Transdermal Drug Delivery

1. Transdermal Drug Delivery

2. Structure, Function & Topical treatment of Human Skin Anatomy & Physiology

3. Drugs enter different layers of skin via intramuscular, subcutaneous, or transdermal delivery methods.

4. The epidermis 0.8 mm(Palms & soles) 0.006 mm eyelids. Stratum Germinativum divide & migrate to produce Stratum corneum or horny layer. This permit to human to survive. • The dermis (corium) 3-5 mm thick • The subcutaneous tissue ( sibcutis, hypoderm) (fat)

5. The skin appendages The eccrine sweat glands (2-5 million): • produce sweat ………………….. • Secrete drugs, proteins, antibodies & antigens. Emotional stress increase its secretion (clammy palm syndrome)

6. An eccrine sweat gland: most of the body's sweat production is the result of eccrine gland activity

7. The aporine sweat glands Develop at the pilosebaceous follicle in the armpit. Its milky or oily secretion may be colored & contains: Proteins, lipids, lipoproteins & saccarides. Bacteria metabolize this odorless secretion to give the characteristic human smell.

8. An apocrine gland, which produces little sweat but is responsible for the body's natural 'scent' • Hair follicles • Nails

9. Function of the Skin: I. Mechanical function This depends on a correct balance of lipids, • water-soluble hygroscopic substances (…………………..); • Water. The tissue requires 10 -20% of moisture to maintain its suppleness.

10. Protective function: • Microbiological barrier Acid mantle …………………... The following gland secretion have antibacterial activity: • …………………..; • …………………...

11. Chemical barrier The appendageal shunt route provide only a small fractional area (0.1%). C. Radiational barrier The UV light 290-400 nm is the most damaging. • Short irradiation produces: • …………………..; • …………………..; • …………………...

12. Chronic irradiation produces: • …………………..; • …………………..; • Malignancy. • Sun damaged skin produces: • …………………..; • …………………..; • …………………..; • …………………..; • …………………...

13. Heat barrier & temperature regulation: • To conserve heat; …………………... • To lose heat; blood vessel dilate, eccrine sweat glands pour out their dilute saline secretion, water evaporates. • Electrical barrier Dry skin has low conductivity V. Mechanical shock

14. Rational approach to drug delivery to & via the skin There are 3 main ways to manipulate the problem of formulating a successful topical dosage form: • For epidermal or surface treatment (i.e. …………………..); • For viable skin tissue ( without oral drugs); • For systemic treatment.

15. Dermatologists target the following skin regions: • Skin surface; • Horny layer; • viable epidermis & upper dermis; • Skin glands & systemic circulation. Fig 33.1-33.2

16. Surface treatment (i.e. camouflage or cosmetic, deodorants, surface antiseptic or antibiotics). …………………... • Stratum corneum (S.C.) treatment (i.e. …………………..) • Skin appendages treatment (i.e. …………………...) • Viable epidermis& dermis treatment

17. Cream & gels: • Topical steroids; • …………………..; • …………………..; • Topical 5-fluorouracil & methotrexate eradicate premalignant & some malignant skin tumors, …………………... • Psoralens + UVA therapy (PUVA) mitigate psoriasis; • 5-amino-levulinic acid + visible light irradiation (photodynamic therapy) …………………...

18. Transcutaneous immunization Vaccine Antigens developing transcutaneous immunization (……………………) • Systemic treatment via …………………… Problems of this way: • The body absorbs drugs ……………………; • Drugs are lost by …………………….

19. Drug Transport Through the Skin Basic principles of diffusion through membranes: The diffusion process: Fick’s Law of Diffusion: Fig 33.3

20. Complex Diffusional Barrier • Skin Transport Relate the intrinsic properties of the skin with the properties of the drug. • Routes of Penetration: Figure 33.1

22. Sebum & Surface Material (0.4-10 m) It hardly affect the Transdermal absorption (TDA) • Skin Appendages (0.1% of the total available area) Acts before the steady state.

