Download (1) Manipulate the barrier

Approaches to topical treatment
(1)
(2)
(3)
(1) Manipulate the barrier
(2) Direct drugs to viable skin
tissues
(3) Skin treatment for systemic
conditions
Target regions of topical treatment
Interfacial boundries
(1) Surface
(2) Stratum
corneum
Penetration routes
Drug dissolves
diffuses, releases
from vehicle
Partition/diffusion
stratum corneum
(3) Appendages
Pilosebaseous unit
Some treatments
1. Camouflage
2. Protective layer
3. Insect repellant
4. Antimicrobial
1. Emoliency
2. Keratosis
Ecrine 1. Antiperspirant
gland 2. Exfolient
3. Antibiotic
4. Depilatory
Interfacial boundries Penetration routes
Some treatments
(con’t)
(4) Viable
epidermis
Partition/diffusion
viable epidermis
1. Antiinflammatory
2. Anaesthetic
Dermis
corneum
(5) Circulation
Partition/diffusion
dermis
Removal via
circulation
3. Antipruritic
4. Antihistamine
1. Transdermal delivery
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-NitroTM
(Ciba/Pharmaco)
Drug-in-Adhesive
Multi-Layer
DeponitTM
(Pharma-Schwartz)
Backing
Drug
Drug-in-Adhesive
Single-Layer
Nitrodisc (Searle Pharma)
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 membranes
Homogenous
membrane
Aqueous
pores
Cellulose
fibres
(1) Diffusion - random molecular motion. Must have concentration gradient.
K
D
C0
Donor
solution
h
Cd
C1
C2
Donor
Cr
Receptor
Fick’s law of diffusion
dM SDC1  C2 
J

dt
h
Since K = C1 = C2
Cd Cr
Where, dM = change in mass transferred
dt in change of time t
D = diffusion constant
C1 = concentration in donor
compartment
C2 = concentration in receptor
compartment
S = surface area of membrane
dM SDK Cd  Cr 

dt
h
Under sink conditions and rearranging all constants,
M r  PSC d t
Where, P = permeability constant
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 barriers
Stratum corneum
Epidermis
Dermis
Subcutaneous
1
1
1
1
R  

...
t P DK
D K
D K
t
1 1
2 2
n n
Where, Rt = Total diffusing resistance
Pt = Thickness – weighted
permeability coeff.
Parrallel
dM SDK Cd  Cr 

dt
h
FOR EACH
Sample questions
• Flux of a drug Y across the stratum corneum is
0.1g/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 percutaneous
diffusion
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 transappendageal 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
Attributes of a Passive TDD Drug Candidate
•
•
•
•
•
•
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)
Hints
• Know how each of these factors affect skin
permeability