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Drug Administration to Skin
Lecture 4-5
116
Pharmacology
Graduate
02/07/2012

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Term
What are the local effects of drugs applied to the surface of the skin? What are the local effects on the stratum corneum? What about the epidermis and dermis?
Definition
Local effects on the surface of the skin include hydration, action against surface microorganisms, and prevention of mosquito bites. Local effects on the stratum corneum include sunscreens and keratolytic agents. Local effects on the epirdermis and dermis include treatment of infections.
Term
For systemic effects to be achieved, what type of delivery is necessary? Where must the drugs reach?
Definition
Transdermal delivery is necessary. The drug molecules must reach the blood capillaries in the dermis.
Term
What are the advantages of transdermal systemic delivery?
Definition
The drugs do not have to first pass the hepatic metabolism.
Blood levels are consistent for a long-term delivery.
You can substitute it for an oral route when vomiting and diarrhea occur.
It is convenient for the patient.
Term
What are the disadvantages of transdermal systemic delivery?
Definition
You are limited to drugs with good permeability.
Possibly skin irritation could occur.
Term
The epidermis is ___a___ thick.
The dermis is __b___ thick.
A synonym for topical is ___c___.
A synonym for transdermal is __d__.
Definition
(a) 100micrometers
(b) 1000 micrometers
(c) epicutaneous
(d) percutaneous
Term
What is the epidermis composed of? The dermis?
Definition
The epidermis is avascular. The dermis is composed of connective tissue with vasculature.
Term
What must the drug molecules cross in transdermal delivery?
Definition
Entire epidermis, portion of the dermis, and wall of the capillary.
Term
What is the main barrier to transport?
Definition
Stratum corneum - top layer
Term
What does the stratum corneum consist of?
Definition
Flat keratinized envelopes embedded in a highly organized lipid matrix. The envelopes are mostly impermeable to drug molecules. Drugs mostly diffuse through the lipid matrix.
Term
Viable epidermis contains how many layers of viable cells? What are they? What are they made of?
Definition
4: Stratum lucidum, granulosum, spinosum, and basale.

Their composition is 95% keratinocytes, melanocytes, Langerhans, and Merkel cells.
Term
The stratum corneum consists of flat keratinized envelopes embedded in a lipid matrix. It is visualized as a ____.
Definition
brick and mortar model
Term
How many layers of flat, keratinized envelopes are in the SC? Where are there more?
Definition
About 5. There are more at the bottom of the feet, palms, and fingers.
Term
Describe the contents of the envelopes of the SC.
Definition
They contain covalently bound lipids on the surface and are filled with dead corneocytes containing keratin and water.
Term
Describe the content of the lipid matrix.
Definition
It consists of cholesterol, free fatty acids, ceramides, and phospholipids (about 5%). It has a multilamellar structure composed of interacting bilayers.
Term
Drugs mostly diffuse through which part of the SC? How?
Definition
Drugs mostly diffuse through the lipid matrix of the SC, utilizing trans-bilayer transport.
Term
What are the four types of transdermal transport mechanisms? What is the main form of transport?
Definition
(a) paracellular transport through lipids of SC - most preferred
(b) through a hair follicle
(c) through sweat ducts
(d) transcellular transport through dead keratinocytes of SC
Term
What is Dm? How could you increase it? What would this do?
Definition
Dm is the diffusion coefficient in the lipids. If you increased it you would enhance transdermal permeation. You could do this by modifying the drug to achieve intermediate lipo, amphi, and cephalophilicity. You could also do this by modifying the stratum corneum using chemical enhancers.
Term
What is Pm? How could you increase it?
Definition
Pm is the partition coefficient (lipids/vehicle). You could increase it by modifying the drug to achieve intermediate lipophilicity. You could also modify the vehicle.
Term
What is the cD and how could you increase it? What is the h and how could you decrease it?
Definition
cD is the concentration of the drug in the donor compartment. You could modify the vehicle to increase it. THe h is the thickness of the barrier. Two ways you could decrease it would be abrasion and micro-needle devices.