23. After the steady state is considered neglect. Uses: • Immunization (i.e. naked DNA in topical application); • Anti hair loss of alkaloids of transgenic plant (……………………); • Liposomes. Usually: Molecules > 10 m ……………………; Molecules around 3-10 m ……………………; Molecules < 3 m …………………….

24. Epidermal Route (stratum corneum): • Intracellular -route (bricks) = s.c. [corneocytes, consisting of hydrated keratin] • Intercellular -route (mortar) composed of: Lipid; cholesterol; ceramide; ..etc.

25. Topically applied agents (steroids, creseofulvin,..) form a depot by binding within the stratum corneum. Thus, psoriasis ……………………. • Viable layer (particularly the epidermis) ……………………. • Dermis layer contains capillaries so the residence time of a hydrophilic drug ……………………. • Dermis may bind lypophilic drugs ( testosterone) ……………………

26. Conclusions: • S.c. is the rate limiting step. • The fraction of a drug that penetrates the skin via any route depends on: • Physicochemical nature of the drug: (……………………), • Timescale of observation, • ……………………, • ……………………, • How vehicle components temporarily change the properties of the S.C.

27. Properties That influence Transdermal Delivery: • Release of the drug ……………………; • Penetration through ……………………; • Activation of the ……………………. Figure 33.4

28. Factors that complicate drug penetration: • The non homogeneity of tissue; • ……………………; • ……………………; • ……………………; • ……………………;

29. 6. ……………………; 7. Cell transport to & through S.C; 8. ……………………; 9. ……………………; 10. The drug & emulsion components may modify progressively the skin.

30. Factors that complicate the skin absorption: • Biological factors; • PhysicochemicalFactors. Biological Factors: • Skin Conditions: Chemicals & solvents may open the complex & dense structure of the skin (……………………). • Skin Age: ……………………> permeable than adult tissue, but there is no dramatic difference.

31. ……………………; • ……………………: Permeability depends on: • ……………………; • ……………………; • ……………………. Plantar & palmar Callus (400-600 m), while other sites (10-20 m), But permeability of plantar & palmer is > than other sites.

32. Why Post Auricular skin was employed for the administration of Hyoscine (scopolamine)? a. Thinner skin; b. Less dens skin; c. ……………………; d. ……………………; e. ……………………. Face skin is >> permeability than other sites.

33. Skin metabolism About 5% of topical drugs can be metabolized by the skin. • Species differences. Physicochemical Factors such as: • Skin Hydration: Moisturizers such: ……………………. Dryer such as: ……………………. Order of Occlusion: Plastic film of TD patch > lipophilic ointment > W/O > O/W creams. Table33-1

35. Temperature & pH: D  T Occlusive vehicles →↑ T (few degree) Regarding pH, ……………………. • Diffusion coefficient (D): D of gases > than D of liquids > than D of molecules in s.c. > than D of solids. D depends also on many intrinsic factors like: Binding (depot) of drugs to s.c. ↑ L:

36. So, binding or gives L, therefore, in order to see m> 0 we have to saturate all binding sites in s.c., thus the remaining drug permeates & starts to increase

37. Drug Concentration Eq. 33,3 • Partition coefficient (K) K varies ……………………. Triamcinolone systemic = ……………………. Triamcinolone topical = ……………………. Triamcinolone acetonide topical = ……………………. Of 23 esters of betamethasone tested, the 17-valerate has …………………….

38. In the family of Hydrocortisone: • Side chain lengthens from 0 to 6 C , ↑ K & the anti-inflammation activity. • For C > than 6, K ↑, while the anti-inflammations index ↓. Maximizing solubility ↑ Δ C but ↓ K, so it is better to non over-solubilize the drug, if the aim is to ↑ drug penetration. Surface activity & Micellization, Effect of surfactant on skin: • ↓ interfacial tension (……………………); • Changes ……………………; • Disruption of intercellular lipid packing in the s.c.

