Transdermal Drug Delivery Flashcards
state how to deliver a drug through Transdermal delivery
Iontophoresis
microneedles
explain Transdermal patches
Transdermal patches- medical adhesives placed on the skin to deliver a dose of medication through the skin into the bloodstream
what was the first transdermal delivery
1st Transdermal drug delivery- TransdermalScop (1979) scopolamine based patch for motion sickness, nausea and vomiting
The highest selling transdermal patch is _________________
the nicotine patch
state facts about the skin
Skin is the largest human organ and serves primarily as a protective coating
Barrier to microorganisms Barrier to abrasion and physical damage Protection from UV radiation Prevents excessive water loose/gain Provides mean of regulating body temperature Transduces sensory information
explain the fact about the skin absorption
Despite the relative importance of the protective function of the skin, it largely resides in the outermost layer, known as stratum corneum
Skin is permeable to lipid-soluble low molecular weight drugs
Epidermis, dermis and hypodermis (subcutaneous tissue)
advantages of transdermal delivery
Avoids hepatic first pass metabolism – !Skin Metabolism!
Avoids pain associated with injections
Continuous “Sustained Release” drug delivery with infrequent dosing
Permits self-administration – Vaccines
Non-invasive (no needles or injections) – Needle injuries /contamination
Improves patient compliance
Reduces side effects
Allows removal of drug source
Patient preferred
disadvantages of transdermal delivery
Potent drugs only (few mg/24 hours) Lag Time (not good for acute conditions) Development of tolerance Poor diffusion of large molecules Allergic and Irritant reactions
what are the routes in transdermal absorption?
Trans cellular route
Intercellular route
Trans follicular route
state facts about Trans cellular route
Water soluble drugs
99% of relative surface are 25 m diffusion path length
Drug Delivery is through the lipid structures of SC + corneocytes
state facts about Intercellular route
Lipid-soluble drugs
0.70% of relative surface are 350 m diffusion path length
Drug diffuses through endogenous lipid within SC
state facts about Trans follicular route
0.10% of relative surface are 200 m diffusion path length
state the Formulation principles
Select a suitable drug
Release the drug
Use thermodynamics
Alcohol can help
Occlusion
describe “Release the drug” as a formulation principle
Appropriate release e.g. rapid release or sustained over 7 days
If lipophilic drug in lipophilic base then drug will stay in formulation, aqueous base more suitable
Vehicle should not retain drug
describe “Use thermodynamics” as a formulation principle
Use concentration gradient in favour by using drug at near saturated solution levels (solid or saturated solutions has maximum thermodynamic activity)
- Drive to escape vehicle is high
If drugs is added to finely divided suspension formulation with saturated drug, drug concentration increases, but no ‘effective concentration’ which is soluble drug therefore flux is the same
If this suspension becomes diluted then particles dissolve and saturation is still maintained until drug reduces below saturation
describe “Alcohol can help
“ as a formulation principle
Many formulations contain low MW alcohols or other volatile ingredients
Alcohols partition into skin and provide a transient reservoir into which drug can partition
May improve the diffusion coefficient of drug into stratum corneum
Good solvent but evaporates from skin
Ibuprofen hydro-alcoholic gels: ibuprofen has low solubility (1mg/ml) in water, but 10mg/ml can be dissolved in 20:80 w/w ethanol:water. Gel of 5mg/ml rubbed into skin will loose ethanol by evaporation, formulation becomes more aqueous and saturated. Maximum thermodynamic activity and therefore transport into skin.
describe “Occlusion” as a formulation principle
Covering skin with impermeable membrane
Hydrates skin by blocking trans epidermal water loss (TEWL) to environment
Water content of SC can rise to 400 % dry weight which improves transdermal and topical delivery
Some preparations require it (EMLA – lidocaine and prilocaine)
Some inadvertent – hydrocortisone ointment to treat nappy rash under tight fitting waterproof nappy
Only under care of GP etc. Very short term treatment if no other barrier cream helps.
Growth inhibition and thins the skin
what is the take home message from the lecture slide?
Low Molecular weight
Less than 500 Daltons
Lipophilic character (log Poctanol/water)
Drug possessing both water and lipid solubility are favourably
absorbed through the skin
Log P=1-4 generally required for optimal transdermal permeability
Sufficient solubility in water at pH 6-7.4
more than 1mg/mL if targeted drug delivery rate is in the mg/day range
Low dosage administration
what are factors for the Fundamentals of skin permeation
penetration partitioning diffusion permeation absorption
state facts about Fundamentals of skin permeation
The movement of matter from one region to another following random molecular motion
The rate of transfer (the flux) per unit area is proportional to the concentration gradient across a membrane (i.e. skin)
In the direction of diffusion (from most concentrated to least concentrated regions)
Defined by Fick’s First Law of Diffusion
Sink conditions
Fick’s second law of diffusion states that the rate of change of concentration with time at a point with in diffusional field is proportional to rate of change in the concentration gradient at that point
state facts about Fundamentals of skin permeation
The movement of matter from one region to another following random molecular motion
The rate of transfer (the flux) per unit area is proportional to the concentration gradient across a membrane (i.e. skin)
In the direction of diffusion (from most concentrated to least concentrated regions)
Defined by Fick’s First Law of Diffusion
Sink conditions
Fick’s second law of diffusion states that the rate of change of concentration with time at a point with in diffusional field is proportional to rate of change in the concentration gradient at that point
what are the Two important parameters important for the Fundamentals of skin permeation
lag-time and steady state flux
what is lag time and steady state flux?