Term
What are some electrically assisted methods used to improve penetration?
Definition
Iontophoresis and electroporation.
Term
What are some methods use to bypass or remove the stratum corneum to improve penetration?
Definition
High velocity particles such as jet injectors, micro-needles, dermabrasion using aluminum oxide crystal or laser.
Term
What are 4 mechanisms of chemical penetration enhancers?
Definition
Inserting a PE into the SC, Creation of pools, lipid extraction, and keratin denaturation.
Term
What does PE insertion do to the membrane?
Definition
It provides disorganization, fluidization, and alters the solubility in the SC.
Term
What does the creation of pools in the SC do to the membrane?
Definition
It provides phase separation and increases hydration.
Term
What does keratin denaturation do to the membrane?
Definition
It provides swelling and is effective on desmosomes.
Term
What does lipid extraction do to the membrane?
Definition
Provides disorganization.
Term
List examples of each of the following:
PE insertion, keratin denaturation, creation of pools, and lipid extraction.
Definition
PE insertion: azone, terpenes, ethanol, DMSO
Creation of pools: azone, oleic acid, and water
Keratin denaturation: poly-arginine
Lipid extraction: monoolein, ethanol
Term
To have intermediate lipophilicity, what must your logP value be.
Definition
Between 0 and 3.
Term
What is a good molecular weight for a drug to have good trans-bilayer permeability?
Definition
Under 500 g/mol.
Term
For a drug to have good trans-bilayer permeability, it must have a significant fraction of ___ molecules.
Definition
nonionized
Term
What are the 2 characteristics of a good vehicle for skin permeation?
Definition
Must dissolve the drug but not retain it.
Must lead to the appropriate ionization of the drug.
Term
For skin, what improves absorption?
Definition
Hydration improves absorption.
Term
What are 3 advantages for transdermal patches?
Definition
(1) steady flux - extended therapy with a single application
(2) skip (hepatic) first-pass metabolism and GI problems
(3) convenience and comfort
Term
List the disadvantages of transdermal patches.
Definition
Possibly skin irritation, very small number of drugs are suitable for a patch.
Term
For a patch with a membrane, the rate of drug delivery is __a__. Drug diffusion in the liquid matrix is fast and drug delivery follows __b__ kinetics.
Definition
(a) lower than the absorption capacity of the skin.
(b) pseudo-first order
Term
For a patch with contact (semisolid matrix), if the diffusion rate in the matrix does not limit release, the rate is __.
Definition
higher than the absorption capacity of the skin, which becomes a reservoir for the drug.
Term
In a patch with contact, the delivery from the patch follows ____ kinetics.
Definition
Zero order
Term
For a patch with contact, if the diffusion in the matrix DOES affect release, the _a__ zone originates in the matrix and __b__ diffusion --> the time has a __c__ n.
Definition
(a) depeletion
(b) slows down
(c) diffusional exponenet, n
Term
Name the 2 locations adhesive can be found on a patch.
Definition
periphery and face
Term
Name 5 qualities of adhesive.
Definition
(1) not irritate or sensitize skin
(2) allow fast adherence with minimum pressure
(3) support the patch holding in place for the intended time period but allow easy peel-off
(4) be compatibly with other components
(5) not influence drug release, when covering the face of the patch
Term
List 3 main characteristics of backing film.
Definition
(1) occlusive / impermeable
(a) retain skin hydration /moisture - increase skin penetration
(b) avoid evaporation of vehicleand changes in drug concentration in the reservoir
(c) not allow drug diffusion through backing
(d) protect product during use
(2) flexible
(3) transparent or pigmented
Term
List examples of backing film (2).
Definition
polyethylene and polypropylene.
Term
Name a potential problem in a Drug-in-adhesive patch.
Definition
Drug may affect stickiness of the patch.
Term
Name 2 examples of drug-in-adhesive patches. What are they / what do they do?
Definition
Climara and Berlex.