40. Molecular size & shape Absorption depends on: • …………………… • …………………… • ……………………. All the above factors are difficult to be evaluated. Ideal Molecular Properties for Drug Penetration: • A low MW (< 600 Da) when D will tend to be ↑; • An adequate solubility in oil & water; • ……………………; • ↓ melting point; ……………………. Nicotine Patches has all the above mentioned.

41. The nicotine patch is a type of transepidermal patch designed to deliver nicotine, the addictive substance contained in cigarettes, directly through the skin and into the blood stream. • The drug leeches slowly out of the reservoir, releasing small amounts of the drug at a constant rate for up to 24 hours

42. Drug permeation through Skin S.C. rate Controlling Step: Assumptions: • S.C. → the rate-limiting step; • Skin is homogenous intact membrane; • Appendages are unimportant; • Only a single non-ionic drug species is important, dissolving to form an ideal solution unaffected by pH, & dissolution is not rate limiting; • Only drug diffuse from the vehicle. • Formulation components neither diffuse nor evaporate, & skin secretions do not dilute the vehicle;

43. Diffusion coefficient is constant with time or position in the vehicle or horny layer; • Penetrant reaching viable tissue sweeps into the circulation maintaining sink conditions below the S.c; • Donor phase depletes negligibly, i.e. constant [drug] in the vehicle; • Vehicle doesn't alter skin permeability during an experiment (i.e. changing s.c. hydration or acting as penetration enhancer); • Drug remains intact & unaltered; • Flux estimates are steady-state value.

44. S.C. not rate controlling: This happens in absence of s.c. (i.e. damaged skin) or in the presence of TDS. Here the release of the drug from the vehicle → the rate-limiting step & the skin act as a sink. • Absorption from solution: skin a perfect sink Assumption: • Only a single drug species is important, it is in true solution, & it is initial uniformly distributed through the skin; • Only the drug diffuses out of the vehicle.

45. Other components do not diffuse or evaporate & skin secretion do not pass into the vehicle. • The D does not alter with time or position within the vehicle; • When the penetrant reaches the skin, it absorbs instantaneously.

46. Under these limitation eq. 33.9 represents the relationship between: m, the quantity of drug released to the sink/unit of area; Co, the initial concentration of solute in the vehicle; Dv, the diffusion coefficient of the drug in the vehicle, & t, the time after application. Fig 33.5, 33.6

47. Absorption from suspensions: skin a perfect sink Equation 33.11 is derived for a simple model system under the following conditions: • The suspended drug is micronized so that particle  are << than the vehicle; • The particles are uniformly distributed & do not sediment in the vehicle; • The total amount of drug, soluble & suspended, /unit volume (A) is much >> than Cs, the solubility of the drug in the vehicle;

48. d. The surface to which the vehicle is applied is immiscible with the vehicle, i.e. skin secretions do not enter the vehicle; e. Only the drug diffuses out of the vehicle components neither diffuse nor evaporate; f. The receptor, Which is the skin, operates as a perfect sink.

49. Methods for studying transdemal drug delivery • What is the drug flux through the skin & how do the apparent D, K, & SARs control it? • What is the main penetration route-across the s.c. or via the appendages? • Which is > important clinically or toxicologically-transient diffusion (possibly down the appendages) or steady-state permeation (usually across the intact s.c.)? • Does the drug bind to the s.c., the viable epidermis? • Does it form a depot in the subcutaneous fat or penetrate to the deep muscle layers?

50. 6. What is the rate limiting step in permeation-drug dissolution or diffusion within the vehicle or patch; partitioning into, or diffusion through, the skin layers; or removal by the blood, lymph or tissue fluids? 7. How do skin condition, age, site, blood flow & metabolism affect topical bioavailability? 8. Are differences between animal species important? 9. How do vehicles modify the release & absorption of the medicament? 10. What is the optimal formulation for a specific drug-an aerosol spray, a solution, suspension, gel, powder, ointment, cream, paste, tape or delivery devices?