Approaches to topical treatment (1) (1) Manipulate the barrier (2) (2) Direct drugs to viable skin tissues (3) (3) Skin treatment for systemic conditions

Target regions of topical treatment Interfacial boundries Penetration routesSome treatments (1)SurfaceDrug dissolves1. Camouflage diffuses, releases2. Protective layer from vehicle3. Insect repellant 4. Antimicrobial (2) StratumPartition/diffusion1. Emoliency corneumstratum corneum2. Keratosis (3) AppendagesPiloseba-Ecrine1. Antiperspirant seous unitgland2. Exfolient 3. Antibiotic 4. Depilatory

Interfacial boundriesPenetration routesSome treatments (5) CirculationRemoval via1. Transdermal delivery circulation2. Nitroglycerin (4) ViablePartition/diffusion epidermisviable epidermis 1. Antiinflammatory 2. Anaesthetic DermisPartition/diffusion3. Antipruritic corneumdermis4. Antihistamine (con’t)

Sample Question Ms. Smiley consulted pharmacist Dr. Thoughtful for an insect repellant to be used on her 2 year old Bliss who has a dry skin problem. To maintain Bliss’s skin smooth and moist, Ms. Smiley has been applying Aquophilic (a water in oil cream). She wanted to know if it is OK to apply insect repellent on the skin that is moisturized with the cream.

Transdermal drug delivery systems (TDDS) Pharmaceutical formulations that are designed to deliver an active drug across the skin into systemic circulation. Substances that possess both aqueous and lipid solubility characteristics are good candidates for diffusion through skin. Types of transdermal control released systems. 1. Membrane controlled systems. 2. Adhesive diffusion - controlled systems. 3. Matrix controlled systems.

TDD Patch Construction Matrix Nitro-Dur (Key Pharma) Reservoir E.g.Transderm-Nitro TM (Ciba/Pharmaco) Drug-in-Adhesive Multi-Layer Deponit TM (Pharma-Schwartz) Drug-in-Adhesive Single-Layer Nitrodisc (Searle Pharma) Backing Drug MembraneAdhesive Liner/Skin

Sample Question Which of the patches outlined in the cartoon can be cut to customize dose according to patient need.

Why transdermal drug delivery? Continous IV administration at a constant rate of infusion is a superior mode of drug delivery IV administration avoids hepatic first-pass metabolism and maintain constant therapeutic drug levels in the body TDD can closely duplicate continuous IV fusion. Hence it is helpful in delivering drugs that undergo significant first pass metabolism and/or have narrow therapeutic index

Sample Question Ibuprofen (Motrin) is usually administered 300 mg every 6 hours for acute muscle pain/inflamation. Orally administered ibuprofen may cause gastric discomfort. Although ibuprofen is lipophilic and might have good skin permeability, transdermal delivery is not an alternative for ibuprofen why?

Principles of diffusion through membranes Homogenous membrane Aqueous pores Cellulose fibres (1) Diffusion - random molecular motion. Must have concentration gradient.

Donor Receptor CdCd C1C1 C2C2 CrCr h D C0C0 Donor solution Permeable membrane Blood K

Where, dM = change in mass transferred dt in change of time t D = diffusion constant C 1 = concentration in donor compartment C 2 = concentration in receptor compartment S = surface area of membrane Since K = C 1 = C 2 C d C r Under sink conditions and rearranging all constants, Where, P = permeability constant Fick’s law of diffusion

Sample Questions What is the flux of drug entering systemic circulation from a patch having a surface area of 10 cm 2, containing 50 mg of drug. The average skin thickness of the patient is 7mm. Diffusion coefficient of the skin is 1 x cm/min. Using the above information, calculate the permeability coefficient of the drug across skin. What is the total amount of drug delivered from the patch into blood stream in 12 hours.

Complex diffusional barriers Stratum corneum Epidermis Dermis Subcutaneous Where,R t = Total diffusing resistance P t = Thickness – weighted permeability coeff.

Parrallel FOR EACH

Sample questions Flux of a drug Y across the stratum corneum is 0.1  g/cm 2 hr and the flux across the rest of epidermis, dermis and sub-dermis is 0.5, 2 and 1.5  g/cm 2 hr, respectively. Calculate the total diffusional resistance across the skin for drug Y. The flux of drug Y across hair follicles, sweat glands and sebaceous glands is 10 -5, and  g/cm 2 hr. What is the total appendageal flux of drug Y. What is the total flux of drug Y across the skin, both transdermal and trans-appendageal combined.

Factors influencing the rate of percutaneous diffusion Factors influencing the rate of percutaneous diffusion 1. Diffusant solubility (C 0 ) 2. Partition coefficient (K) 3. pH variation (K) 4. Co-solvents (K and C 0 ) 5. Surface activity and micellization (C 0 ) 6. Complexation (K) 7. Diffusivity (D)

Sample Questions Diffusion coefficient of drug A is and the diffusion coefficient of drug B is if all the other parameters are constant, which drug is likely to have better flux across skin. If the surface area of patch A is 2 cm 2 and that of patch B is 4 cm 2, which of these two patches is likely to have more drug delivered across skin and by what extent. Log K of drug X is -1, log K of drug Y is 2 and that of drug Z is 4, which is more likely to have better transdermal permeability and which is more likely to have better trans- appendageal permeability.

Factors that effect percutaneous absorption Biological factors 1. Skin age 2. Skin condition 3. Regional skin sites 4. Skin metabolism 5. Circulatory effects

Hints Know how each of these factors affect skin permeability

Physicochemical factors 1. Skin hydration 2. Drug/skin binding 3. Temperature 4. Penetration enhancers 5. Drug/vehicle interaction

Hints Know how each of these factors affect skin permeability

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

Hints Know how each of these factors affect skin permeability