Estradiol in polyacrylate glue.
-Treats symptoms from deficiency of estrogen production
-transdermal delivery helps avoid rapid and extensive hepatic metabolism of estradiol
-patch applied once or twice a week
Term
What is another name for a matrix controlled device?
Definition
A monolithic patch.
Term
Name an example of a matrix-controlled device. What does it do?
Definition
Testoderm (Alza)
-testosterone in matrix of ethylene-vinyl acetate copolymer
-treatment of testosterone deficiency
-applied daily to scrotal skin
Term
What's another name for a membrane controlled device?
Definition
A reservoir patch.
Term
When is the release rate constant in a membrane-controlled patch?
Definition
When the reservoir is saturated.
Term
What is a loading dose?
Definition
A small amount of drug added to the adhesive layer to initate prompt absorption and therapeutic effect.
Term
What are 2 example of membrane-controlled devices? What are the contents of their reservoirs?
Definition
Estraderm / Novartis for delivery of 17beta-estradiol
-reservoir: hydroxypropyl cellulose and alcohol
Trandserm Scop (Novartis) for scopolamine to treat motion sickness
-reservoir: mineral oil, polyisobutylene and loading dose
Term
What is the average electrical current used in iontrophoresis? What does it do?
Definition
0.5mA/cm2
Small electrical current applied to the skin to increase the delivery of charged molecules.
Term
Iontrophoresis is used in physical therapy for delivery of ____.
Definition
NSAIDS.
Term
What are the 3 mechanisms used in iontrophoresis?
Definition
(1) repulsion of like charges
(2) disruption of SC
(3) increase hydration in SC
Term
What does the drag in electrosmotic flow do?
Definition
Increase the permeation of uncharged, polar molecules.
Term
What is electroporation and what does it do?
Definition
Short, strong pules of electric current. Creates transitional small pores in SC.
Term
What is sonophoresis? What does it do?
Definition
It is the application of ultrasound energy to change the SC. It provides cavitation, or the formation of a hydrophilic channels in the SC. Typical frequency - 1Mhz.
Term
How does heat affect the stratum corneum?
Definition
Increases blood vessel permeability and circulation. It also increases drug solubility in skin.
Term
What are microneedles and how do the work? Are the needles solid or hollow?
Definition
Microprojections between 100micrometers and 1000micrometers long combined in a piece of polymer that works as a patch. The needles penetrate the top layers of skin and allow the drug to pass through the skin easily. The needles can be solid or hollow.
Term
List 8 characteristics of high velocity particles or jet injections.
Definition
(1) Combine parenteral and transdermal drug delivery methods
(2) overcome needle phobia
(3) no pain
(4) fire fine, solid particles through SC using high-pressure helium gas
(5) decrease the risk of infections associated with needles
(6) accurate dosing
(7) target different skin layers
(8) planned for vaccines and insulin
Term
What are the 3 steps to measuring skin permeation?
Definition
(1) Measure transport across skin
(2) Track drug in penetration in the skin
(3) Measure relevant endpoints
Term
How can you measure transport in excised skin?
Definition
HPLC, Fluorimetry (in vitro)
Term
How do you track the drug penetration into the skin?
Definition
infrared spectroscopy, differential scanning, calorimetry, fluorescence spectroscopy, blood analysis (in vitro and in vivo)
Term
How do you measure relevant endpoints?
Definition
Efficacy studies (in vivo)
Term
How do you measure the transport across excised skin using a penetration assay? What type of skin can be used? Which is the best animal surrogate?
Definition
Use the Franz diffusion cell.
Human, pig, rat, nude mice, rabbit
Pig is best animal surrogate.
Term
How does confocal fluorescence microscopy work?
Definition
The fluorescent permeants absorb light and emit it at a longer wavelength. The wavelength is longer in nonpolar lipid environment, so the permeant moelcules in lipids fluoresce differently from those in water.
Term
What 5 things must you do for in vivo assays?