Lag-time: effects the time period that is required to reach therapeutic level
LT=h^2/ 6D
Steady state flux: determines whether therapeutic levels can be reached
Maximise ___ and ________( affinity for SC > affinity to the vehicle)
Cv and Kp
In steady state situation:
Jss = ______________ = ___________________
Jss = {DP/h} Cv = Kp Cv
Jss= flux of drug (g/m2)
D = drug’s apparent diffusivity in the stratum corneum (m2/s)
P= the stratum corneum-formulation partition coefficient
h= thickness of the barrier
Cv = Concentration in vehicle (donor solution)
kp= drug’s permeability coefficient across the skin (formulation dependent)
(Assuming that Cv (formulation concentration) is constant and on the other side of the membrane “sink conditions” prevail or the local concentration Cd is much less compared to Cv)
in The steady state concentration profile (Fick’s Law), when we assume that :
the drug concentration in the topical (Cv – C vehicle) is constant
on the other side of the membrane “sink conditions” prevail
DUE TO THE EFFICIENT UPTAKE OF DRUG BY THE DERMAL MICROCIRCULATION
what happens
Thus Cd (local concentration) is much less than the Cv and Cv-Cd ~ Cv
At steady state, the concentration gradient across the membrane is linear , and thus Ficks Law 1st of diffusion applies
Fick’s first law relates the diffusive flux to the concentration under the assumption of steady state. It postulates that the flux goes from regions of high concentration to regions of low concentration, with a magnitude that is proportional to the concentration gradient (spatial derivative). In one (spatial) dimension
And Thus the Flux J is calculated
what are the facts when you Consider the steady state situation in slide 23
The drug concentration in the topical (Cv – C vehicle) is constant
On the other side of the membrane “sink conditions” prevail
DUE TO THE EFFICIENT UPTAKE OF DRUG BY THE DERMAL MICROCIRCULATION Thus Cd (local concentration) is much less than the Cv and Cv-Cd ~ Cv
At steady state, the concentration gradient across the membrane is linear , and thus Fick’s Law 1st of diffusion applies
Fick’s first law relates ____________________
the diffusive flux to the concentration under the assumption of steady state. It postulates that the flux goes from regions of high concentration to regions of low concentration, with a magnitude that is proportional to the concentration gradient (spatial derivative). In one (spatial) dimension
And Thus the Flux J is calculated
The rate of transfer (the flux) per unit area is proportional to __________________
he concentration gradient across a membrane (i.e. skin)
state transdermal drugs, their molecular weight and indication
Buprenorphine = chronic pain Capsaicin = neutropathy pain
Clonidine = hypertention
Diclofenac epolamine = Acute pain
Estradiol= Menopausal symptoms
Estradiol/levonorgestrel =Menopausal symptoms
Estradiol/norethidrone = Menopausal symptoms
Ethinyl = Contraception
Fentanyl = Chronic pain
Granisetron = Chemo-induced emesis
Influenza-virus vaccine = Influence virus
lidocaine with tetracaine = Local dermal analgesia
Methylphenidate = Hyperactivity disorder
Nicotine = Smoking cessation
Nitroglycerin = Angina pectorls
Oxybutynin = Overactive bladder
Rlvastigmine = Dementia
what are the general formulation options?
General:
semi-solid formulation for increased residence time
transdermal patches for extended drug delivery through the skin
liquid formulation for rapid short term input of permeant into skin
how do skin types affect choice of formulation?
Skin type may affect choice of formulation:
Normal to oily: often gels
Normal to dry: often lotions
Dry skin: creams
Skin site: hairy areas often lotions, gels and sprays and where skin touches or rubs creams or lotions
how does Clinical rational mainly dictates choice for topical delivery
Wet, vesicular or weeping lesion - ‘wet’ usually aqueous based formulation (cream, lotion, gel)
- Hydrophilic drug: Aqueous based system including water May contain co-solvents e.g. propylene glycol Avoid alcohol -Hydrophobic drug: Mineral oils or aqueous with co-solvent e.g. water with propylene glycol but avoid alcohol
Dry, thickened scaly lesion – ‘dry’ usually fatty formulation (ointments and pastes)
-Oils and waxes which may include surfactants, glycols depending on formulation and drug solubility
