeesi Permeabiliteetti nousee Migraatio Elektro-osmoosi Lääkeaineet Vaihtelu

11 Skin permeability experiments issues: availability of the skin samples animal skin usually not good model variability and quality of the human skin samples (--> usually n = 10) - cell culture models in general too leaky (exception ROC model) - maintenance of the concentration gradient (suspension to the donor compartment) - vehicle effects - steady state vs transient experiments

12 Organotypic REK culture Continuous cell line REK (rat epidermal keratinocytes). REK keratinocytes are seeded and grown on type I collagen lattice at air-liquid interface without feeder cells REK cell line undergoes essentially normal morphological stratification and differentiation Cornified layer = stratum corneum Stratifying keratinocytes Collagen gel Insert membrane Culture medium (=DMEM + 10% FBS)

Corticosterone Permeability x 10 6 cm/s TEWL (g/m 2 /h) Vitamin C Enhances Epidermal

20 0.1 1 2 3 4 5 6 7 0 1 wk 2 wk 3 wk NHS Weeks in culture The permeability

per unit area (dpm/h per cm 2 ) and Cd is the donor phase concentration of H 3

13 Corticosterone Permeability x 10 6 cm/s TEWL (g/m 2 /h) Vitamin C Enhances Epidermal Barrier Formation 100 A Control Vitamin C B Control Vitamin C NHS wk 2 wk 3 wk NHS Weeks in culture The permeability coefficients were calculated from kp = Jss/Cd, where Jss is the steady-state flux per unit area (dpm/h per cm 2 ) and Cd is the donor phase concentration of H 3 -corticosterone (dpm/ml). Kp for 3 weeks old vitamin C treated culture = 1.84 Kp for cadaver skin = 1.38

14 Lääkeaineen rasvaliukoisuus ei yksinään ratkaise ihon läpäisevyyttä HEM = ihmisiho; ROC = solumalli

15 Huom. skaala on noin 1000x Solumallin läpäisevyys korreloi hyvin ihmisihon läpäisevyyden kanssa.

16 Delivery aspects Permeability and Its Enhancement Delivery Methods - enhancers - liposomes - gels - iontophoresis - electroporation - ultrasound - microneedles

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