Definition
(1) evaluate transdermal percutaneous availability
(2) evaluate systemic bioavailability
(3) establish bioequivalence between different formulations
(4) evaluate efficacy
(5) evaluate skin irritation - options: cell and tissue culture
Term
If there is not drug content in an ointment, what can it be used as?
Definition
A moisturizer.
Term
What is the key component determining the character of an ointment?
Definition
The base.
Term
Name the 4 types of ointment bases.
Definition
Hydrocarbon / oligeanous / fatty
Absorption
Water-soluble
Water-removable
Term
Name the 8 characteristics of an ointment base.
Definition
Water content, Affinity for water, Spreadability, Washability, occlusiveness, drug incorporation potential, uses, disadvantages.
Term
What is the water content for an oleaginous base?
Definition
Anyhydrous - practically water-free
Term
What is an oligeanous base's affinity for water?
Definition
minimal - hydrophobic material
Term
What is the spreadability and washability of an ointment made with a fatty base?
Definition
Both are difficult.
Term
What is the drug incorporation potential of an ointment made with a fatty base?
Definition
Solids (hydrophobic) or oils
incorporation of very small volumes of aqueous solutions or hydrophilic agents.
Term
Is a hydrocarbon base occlusive?
Definition
Yes.
Term
What are the uses of a hydrocarbon base?
Definition
Emollients (skin softening), moisturizers
Retention on the skin for long time
vehicles for hydrolyzable drugs, slow release
Term
What are the disadvantages of hydrocarbon bases?
Definition
greasy, difficult to wash off, may stain clothes
Term
What are some examples of hydrocarbon ointments?
Definition
petrolatum, diaper rash ointments, yellow and white ointment
Term
What is white petrolatum?
Definition
Decolorized, more esthetically pleasing.
Mixture of semisolid hydrocarbons obtained from petroleum.
Mixed with mineral oil to change consistency.
Term
What is soft petrolatum base?
Definition
It contain 10% oil.
Minral oils acts also as a levigating agent - facilitating smooth, homogenous consistency.
Term
What is yellow ointment?
Definition
MIxture of petrolatum (95%) and purified yellow wax (5%, extracted from bee honeycomb)
Term
What is white ointment?
Definition
Mixture of white petrolatum and bleached / purified wax.
Term
What are absorption bases?
Definition
They are made for slow drug release.
They are anhydrous hydrophilic bases that allow incorporation of water to form water-in-oil (w/o) emulsions.
Fatty compounds + w/o surfactant as emulsifier.
Emulsion formed when aqueous solution (with or without drug) is added.
Term
What is an example of an absorption base?
Definition
Hydrophilic petrolatum (Aquaphor - OTC - diaper rash)
Cholesterol, stearyl alcohol, white wax, white petrolatum.
The stearyl alcohol acts as an adjuvant emulsifier, aiding in firmness and heat stability.
Term
(absorption base) What is an example of a hydrous base that are w/o emulsions?
Definition
Hydrous Lanolin - isolated from sheep wool (allergenic), viscous, contains 0.25% water and dissolves more.
Term
Describe 8 characteristics of anhydrous absoprtion bases. How are hydrous absorption bases different?
Definition
Water content - Anhydrous
Affinity for water - Hydrophilic - absorb water after agitation
Spreadability - moderate
Washability - poorly washable
Drug incorporation potential - solids or oils
Allow incorp. of low volume of aqueous solutions or hydrophilic agents.
Occlusiveness: intermediate
Uses: emollients, vehicles for drugs instable in water, aqueous solutions, and non-hydrolyzable drugs
Disadvantages: Greasy, difficult to remove, may stain clothes

Hydrous:
contains water, moderate to easy spreadability,
Term
Describe water-removable bases.
Definition
o/w emulsions.
oil coponent + water + o/w surfactants
HLB 8-18
Water content >45%
Drug release from the ointment is generally fast.
Most common ointment base used.
Term
Water-Removable bases...
