Approaches to topical treatmentApproaches to topical treatment

(1)

(1) Manipulate the barrier(2)

(2) Direct drugs to viable skin tissues

(3)

(3) Skin treatment for systemicconditions

Target regions of topical treatmentTarget regions of topical treatment

Interfacial boundries Penetration routes Some treatments

(1) Surface Drug dissolves 1. Camouflagediffuses, releases 2. Protective layerfrom vehicle 3. Insect repellant

4. Antimicrobial

(2) Stratum Partition/diffusion 1. Emoliency corneum stratum corneum 2. Keratosis

(3) Appendages Piloseba- Ecrine 1. Antiperspirantseous unit gland 2. Exfolient

3. Antibiotic4. Depilatory

Interfacial boundries Penetration routes Some treatments

(5) Circulation Removal via 1. Transdermal deliverycirculation 2. Nitroglycerin

(4) Viable Partition/diffusion epidermis viable epidermis

1. Antiinflammatory2. Anaesthetic

Dermis Partition/diffusion 3. Antipruritic corneum dermis 4. 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

MatrixNitro-Dur (Key Pharma) Reservoir

E.g.Transderm-NitroTM

(Ciba/Pharmaco)

Drug-in-AdhesiveMulti-LayerDeponitTM

(Pharma-Schwartz)

Drug-in-Adhesive Single-Layer

Nitrodisc (Searle Pharma)

Backing Drug Membrane Adhesive 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 membranesPrinciples of diffusion through membranes

Homogenousmembrane

Aqueouspores

Cellulosefibres

(1) Diffusion - random molecular motion. Must have concentration gradient.

Donor Receptor

CdC1

C2

Cr

h

D

C0 Donorsolution P

erm

ea

ble

me

mb

ran

e

Blo

od

K

h

CCSD

dt

dMJ 21

Where, dM = change in mass transferred dt in change of time t

D = diffusion constantC1 = concentration in donor compartmentC2 = concentration in receptor compartmentS = surface area of membrane

Since K = C1 = C2

Cd Cr

dM

dt

SDK C C

hd r

Under sink conditions and rearranging all constants,

M PSC tr d Where, P = permeability constant

Fick’s law of diffusionFick’s law of diffusion

Sample Questions

• What is the flux of drug entering systemic circulation from a patch having a surface area of 10 cm2, containing 50 mg of drug. The average skin thickness of the patient is 7mm. Diffusion coefficient of the skin is 1 x 10-5 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 barriersComplex diffusional barriers

Stratum corneum

Epidermis

Dermis

Subcutaneous

nKnDKDKD

tP

1...

22

1

11

11t

R

Where, Rt = Total diffusing resistancePt = Thickness – weighted permeability coeff.

Parrallel

dM

dt

SDK C C

hd r

FOR EACH

Sample questions

• Flux of a drug Y across the stratum corneum is 0.1g/cm2 hr and the flux across the rest of epidermis, dermis and sub-dermis is 0.5, 2 and 1.5 g/cm2 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, 10-6 and 10-5 g/cm2 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 percutaneousdiffusion

Factors influencing the rate of percutaneousdiffusion

1. Diffusant solubility (C0)

2. Partition coefficient (K)

3. pH variation (K)

4. Co-solvents (K and C0)

5. Surface activity and micellization (C0)

6. Complexation (K)

7. Diffusivity (D)

Sample Questions

• Diffusion coefficient of drug A is 10-6 and the diffusion coefficient of drug B is 10-4 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 cm2 and that of patch B is 4 cm2, 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 absorptionFactors that effect percutaneous absorption

Biological factorsBiological 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 factorsPhysicochemical 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 oC)• 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