Definition
Contain water, hydrophilic and lipophilic components, easy spreadability and washability (resembles creams).
Can incorporate solids: hydrophilic or small amounts of hydrophobic compounds allow dilution with water.
They are not occlusive.
Can be used as emollient, vehicles for solids, aqueous solutions, or non-hydrolyzable drugs.
Term
Water-removable base examples. (2)
Definition
Hydrophilic ointments and vanishing cream.
Term
Water-soluble bases are polymers of ___ with varying number of monomer units. These are called ___.
Definition
Polymers of ethylene oxide.
Polyethylene glycols (PEG).
Term
Water-Soluble bases have a wide range of molecular weights. Describe their appearances at these different weights.
Definition
<600 - clear, colorless liquids
600>1000 - white, wax-like materials

Viscosity increases with increasing molecular weight.
Term
What is the affinity for water, spreadability, washability, drug incorporation potential, and occlusiveness of water-soluble bases?
Definition
hydrophilic - cannot incorporate large amounts of water - loss of viscosity
Easy spreadability and washability
Can incorporate mostly solids.
No occlusiveness.
Term
What is the conjunctiva?
Definition
A thin, vascularized mucous membrane.
Term
What is the sclera?
Definition
Made up of mucopolysaccharides and collagen.
Term
How many membranes does the cornea have?
Definition
3
Term
What is opthalmic delivery limited by?
Definition
structure, permeability, and small surface area of cornea

short residence time of drug on the surface of the eye
Term
What tissues does the drug diffuse through in vaginal absorption?
Definition
Mucosa, submucosa (vasculature connective tissue with no glands), and smooth muscle
Term
Name the 4 main types of gelling agents.
Definition
cellulose derivatives, carbomers, poloxomers, sodium alginate
Term
Name the 4 types of cellulose derivatives.
Definition
Carboxymethylcellulose, methylcellulose, hydroxy ethyl celulose, hydroxy propylcellulose
Term
Which is the only anionic cellulose derivative?
Definition
CMC
Term
What is the ideal pH for CMC?
Definition
7-9
Term
Describe the hydration of each cellulose derivative?
Definition
CMC - hydrates in cold water under stirring
MC - hydrates in hot water under stirring
HEC - hydrates in cold and hot water under stirring
HPC - INsoluble in cold water, above 45, no stirring, hydration for 8-12 hours
Term
Name the additives/special characteristics for each cellulose derivative.
Definition
CMC - none
MC - propylene glycol or alcohol to wet
HEC - provides occlusion
HPC - organic solvent - less hydrophilic drugs
Term
name the incompatibilities for the cellulose derivatives.
Definition
CMC - ethanol and other organic solvents, inrease salt and pH - decrease viscosity
MC - increase salt - precipitation
HEC - alcohol
HPC - none
Term
Name the organic solvents for each cellulose derivative.
Definition
CMC - none
MC - alcohol
HEC - none
HPC - ethanol and other organic solvents
Term
What is carbomer 910 used for? What about carbomer 940?
Definition
910 is used for low viscosity formulationg. 940 is used for hydroalcoholic gel.
Term
When does a carbomer achieve its maximum viscosity and clarity?
Definition
about pH 7
Term
What are carbomers incompatible with?
Definition
salt - formation of rubbery mass
Term
How is aqueous solubilty related to temperature in poloxamers?
Definition
Decrease aqueous solubility with increasing temperature.
Term
What is the most common type of poloxmer?
Definition
407
Term
Where is alginic acid obtained from?
Definition
seaweed
Term
Describe alginic acid.
Definition
Tasteless, odorless, white to yellowish.
Term
What are the concentrations of alginic acid and poloxamers?
Definition
alginic acid - 10%
carbomer - 50%
Term
What pH are gels stable at in an alginic acid?
Definition
4-10
Term
What are calcium salts used for in alginic acid?
Definition
To cross-link alginic acid and increase viscosity
Term
What happens if the pH is less than 3 in a alginic acid?
Definition
There is precipitation.
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